1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ANTIVIRAL DRUGS ADVISORY COMMITTEE
Friday, March 11, 2005
8:00 a.m.
Salons A and B
Hilton Washington DC
North/Gaithersberg
620 Perry Parkway
Gaithersburg, Maryland
2
P A R T I C I P A N T S
Janet A. Englund, M.D., Chair
Anuja M. Patel, M.P.H., Executive Secretary
Committee Members:
John A. Bartlett, M.D.
Victor G. DeGruttola, Sc.D.
Douglas G. Fish, M.D.
John G. Gerber, M.D.
Richard H. Haubrich, M.D.
Victoria A. Johnson, M.D.
Robert J. Munk, Ph.D. (Consumer
Representative)
Lynn A. Paxton, M.D., M.P.H.
Kenneth E. Sherman, M.D., Ph.D.
Eugene Sun, M.D. (Industry
Representative)
Maribel Rodriguez-Torres, M.D.
Lauren V. Wood, M.D.
Ronald G. Washburn, M.D.
Special Government Employee Consultants
(Voting):
Samuel K. So, M.D., B.S.
Kathleen Schwarz, M.D.
Government Employee Consultants (Voting):
Beth P. Bell, M.D., M.P.H.
Ronald Herbert, D.V.M., Ph.D.
Leonard B. Seeff, M.D.
SGE Patient Representative (Voting)
Brett Grodeck
FDA Participants:
Mark J. Goldberger, M.D., M.P.H., CDER
Debra B. Birnkrant, M.D., CDER
Linda L. Lewis, M.D., CDER
James G. Farrelly, Ph.D., CDER
3
C O N T E N T S
Call to Order and Opening Remarks,
Janet Englund, M.D., Chair 4
Conflict of Interest Statement, Anuja
Patel, M.P.H.
Executive Secretary, FDA 7
Overview of Issues, Debra B. Birnkrant,
M.D.,
Director, DAVDP 10
Sponsor Presentation:
Introduction, Elliott Sigal, M.D., Ph.D. 16
Background, Richard Colonno, Ph.D. 20
Nonclinical Safety, Lois Lehman-McKeeman,
Ph.D. 28
Clinical Efficacy and Safety, Evren
Atillasoy, M.D. 37
Resistance, Richard Colonno, Ph.D. 58
Pharmacovigilance and Summary, Donna
Morgan Murray,
Ph.D.
70
Questions from the Committee 77
FDA Presentation:
Carcinogenicity Issues, James G.
Farrelly, Ph.D.. 108
Clinical Issues, Linda L. Lewis,
M.D. 119
Discussion
151
Advisory Committee Discussion of
Questions
Question 1: 185
Question 2: 202
Question 3: 204
Question 4: 221
Question 5: 235
Question 6: 267
4
1 P R O C E E D I N G S
2 Call to Order and Opening
Remarks
3
DR. ENGLUND: Good morning. Welcome,
4
everyone. My name is Janet
Englund. I am the
5
acting chairperson today and I would like to
6
welcome you to the Antiviral Drugs Advisory
7
Committee.
8
Today we are going to discuss the new drug
9
application 21-797 and 21-798 for entecavir tablets
10 and
entecavir oral solution, respectively, by
11 Bristol-Myers
Squibb Company. These drugs are
12
proposed for the treatment of patients with chronic
13
hepatitis B infection.
14
With that, I would like to call the
15
meeting to order and introduce the committee
16
members. In fact, I will have you
introduce
17
yourselves because that would be better.
I would
18
like to just remind everyone on this committee that
19
this is being transcribed and so, before you speak,
20 you
are going to need to identify yourself but, for
21
now, if we could just start maybe with Dr. Sun and
22
just introduce yourself and your affiliation.
23
DR. SUN: Eugene Sun, Abbott
Laboratories.
24
DR. GERBER: John Gerber,
University of
25
Colorado Health Sciences Center.
5
1
DR. WASHBURN: Ron Washburn,
Shreveport VA
2 and
LSU.
3
DR. FISH: Douglas Fish, Albany
Medical
4
College, Albany, New York.
5
DR. HERBERT: Ron Herbert,
National
6
Institutes of Environmental Health Sciences and the
7
National Toxicology Program.
8
DR. SHERMAN: Ken Sherman,
University of
9
Cincinnati.
10
DR. JOHNSON: Victoria Johnson,
University
11 of
Alabama at Birmingham.
12
DR. PAXTON: Lynn Paxton, Centers
for
13
Disease Control and Prevention.
14
DR. WOOD: Lauren Wood, National
Cancer
15
Institute.
16
MR. GRODECK: Brett Grodeck,
patient
17
representative.
18
MS. PATEL: Anuja Patel, Executive
19
secretary for the Antiviral Drugs Advisory
6
1
Committee, the Food and Drug Administration.
2
DR. ENGLUND: I am Janet Englund,
from
3
Children's Hospital and University of Washington,
4 in
Seattle.
5
DR. DEGRUTTOLA: Victor
DeGruttola,
6
Harvard School of Public Health.
7
DR. BARTLETT: I am John A.
Bartlett, from
8
Duke University.
9
DR. HAUBRICH: Richard Haubrich,
10
University of California in San Diego.
11
DR. MUNK: Bob Munk, consumer
12
representative.
13 DR. SEEFF: Leonard Seeff, Liver Disease
14
Branch, NIDDK, National Institutes of Health.
15
DR. BELL: Beth Bell, Centers for
Disease
16
Control and Prevention.
17
DR. SCHWARZ: Kathy Schwarz, Johns
Hopkins
18 University.
19
DR. FARRELLY: Jim Farrelly,
Division of
20
Antiviral Drugs, FDA.
21
DR. LEWIS: Linda Lewis, Division
of
22
Antiviral Drugs, FDA.
23
DR. BIRNKRANT: Debbie Birnkrant,
Division
24
Director, Division of Antiviral Drugs, Food and
25
Drug Administration.
7
1
DR. ENGLUND: And Dr. Mark
Goldberger,
2
from the FDA, will be joining us momentarily. At
3 this point I would like to have Anuja Patel
read
4 for
us the conflict of interest statement.
5 Conflict of Interest
Statement
6
MS. PATEL: Thank you. The following
7
announcement addresses the issue of conflict of
8
interest and is made part of the record to preclude
9
even the appearance of such at this meeting. Based
10 on
the submitted agenda and all financial interests
11
reported by the committee participants, it has been
12 determined
that all interests in firms regulated by
13 the
Center for Drug Evaluation and Research present
14 no
potential for an appearance of a conflict of
15
interest, with the following exceptions:
16
In accordance with 18 USC Section
17
208(b)(3), full waivers have been granted to the
18
following participants, Dr. Johnson for her
19
employer's contract with a federal agency to
8
1
provide virology laboratory support for the adult
2
AIDS clinical trials group. The
contract is funded
3 for
greater than $300,000 per year. Dr.
Gerber for
4
consulting on unrelated matters for the sponsor and
5 a
competitor. He receives less than
$10,001 per
6
year per firm. Dr. Bartlett for
serving on
7
speakers bureaus for two competitors.
He receives
8
greater than $10,000 from one firm and between
9
$5,001 to $10,000 per year from the other. Dr.
10
Sherman for serving on speakers bureaus for two
11
competitors. He receives from
$5,001 to $10,000 a
12
year from each firm. Dr. Munk for
consulting on
13
unrelated matters for a competitor.
He receives
14
less than $10,001 a year.
15
Dr. Schwarz has been granted waivers under
16
(b)(3) and 21 USC 355(n)(4) for her employer's
17
grant to study competing products.
Each grant is
18
funded for less than $100,000 per firm per year.
19 Dr.
Haubrich has been granted a (b)(3) waiver for
20
consulting on unrelated matters for a competitor
21 and
the sponsor. He receives less than
$10,001 per
22
year per firm. Brett Grodeck has
been granted a
9
1 355(n)(4)
waiver for owning stock in a competitor,
2
valued at less than $5,001.
Because the stock in a
3
competitor does not exceed $25,000, 5 CFR
4
2640.202(a)(2) exception applies and a (b)(3)
5
wavier is not required. Dr.
DeGruttola has been
6
granted a (b)(3) waiver for consulting on unrelated
7
matters for two competitors. He
receives less than
8
$10,001 a year from each firm.
9
A copy of the waiver statements may be
10
obtained by submitting a written request to the
11
agency's Freedom of Information Office, Room 12A-30
12 of
the Parklawn Building.
13
In the event that the discussions involve
14 any
other products or firms not already on the
15
agenda for which an FDA participant has a financial
16
interest, the participants are aware of the need to
17
exclude themselves from such involvement and their
18
exclusion will be noted for the record.
19
We would also like to note that Dr. Sun
20 has been invited to participate as an industry
21
representative, acting on behalf of the regulated
22
industry. Dr. Sun is employed by
Abbott
10
1
Laboratories.
2
With respect to all other
participants, we
3 ask
in the interest of fairness that they address
4 any
current or previous financial involvement with
5 any
farm whose products they may wish to comment
6
upon. Thank you.
7
DR. ENGLUND: Thank you, everyone. With
8
that done, I would like to introduce Dr. Debra
9
Birnkrant who will now proceed to give us an
10
overview of the issues and our plan for today.
11 Overview of Issues
12
DR. BIRNKRANT: Good morning. I would
13
also like to welcome our advisory committee members
14 and
consultants to this meeting.
15
Today, as was mentioned, we will be
16
discussing the new drug application for the tablet
17 and
solution formulations for entecavir for the
18
treatment of chronic hepatitis B infection.
19
The last time this committee met to
20
discuss a similar topic was back in 2002 when we
21
presented the new drug application for adefovir,
22 and
on the second day of that meeting we discussed
11
1
general drug development for hepatitis B. Today's
2
meeting gives us another opportunity to discuss
3
this serious problem.
4
The next two slides were downloaded from
5
cdc.gov. This slide shows the
geographic
6
distribution of chronic hepatitis B infection.
7
What you can see in red are high andemic areas in
8 Africa and Asia with hepatitis B prevalence
at a
9
rate more than 8 percent, and this is considered
10
high. In gold we have medium
prevalence areas, and
11 in
green we have low prevalence areas, such as the
12
United States, excluding Alaska.
In the high
13
prevalence areas the lifetime risk of acquiring
14
hepatitis B infection approaches 60 percent and is
15
acquired mainly during childhood, whereas in the
16 low
prevalence areas the lifetime risk is much
17 lower
and occurs in adolescents, adults and
18
well-defined risk groups.
19
This slide shows hepatitis B incidence by
20
year through the years 1966 through 2000 in the
21
United States. What this is
dramatic for is the
22
decline in hepatitis B occurring soon after
12
1
licensure of hepatitis B vaccine.
You can see that
2 the
incidence drops dramatically over the years in
3 the
late '80s and beyond after public health
4
programs adopted hepatitis B vaccination.
5
Although we see this dramatic decrease in
6 the
United States of acute hepatitis B it still
7
remains a major problem. It has
been estimated
8
that chronic hepatitis B infection affects 350-400
9
million subjects worldwide and approximately 1.25
10
million subjects in the United States.
It accounts
11
for, it is estimated, approximately one million
12
deaths per year due to complications of the
13
disease, namely cirrhosis and hepatocellular
14
carcinoma. The treatment options
are quite
15
limited. As you can see, there
are only three at
16
this point, interferon, lamivudine and adefovir
17
dipivoxil.
18
I will briefly touch on the
pros and cons
19 of
these therapies. Interferon is used in a
20
limited patient population, however, it is used for
21 a
definite period of time and in the limited
22
population the effect is durable.
However, the
13
1
side effect profile is somewhat limiting. With
2
interferon we see flu-like syndrome, depression,
3
alopecia and exacerbation of autoimmune disorders.
4 Lamivudine, a nucleoside analog, is much
5
better tolerated, however, subjects taking
6
lamivudine develop resistance at a rate approaching
7 20
percent per year.
8
Adefovir dipivoxil, a prodrug of adefovir,
9 a
nucleotide analog, was approved in 2002.
It is
10
active against lamivudine-resistant virus, and is
11
tolerated well except for nephrotoxicity that
12
appears in decompensated patients, more so, and
13
other advanced patients such as those undergoing
14
transplant.
15
Let's turn now to today's subject, that
16 is,
entecavir. Entecavir is also a
nucleoside
17
analog. It has activity against
HBV polymerase,
18 and
in vitro it inhibits lamivudine-resistant virus
19 at
concentrations 8-32-fold greater than that
20
required for wild type virus.
21
Its antiviral activity has been
22
demonstrated in established animal models. In
14
1
woodchuck, hepatitis virus infected woodchucks with
2
that disease, 67 percent treated with entecavir
3
survived 3 years compared to a 4 percent survival
4
rate in infected historic controls.
So, it appears
5
quite active in this established animal model.
6
Now I will describe pertinent nonclinical
7
pharm/tox findings briefly. There
was an increased
8
incidence of tumors in rodent carcinogenicity
9
studies. Lung tumors were
observed at low
10
multiples of entecavir exposure relative to humans
11 and
it is thought that these tumors may be species
12
specific. Other tumors occurred
at much higher
13
multiples of entecavir exposure relative to humans.
14
This topic will be discussed extensively by
15
Bristol-Myers Squibb and Dr. Farrelly of the Food
16 and
Drug Administration. What we have to
keep in
17
mind here is that the animal data needs to be
18
interpreted in the context of the clinical data,
19 the
severity of the disease and the available
20
treatment options. Turning
to the clinical
21
studies, I would like to commend Bristol-Myers
22
Squibb for their drug development program for
15
1
entecavir. They studied a wide
population in
2
e-antigen positive, e-antigen negative and
3
lamivudine-resistant subjects.
Their trials were
4
multicenter and multinational, using an active
5
control, lamivudine. The
endpoints used were
6
similar to other approved therapies.
7
At today's advisory committee meeting we
8
will be asking you to discuss the clinical trial
9
data in the context of these animal carcinogenicity
10 findings and the implications for human
use. In
11
addition, we will be asking you to discuss the
12
adequacy of the proposed pharmacovigilance study.
13 We
will also pose a question related to pediatric
14
usage.
15
If in the afternoon session when questions
16 are
posed you vote that this drug should be
17
approved, we will then proceed to discuss labeling
18
implications and further post-marketing studies.
19
With that, I would like to just briefly
20
review the agenda. Following my
comments,
21
Bristol-Myers Squibb will present.
This will be
22
followed by a break. Then FDA
will present and the
16
1
presentations will be discussed prior to lunch. At
2 one
o'clock there is an open public hearing.
3
Following that hearing, we will continue the
4
discussion and then pose our questions to the
5
advisory committee. Thank you
very much.
6 DR. ENGLUND: Thank you very much. Now I
7
think we would like to begin with the sponsor
8
presentation by Bristol-Myers Squibb.
9 Sponsor Presentation
10 Introduction
11
DR. SIGAL: Thank you, Dr. Englund
and
12
members of the committee and FDA.
Good morning. I
13 am
Elliott Sigal. I am head of research and
14
development and chief scientific officer for
15
Bristol-Myers Squibb. Today it is
our pleasure to
16
bring you data on entecavir for the treatment of
17
patients with chronic hepatitis B infection.
18
As you heard from Dr. Birnkrant, this
19
disease affects well over actually a million people
20 in
the United States and accounts for approximately
21
5,000 deaths here a year. Outside
the United
22
States another 400 million people are chronically
17
1
infected with hepatitis B so it represents a
2
worldwide public health issue of great importance.
3
We, at Bristol-Myers Squibb, have
4
concluded, based on the data you will hear today,
5
that entecavir represents an important therapeutic
6
advance. Our application is being
considered first
7
here, in the U.S., but we have filed in Europe and
8 in
China, and intend to file elsewhere around the
9
world as part of a larger global commitment.
10
All new therapies present a need to assess
11
both benefits and risks. Years
ago, knowing this
12
compound to be a nucleoside analog, we
13
intentionally completed and analyzed rodent
14
carcinogenicity studies before initiating a Phase
15 III
program. Then we continued to explore
the
16
mechanisms of these rodent findings and we
17
collaborated with health authorities around the
18
world on how to characterize clinical benefit. The
19
goal has been to determine benefits seen in the
20
clinic and weigh those against the potential for
21
risk raised by nonclinical studies.
22
Entecavir has clinical benefits based on
18
1 its
antiviral potency and these are superior
2 suppression of viral replication; a
favorable
3
resistance profile; and improvement in both liver
4
histology and in biochemical abnormalities. To
5
establish all of this we conducted an extensive
6
Phase III program, the first in this field with an
7
active comparator. As the
sponsor, we concluded
8
that the benefits in the clinic, including the
9
resistance profile, outweigh the potential seen of
10
risk in nonclinical studies and entecavir, to us,
11
represents an important therapeutic option for
12
patients with chronic hepatitis B infection.
13
However, as with any new medicine, an
14
assessment of benefit-risk at the time of approval
15 can
only be an estimate. Therefore, our company
is
16
committed to further defining therapeutic benefits
17 and
to understanding any potential human risk with
18
entecavir.
19
To accomplish this we have submitted to
20 FDA
draft pharmacovigilance plans, approaches and
21
observational studies that we plan to conduct to
22
allow for a continuous benefit-risk assessment once
19
1
entecavir is available for patients.
For the
2
medical community these studies will advance the
3
overall scientific knowledge about this disease.
4
Bristol-Myers Squibb has a history of antiviral
5
clinical research in the treatment of patients with
6 HIV
infection. Now with entecavir we are
expanding
7
that commitment to advance the medical science of
8
chronic hepatitis B infection.
9
Furthermore, let me say that our efforts
10 in
the marketplace will be directed to ensure the
11
appropriate use of this new medicine.
We will
12
create a U.S. field organization solely dedicated
13 to
entecavir. It will combine medical
14
professionals and representatives who will be
15
specifically trained in chronic hepatitis B. Their
16
focus will be on a relatively small number of
17
physicians, 3,500, that provide care for nearly all
18 the
U.S. patients treated for chronic hepatitis B.
19
This focused approach will ensure high quality
20
interaction with prescribing physicians and
21
appropriate use of entecavir for patients.
22
Dr. Rich Colonno will now begin the data
20
1
presentation. Dr. Englund, two of
our speakers
2
fell ill over the last 36 hours so you will see a
3 few
different names on the program. One of
our
4
internal hepatologists, Dr. Atillasoy, will be the
5 one
presenting our clinical data. Dr.
Colonno?
6 Background
7
DR. COLONNO: Good morning.
Sorry for the
8
confusion. Entecavir is under
review for the
9
proposed indication shown here, the treatment of
10
chronic hepatitis B disease in adults with evidence
11 of
liver inflammation. The usual dose will
be 0.5
12 mg
daily and a higher 1.0 mg dose is proposed for
13
patients who are lamivudine-refractory.
14
Our presentation will follow the outline
15
shown on this slide, covering nonclinical safety,
16
clinical efficacy, clinical safety, resistance and
17
pharmacovigilance. We have been
assisted in
18
evaluating our data by a number of experts who are
19
listed on the next slide. These
consultants,
20
covering hepatology, health policy, toxicology,
21
pathology and biostatistics, are here and available
22 to
the committee.
23
Dr. Birnkrant and Dr. Sigal outlined the
24
disease burden and consequences of chronic HBV
25
infection. Only about 10-30
percent of people
21
1
currently affected with HBV go on to develop a
2
chronic infection. But the
millions who do, it is
3
sometimes decade-long process that for a
4
substantial number of patients ends with cirrhosis,
5
liver failure, hepatocellular carcinoma, transplant
6 or
death.
7
This is a viral disease and the clinical
8
course of liver injury is driven by the continuous
9
replication of the virus perpetuating a cycle of
10
inflammation. HBV is not
inherently cytopathic but
11
liver cells support a continuous cycle of viral
12
replication that triggers the inflammatory response
13
that over time leads to fibrosis, cirrhosis and
14 liver
cancer. HBV has recently been designated
a
15
carcinogen, in recognition that HBV-induced
16
hepatocellular carcinoma is the fifth most frequent
17
single type of cancer.
18
It has now been shown that the outcome of
19 this
long course of chronic infection with HBV is
22
1 not
just caused by the initial infection but is
2
related to the degree of continued viral
3
replication. This was supported
by a prospective
4
Taiwan cohort study in which three key points
5
emerged: The incidence of
hepatocellular carcinoma
6 and
liver cirrhosis correlated with baseline HBV
7 DNA
levels. The higher the baseline, the
higher
8 the
incidence. Two, persisting elevation of
the
9
viral load over time has the greatest impact on
10
hepatocellular carcinoma risk.
Viral load
11
predicted risk of future hepatocellular carcinoma
12
independent of e-antigen status and serum ALT
13
levels.
14
The concept that viral replication drives
15
disease process is depicted in the schematic shown
16 on
this slide. Viral replication, monitored
by
17
serum HBV DNA levels, drives the downstream
18
inflammation, measured by ALT levels and by
19
histology assessments. These were
our week 48
20
endpoints, and we will be referring to this
21
simplified schematic later in our presentation.
22
Currently, three drugs are approved to
23
1
treat chronic hepatitis B infection, interferon,
2
lamivudine and adefovir.
Interferon is an
3
immunomodulator while adefovir and lamivudine are
4
antivirals whose demonstrated antiviral activity
5 led
to their approval. In their clinical
studies
6
both lamivudine and adefovir were shown to be
7
superior to placebo using the endpoints of liver
8
histology, viral suppression and ALT normalization
9 at
week 48. They decreased viral load, the
first
10
stage of the schema, and interrupted the process
11
measured by ALT and histology, in the center
12
section. Beyond the week 48 data
points,
13
lamivudine has now shown superiority to placebo in
14
affecting some of the long-term outcomes seen in
15 the
far right-hand slide of the schema,
16
characterized as disease progression.
17
In the recent landmark paper by Liaw et
18
al., lamivudine treatment was prospectively
19
compared with placebo in patients with compensated
20
cirrhoses who are at greatest risk for disease
21
progression, including HCC and worsening cirrhosis.
22
With lamivudine treatment by 32 months the rate of
24
1
disease progression was significantly reduced
2
relative to placebo, 8 percent versus 18 percent.
3
This study confirmed the hypothesis that effective
4
antiviral therapy results in a better long-term
5
clinical outcome than indicated by the week 48
6
histology, virology and ALT endpoints.
7
The study also pointed out that a
8
development of resistance to a particular antiviral
9
therapy limits its benefit. By
the end of the
10
study roughly half of the lamivudine-treated
11
patients who had developed lamivudine resistance,
12 or
YMDD virus, and these patients had twice the
13
percentage of disease progression when compared to
14
those where the virus remained fully susceptible,
15 11
percent versus 5 percent respectively.
16
So, while lamivudine is effective and
17
lacks the tolerability concerns of interferon and,
18
unlike adefovir, does not require careful
19
monitoring of renal function, resistance impacts
20 the
ability of lamivudine to deliver long-term
21
benefits. While the study
confirmed that antiviral
22
treatment provides benefit, it also suggested that
25
1 a
more effective antiviral with both greater
2
potency and less resistance will be more
3
efficacious in preventing downstream clinical
4
disease.
5
This morning you will see that entecavir,
6 by
the accepted and proven histologic, virologic
7 and
biochemical endpoints of our studies, was
8
superior to lamivudine. We will
demonstrate that
9
entecavir is effective, safe and well tolerated;
10 has
excellent potency and very low rates of
11
resistance; and maintains future options because it
12
doesn't select for lamivudine or adefovir
13
resistance and is, therefore, an important advance
14 in
therapy for chronic HBV disease.
15
The activity of entecavir results from its
16
being a cyclopentyl guanosine analog.
It is a
17
selective and potent inhibitor of HBV replication.
18 It
has no significant activity against HIV.
The
19
selectivity contributes to its safety since it is a
20
poor substrate for sailor DNA polymerases and does
21 not
inhibit human mitochondrial or gamma
22
polymerase. Its potency reflects
the fact that it
26
1
inhibits all three functional activities of the HBV
2
polymerase, priming, DNA-dependent synthesis and
3
reverse transcription. It is also
a function of a
4
highly efficient conversion of entecavir to its
5
active form entecavir triphosphate, seen
6
consistently in a wide variety of cell types.
7
Entecavir undergoes rapid and efficient
8
phosphorylation by sailor enzymes at low
9
concentrations, and can be detected within one
10
hour. Once formed, the
intracellular half-life of
11
entecavir triphosphate is approximately 15 hours.
12
With an EC
50 of 4 nM it
is
the most potent inhibitor
13 of
hepatitis B virus. Entecavir is greater
than
14 300
times more potent than either of the available
15
agents, lamivudine or adefovir, or two newer agents
16
under development dibividine[?] and tenofovir.
17
Animal models of HBV have been developed
18
using woodchucks and ducklings and entecavir
19
demonstrated impressive potency in these systems as
20
well. The woodchuck model is of
particular
21
importance because it has been predictive of the
22
efficacy and safety of drugs subsequently used in
27
1
humans to treat hepatitis B virus.
The antiviral
2
susceptibility of the woodchuck hepatitis B virus,
3 or
WHBV, is similar to the human virus. In
this
4
model greater than 95 percent of chronically
5
infected animals will development HCC and die, and
6
less than 5 percent will survive to age 4.
7
In our study, animals standard established
8
chronic infection were dosed with entecavir at 0.5
9
mg/kg, a dose that results in exposure levels of
10
approximating the exposure in humans with the 1 mg
11
dose. The drug was initially
administered daily
12 for
2 months and then weekly for a total of 14-36
13
months. In both groups entecavir
treatment
14
resulted in viral DNA levels being reduced by as
15
much as 8 logs to undetectable levels.
The
16
reductions were sustained for up to 3 years, with
17 no
evidence of virologic rebound or resistance.
18
The study compared the
improvement in
19
survival versus historical controls, shown in grey.
20 The
11 woodchucks, represented by the yellow bars,
21
started treatment at 8 months of age as soon as a
22
chronic infection was verified. They had 4-year
28
1
HCC-free survival of 50 percent and 80 percent
2
respectively for the 14- and 36-month treatment
3
groups. The non-concurrent
historical control had
4 a survival rate of 4 percent. Although the numbers
5 of
animals were small, these results were of high
6
statistical significance.
Surviving animals were
7
also shown to have no histological evidence of HCC
8
development upon subsequent examination.
9
In summary, the nonclinical data and the
10
expected benefit of antiviral treatment supported
11
going forward with development of entecavir for
12
treatment of chronic HBV infection.
As with any
13 drug
being developed for long-term chronic dosing
14 in
humans, the carcinogenicity potential of
15
entecavir was evaluated in lifelong dosing studies
16 in
rats and mice. Dr. Lois Lehman-McKeeman
will
17 now
present this data.
18
Nonclinical Safety
19
DR. LEHMAN-MCKEEMAN: Today's
discussion
20 of
the nonclinical safety of entecavir is focused
21 on
the rodent carcinogenicity studies.
Entecavir
22 was
identified as a carcinogenic hazard in rats and
29
1
mice, and the benefit-risk evaluation for entecavir
2
must consider this risk identified in animals
3
relevant to the human clinical benefit.
4
For background on the rodent data, I will
5
briefly describe the design, conduct and
6
interpretation of these studies.
Rodent
7
carcinogenicity studies are lifetime studies,
8
typically 2 years, and group sizes are large with
9 50-60
animals per sex per group. Dose
selection is
10
critical, and highest dosage is expected to
11
represent a maximum tolerated dose, or MTD. The
12
simplest definition of an MTD is a dose that causes
13 no
more than a 10 percent decrease in body weight
14
gain relative to controls. The
lower dosages
15
studied, typically 2 additional levels, are
16
selected to be some fraction of the MTD or some
17
multiple of the relevant human clinical exposure.
18
At the end of the study all tissues are
19
evaluated microscopically for tumors.
Several
20
tissues in rats and mice are prone to spontaneous
21
tumor development. For example,
in mice there was
22 a
relatively high background rate of tumors in
30
1
liver and lung, while in rats liver, pituitary and
2
mammary gland tumors occurred at high spontaneous
3
rates. So, finding tumors in
animals, including
4
controls, is not surprising and we rely on
5
statistical methods and an understanding of
6
historical control tumor rates to identify those
7
that are drug related.
8
Statistical significance in rodent tumors
9 is
established by sequentially testing for a linear
10
dose-dependent trend starting with all dose groups.
11
Tumor incidence is adjusted for survival and the
12
time and cause of death and the level of
13
statistical significance varies with whether a
14
tumor is common or rare. The more
common the
15
tumor, the more rigorous the statistical analysis.
16
When the results identify a positive trend, data
17 are
reanalyzed by dropping the highest dose and
18
repeating the test. This cycle is
repeated until
19 no
significant trend is observed.
20
With that as an overview on rodent
21
carcinogenicity studies, let's review the results
22 for
entecavir. These results have been
reviewed
31
1
with the FDA's Executive Carcinogenicity Assessment
2
Committee, or CAC, and the full CAC and a number of
3
tumor sites were concluded to be relevant to human
4
safety.
5
Entecavir-induced tumors followed two
6
distinct patterns. The first
pattern was observed
7 in
tissues that showed preneoplastic changes, that
8 is,
sites were early changes, consistent with the
9
increased likelihood of tumor development, were
10
observed. The only site that
showed this pattern
11 was
the mouse lung.
12
The second pattern of increased tumors was
13 in
tissues that showed no evidence of preneoplastic
14
changes and occurred at high exposure multiples
15
relative to anticipated human exposure.
These
16
tumors included liver carcinomas in male mice;
17
vascular tumors in female mice; gliomas in male
18
rats; and gliomas, liver adenomas and skin fibromas
19 in
female rats.
20 In addition to listing the tumor
sites,
21
let's look at the incidences observed in these
22
studies. Entecavir was dosed to
mice across a dose
32
1
range of 0.004 mg/kg to 4 mg/kg.
To orient you to
2
this slide, the dosages are shown in the top line
3 and
the exposure multiples are noted below the
4
dosages representing the comparison of the plasma
5
area under the curve in mice relative to human
6
exposure at the 0.5 mg or 1 mg dose.
The exposures
7 are
presented as those in the males, followed by
8 the
females. 4 mg/kg was an MTD and this
dose
9
represented at least a 40-fold multiple over the
10
human exposure at 1 mg.
11
The mouse lung is a major target organ for
12
tumor development following entecavir treatment.
13
Lung tumors are common in mice.
There was a 12
14
percent incidence of tumors in the control males in
15
this study.
16 Entecavir increased the incidence of
lung
17
adenomas with a statistical increase in tumors,
18
here noted in yellow, observed at the 0.4 mg/kg
19
dose in males. This dose is 3-5
times higher than
20
human clinical exposure. Lung
adenomas were
21
further increased at the 2 higher dosages and at 4
22
mg/kg entecavir increased the incidence of lung
33
1
carcinomas.
2
In female mice lung tumors occur at a
3
higher spontaneous rate than in males, with a
4
background incidence of 20 percent in this study.
5
Entecavir increased pulmonary tumors in female mice
6 but
the statistical significance was noted only at
7 the
highest dose.
8
Other toxicology studies indicated that
9
entecavir elicited unique changes in the mouse
10
lung, and we conducted experiments to define these
11
changes and to determine whether they were linked
12 to
the increased susceptibility to tumor
13
development. The results showed
preneoplastic
14
changes in the mouse lung that consisted of
15
increased numbers of macrophages and Type II
16
pneumocyte hyperplasia. Cell
proliferation is a
17
recognized risk factor for tumor development and
18
entecavir caused a sustained proliferation of Type
19 II
pneumocytes. Most mouse lung tumors
arise from
20
Type II pneumocytes and these cells were identified
21 as
the progenitor cells for entecavir-induced lung
22
tumors as well. The increased
numbers of
34
1
macrophages was required to support the
2
proliferation of the Type II pneumocytes and
3
entecavir increased the number of alveolar
4
macrophages in the lung because it was chemotactic
5 for
mouse monocytes.
6
In contrast to the mouse, no similar
7
changes were observed in the lungs of rats, dogs or
8
monkeys treated with entecavir.
Finally, although
9
entecavir was chemotactic for mouse monocytes, it
10 was
not chemotactic for human monocytes, suggesting
11
that an accumulation of macrophages in the human
12
lung would be unlikely to occur.
The results
13
suggest that entecavir causes unique effects in the
14
mouse lung and lung tumors observed in mice may be
15
species specific.
16
The second presentation of entecavir-
17
induced tumors in mice was in organs that, unlike
18 the
lung, showed no evidence of preneoplastic
19
change. In males entecavir
increased the incidence
20 of
liver carcinomas and in females entecavir
21
increased the incidence of vascular tumors,
22
specifically hemangiomas. In both
cases there was
35
1 no
dose response relationship noted, with tumors
2
observed only at the highest dosage.
3
We have not explored mechanisms underlying
4 the
high dose tumor findings on an organ by organ
5
basis, but we have looked at whether a common mode
6 of
action may contribute to tumor development.
7
Entecavir is phosphorylated to entecavir
8
triphosphate, the active form that inhibits viral
9
replication, and we determined that, likely by
10
competing for phosphorylation as depicted here,
11
entecavir disrupts deoxynucleotide triphosphate
12
pools, dNTP pools, in male mouse liver.
Data in
13 the
scientific literature demonstrates that such
14
perturbations disrupt the fidelity of DNA synthesis
15 and
repair. We conclude that changes in the
dNTP
16
pools may explain tumor findings, particularly when
17
there is a high dose response for tumor
18
development.
19
Moving on to rats, in Sprague-Dawley rats
20
entecavir was dosed to males at dosages up to 1.4
21
mg/kg or to females at dosages up to 2.6 mg/kg.
22 The
4 dosage levels are noted here along with the
36
1
exposure multiples as were presented on the mouse
2
slides relative to the 0.5 mg or 1 mg clinical
3
dose. Maximum exposures were at
least 35 times
4
human exposure in male rats or 24 times human
5
exposure in female rats. In rats
all tumors
6
observed were consistent with the second pattern of
7
tumor presentation, that is, no evidence of
8
development of preneoplastic change.
9
In males and females entecavir increased
10 the
incidence of gliomas with statistical
11
significance only at the highest dosage.
In
12
females entecavir increased the incidence of liver
13
adenomas and skin fibromas. As
determined in mice,
14 we
have postulated that the dNTP pool perturbations
15
resulting from high doses of entecavir that
16
overwhelm the strict regulation of nucleotide
17
metabolism may explain entecavir-induced tumors in
18
rats.
19
Carcinogenicity studies in rodents
20
identify whether a compound is a carcinogenic
21
hazard. In the absence of data in
humans it is
22
assumed that carcinogenic effects in rodents
37
1 suggest a possible carcinogenic risk in
humans.
2
However, to extrapolate these findings to humans
3
other relevant data, such as genetic toxicity and
4
species differences in biological response, along
5
with dose-response relationships and exposure
6
comparisons, are important considerations that may
7
increase or decrease the likelihood of human cancer
8
risk. For entecavir there is
evidence suggesting a
9
unique biological response in the mouse lung and
10 mouse
lung tumors may be species specific.
11
Extrapolation of the other tumor findings
12 is
more difficult, but the weight of evidence
13
suggests that human risk is minimal because rodent
14
tumors were observed at dosages that greatly exceed
15
human clinical exposure.
16
Dr. Evren Atillasoy will now review the
17
benefit of entecavir as determined from the Phase
18 III
clinical trials.
19 Clinical Efficacy and Safety
20
DR. ATILLASOY: Thank you and good
21
morning. The entecavir clinical
development
22
program is comprehensive and assesses the efficacy
38
1 and
safety of entecavir for the treatment of
2
chronic hepatitis B infection.
The experience was
3
broad with major disease patterns well represented.
4
Studies addressed hepatitis B e-antigen positive
5
patients and e-negative disease, and assessed
6
entecavir in lamivudine-refractory as well as
7
nucleoside-naive patients.
8
The global program recruited patients from
9 5
continents in over 30 countries.
Separate
10
programs are in progress in China and Japan. The
11
studies that contribute to the NDA review provide
12
analyzed data on approximately 1,500
13
entecavir-treated patients.
Entecavir is the first
14
nucleoside program to be evaluated for HBV using an
15
active comparator, lamivudine, which was the only
16
approved HBV nucleoside at the time that the
17
program was initiated.
18
The map of the clinical program
19
illustrates the sense of the size, breadth and
20
complexity. The core of the
program is represented
21 by
the green box and includes the three Phase III
22
studies you will be hearing about today.
Small
39
1
studies in special populations include experiences
2 in
liver transplant patients, co-infected
3
HIV-positive patients and decompensated patients,
4 the
trial which we are still actively enrolling.
5
Two long-term rollover studies provide for
6
prolonged observation and data collection. Study
7
901, at the bottom left, provides an ongoing
8
treatment option for those patients in whom
9
long-term treatment is appropriate.
Study 049 is a
10
post-treatment observational study, designed to
11
collect long-term safety and efficacy information.
12 All
Phase III patients have the opportunity to
13
enroll in these trials. These
data in 049 have not
14 yet
been analyzed.
15
Dose selection for entecavir anticipated
16
that lamivudine-refractory patients would require a
17
higher dose than naive patients because of the
18
higher EC
50 of
lamivudine-resistant
virus in vitro.
19 An
earlier proof of principle study testing doses
20
over a range from 0.5 mg to 1 mg daily hinge on
21
overlapping responses for the highest doses of 0.5
22 mg
and 1 mg daily. Therefore, these doses
were
40
1
used as the highest ones tested in dose selection
2
studies, 0.5 mg in naive patients, in yellow on the
3
left graph, and 1 mg refractory patients, in orange
4 on
the right graph. The lamivudine control
is
5
represented in blue in both graphs.
6
A dose response was demonstrated in each
7
population, with the greatest responses occurring
8 at
the two highest doses with diminishing
9
incremental benefit at the last increase.
10
Entecavir 0.5 mg daily and 1 mg daily were taken
11
forward as the doses to be tested for Phase III for
12
naive and refractory patients respectively.
13
Clinical efficacy--Phase III included
14
trials in three disease settings, nucleoside-naive
15
e-antigen positive patients, nucleoside e-antigen
16
negative patients and lamivudine refractory
17
e-antigen positive patients. The
definition of
18
lamivudine refractory was that patients must have
19
clinical failure after at least 6 months of
20
lamivudine, or earlier failure with the
21
confirmation of lamivudine-resistant virus.
22
Clinical failure was defined as detectable viremia
41
1
using the bDNA assay. Today's
presentation of
2 clinical results will be by treatment
population
3
rather than study number.
4
Lets turn to study design across Phase
5
III. Patients were screened and
randomized 1:1 to
6
either entecavir or lamivudine in a double-blind
7 fashion and were treated for a minimum of 52
weeks.
8
Lamivudine-refractory patients who were required to
9
have breakthrough viremia while on lamivudine were
10
switched on treatment day 1 directly from
11
lamivudine to blinded study drug without a period
12
either of overlap or washout.
Liver biopsies were
13
obtained at baseline and at week 48 for assessment
14 of
the primary efficacy endpoint, histologic
15
improvement. Patient management
at week 52 was
16 based
on lab results using data from the week 48
17
visit, with results of the 24 follow-up period
18
presented in the briefing document that you have.
19
Inclusion criteria, let's talk about these
20 for
the three studies. Inclusion criteria
required
21
that patients needed to have compensated liver
22
disease, together with an elevated ALT, or were
42
1
required to have detectable viremia by bDNA. The
2
different virologic characteristics of the
3
e-antigen positive and e-antigen negative disease
4
patients resulted in different minimal requirements
5 for
enrollment by HBV DNA.
6
The baseline demographics of each study
7
population are consistent with the characteristics
8
expected for the patient population.
In the
9
presentations that follow results for the naive
10
e-antigen positive patients will appear on the left
11 of
the slide. In the middle you will see
data for
12 the
naive e-antigen negative patients and on the
13
furthest right you will see results for the
14
lamivudine-refractory e-antigen positive
15
population. Within each study the
16
entecavir/lamivudine study groups were well matched
17 for
demographic characteristics.
18
Turning to baseline HBV characteristics,
19
these are also expected to differ according to the
20
pattern of disease studied.
Again, within each
21
study the entecavir/lamivudine treatment groups
22
were well matched for baseline HBV disease
43
1
characteristics. Looking across
studies, HBV
2
e-antigen positive patients, whether
3
nucleoside-naive or lamivudine-refractory, had mean
4 HBV
DNA values that were approximately 2 logs
5
higher than the mean value for the e-antigen
6
negative population.
7
Finally baseline histology across the
8 studies
showed a higher mean necroinflammatory
9
score, using Knodell, than nucleoside-naive
10
subjects. Only a minority had
biopsy evidence for
11
cirrhosis as classified by Knodell fibrosis score
12 of
4. This is because participants were
selected
13 to
have compensated liver disease.
14
Patient disposition--patient disposition
15 for
the first 48 weeks across the three studies
16
demonstrates high retention rates, with at least 94
17
percent of entecavir-treated patients completing 48
18
weeks of treatment in each of the three studies.
19
Lamivudine retention rates ranged from 87-95
20
percent, with the lowest rate in the
21
lamivudine-refractory study.
22
In all three studies, paired biopsies were
44
1
scored using a single reader, who was Dr. Zachary
2
Goodman. Dr. Zachary Goodman was
blinded to drug
3
assignment as well as the temporal sequence of the
4
paired biopsies. Dr. Goodman also
read the
5
biopsies for lamivudine and adefovir registrational
6
programs.
7
Overall, paired baseline and week 48
8
biopsies were available for efficacy assessment in
9 88
percent of patients. Histologic
improvement at
10
week 48 as compared to baseline is the primary
11
efficacy endpoint in these trials.
Histologic
12
improvement was defined as at least a 2-point
13
reduction in the Knodell necroinflammatory score
14
with no concurrent worsening in Knodell fibrosis.
15
In order for a biopsy pair to be
16
evaluable, the baseline sample must have had enough
17
tissue pathologically and it also must have had a
18
necroinflammatory score of at least 2, and 89
19
percent of patients had a baseline biopsy that fit
20
these criteria and constitute the evaluable
21
baseline histology cohort.
Patients from the
22
evaluable cohort who had missing or inadequate week
45
1 48
specimens were considered to have no
2
improvement. Therefore, the
primary analysis for
3
histologic improvement is analogous to a
4
non-completer or equal failure analysis but is
5
applied to the evaluable cohort rather than the
6
all-treated population.
7
The nucleoside-naive studies were designed
8
with two-stage testing. The first
test was for
9
non-inferiority and, if that was met, then
10
superiority was tested.
Non-inferiority is
11
established if the lower confidence limit is above
12
minus 10 percent. Superiority is
met if the lower
13
confidence limit is above zero.
In comparing two
14
active treatments it was expected that differences
15 in
histologic improvement, a downstream endpoint,
16
might take longer than 48 weeks to emerge.
17
Nevertheless, at week 48 entecavir 0.5 mg daily was
18
superior to lamivudine 100 mg daily for histologic
19
improvement in both nucleoside-naive populations.
20
Entecavir achieved a 72 percent response rate in
21
naive e-antigen positive patients and a 70 percent
22
response rate in the naive e-negative population.
23
Looking to the study in
24
lamivudine-refractory patients, this was designed
25 for
superiority. Two independent co-primary
46
1
endpoints were evaluated because histologic
2
response hadn't been characterized in this
3
population previously. The first
co-primary
4
endpoint is histologic improvement, as we have
5
discussed. The second is a
composite reflecting
6
both virologic response and hepatic inflammation as
7
measured by serum ALT. Entecavir
1 mg daily was
8
superior to continued lamivudine 100 mg daily for
9
both co-primary endpoints, and 55 percent achieved
10 the
endpoint of histologic improvement; likewise,
11 55
percent achieved an HBV DNA below the detection
12 of
the bDNA assay, together with an ALT less than
13
1.25 times the upper limit of normal.
Changes in
14
fibrosis are expected to follow changes in
15
necroinflammation. While the
primary endpoint,
16
histologic improvement, assessed primarily
17
necroinflammation, secondary histologic endpoints
18
included an assessment of changes in fibrosis using
19 the
Ishak scoring system.
20
The numbers in the circles along the zero
21
line represent the proportions with no change,
22
while the bars above and below the line represent
23 the
proportions with improvement and worsening
24
respectively. In the two naive
studies entecavir
25 and
lamivudine are comparable. This is not
47
1
unexpected as week 48 is relatively an early time
2
point for assessing this downstream endpoint,
3
especially when comparing two active treatments.
4 The
effect of large differences, however, can be
5
seen in lamivudine-refractory patients.
Here
6
entecavir was superior to lamivudine for
7
improvement in fibrosis. The
distribution of
8
responses in entecavir-treated patients mirrors
9
that in the naive studies and 34 percent had
10
improvement while only 11 percent worsened while on
11
entecavir. This compares to only
16 percent
12
improvement and 26 percent worsening for continued
13
lamivudine.
14
Non-histologic secondary
endpoints were
15
also assessed at week 48. These
included
16
virologic, biochemical and serologic endpoints.
48
1
These assessments are all used routinely in the
2
clinical management of patients with chronic HBV.
3
Treatment comparisons were made using a
4
non-completer or equal failure analysis, and all
5
treated patients were counted in the denominator.
6
Results for virologic endpoints
7
demonstrate superiority for entecavir in all three
8
populations studied. The
proportion of patients
9
achieving an HBV DNA less than 400 copies/mL by PCR
10 is
presented here as a function of time on
11
treatment, and 69 percent of naive e-antigen
12
positive patients treated with entecavir achieved
13 an
HBV DNA of less than 400 copies/mL as compared
14 to
38 percent for lamivudine, an absolute
15
difference of 31 percentage points.
16
The lower baseline viremia and e-antigen
17
negative patients is associated with higher rates
18 of
viral suppression. Here, 91 percent of
19
entecavir-treated patients achieved an HBV DNA less
20
than 400 copies as compared to 73 percent for
21
lamivudine, an absolute difference of 18 percentage
22
points. In both populations there
is an early
49
1
separation response, with superiority for entecavir
2 as
early as week 24. This was the first
time point
3 in
which a PCR measurement was taken.
4
In the lamivudine-refractory population
5
entecavir was also superior to continued
6
lamivudine, with early separation during the first
7 24
weeks of treatment, and 21 percent of
8
entecavir-treated patients achieved an HBV DNA less
9
than 400 copies.
10
An additional way of assessing virologic
11
response is looking at the mean log reduction in
12 HBV
DNA from baseline. For this analysis
results
13
depend upon the characteristics of the population
14
studied and the HBV DNA used. The
maximum
15
reduction possible for a particular population
16
depends on the starting baseline values for those
17
individuals. In a responder the
endpoint will
18
reflect the lower limit of detection for an assay.
19
Therefore, comparisons of this endpoint across
20
different populations must account for differences
21 in
baseline characteristics and HBV DNA assay.
22
Entecavir is superior to lamivudine across
50
1 all
three populations. Naive e-antigen
positive
2
patients who started out with an HBV DNA of 9.7
3
logs in wild type virus demonstrate--so that
4
entecavir demonstrates its full potential with a
5
mean decrease of nearly 7 logs at week 48,
6
differing by 1.5 logs or 30-fold from lamivudine.
7 In
the e-negative population the 5-log decrease for
8
entecavir approximates the maximal change possible
9
given the lower starting HBV DNA and the PCR limit
10 of
quantitation at 2.5 logs, or 300 copies/mL.
In
11 the
lamivudine-refractory population entecavir
12
achieves a substantial 5.1-log decrease in HBV DNA.
13
Viral suppression also leads to reduced
14
hepatic inflammation as judged by ALT.
Here,
15
entecavir is superior to lamivudine for
16
normalization of ALT in all three populations. As
17
expected, the largest treatment difference is seen
18 in
the refractory population.
19
Reduced viral replication may also induce
20 an
immunologic response resulting in HBe antigen
21 seroconversion. The precise biology of this
22
interaction is poorly understood.
In the naive
51
1
e-antigen population entecavir and lamivudine are
2
comparable for seroconversion with response rates
3 of
21 and 18 percent respectively.
4
In summary, across the three Phase III
5
studies entecavir is consistently superior to
6
lamivudine for histologic improvement, virologic
7
response and ALT normalization.
For the four key
8
endpoints across the three studies there were 11
9
efficacy comparisons. Entecavir
demonstrates
10
statistical superiority to lamivudine in 9 of these
11 11,
with confidence intervals for treatment
12
differences lying to the right of zero.
The two
13
seroconversion endpoints favor entecavir
14
numerically and establish non-inferiority with
15
confidence intervals lying above the minus 10
16
boundary. In addition, the mean
log reduction is
17
consistently superior for entecavir, ranging from
18 5-7
logs across the three populations.
19
Let's move to safety. The
clinical
20
profile of entecavir has been extensively
21
characterized. The format for the
safety
22
presentation will differ slightly from that of the
52
1
efficacy presentation. These
analyses use
2
augmented patient cohorts and integrate data across
3 studies
in order to increase the sensitivity to
4
possible safety signals.
5
The nucleoside-naive lamivudine-refractory
6
populations are considered separately, primarily
7
because the exposure to entecavir differs with
8 dose. The safety cohort includes patients from 10
9
analyzed Phase II and Phase III studies.
For the
10
Phase III populations mean treatment duration was 5
11
weeks longer for entecavir-treated naive patients
12 and
17 weeks longer for entecavir-treated
13
refractory patients. The
follow-up observations
14
were consistently longer for entecavir than for
15
lamivudine across all populations.
16
Follow-up is defined as the period of
17
post-treatment follow-up during which no
18
alternative HBV therapy was given.
Its duration
19 was
shorter in refractory patients as compared to
20
naive patients due to earlier initiation of
21
alternative therapy or early enrollment into an
22
entecavir rollover trial.
Observation periods for
53
1 the
safety cohort are expanded to include
2
open-label treatment and post-treatment observation
3 on
alternate HBV therapy.
4 The safety presentation is divided
into
5
three sections, general safety, hepatic safety and
6
malignant neoplasms. General
safety analyses
7
provide standard assessments for rates of clinical
8
adverse events and laboratory abnormalities. All
9
analyses use data from all treated patients in the
10
selected studies. Analyses are
cumulative from the
11
first day of dosing through the last contact with
12
each patient. Therefore, year 2
data are included
13 for
some patients.
14
Rates for three standard safety
15
assessments--discontinuations due to an adverse
16
event, serious adverse events and deaths, were low
17 for
both treatments across both populations.
The
18
types of serious events reported for entecavir and
19
lamivudine were comparable, and no individual
20
serious adverse event occurred in more than one
21
percent of patients. None of the
events leading to
22
death was considered related to study drug.
23
In terms of adverse events, on treatment
24
adverse events were generally mild to moderate in
25
severity and were common, reflecting the long
54
1
duration of study observation.
The frequencies of
2
individual events and the types and distribution of
3
these events were comparable for both treatment
4
groups across both populations.
5
Hepatic safety--hepatic safety focuses on
6
hepatic flares because these can represent an
7
important clinical risk in the treatment of
8
hepatitis B regardless of the specific therapy
9
which is used. ALT flares were
defined as
10
increases in ALT greater than 10 times the upper
11
limit of normal and 2 times the patient's own
12
reference value. The reference
value was the
13
baseline value for on-treatment flares.
For
14
off-treatment flares the reference was the lower of
15 the
baseline or the end of treatment value.
16
Rates for on- and off-treatment flares are
17
consistently less than 10 percent for entecavir.
18 Of
note, the median time from stopping therapy to
19 an
off-treatment flare is substantially longer for
55
1
entecavir. The delayed time
course for
2
off-treatment flares for entecavir may be related
3 to
the extent of virologic suppression achieved on
4
treatment.
5
ALT flares are frequently
asymptomatic. A
6
deterioration in hepatic function can, however,
7
occur without ALT changes that meet this flair
8
definition. Therefore, we
performed analyses to
9
identify individuals meeting flair criteria who had
10
associated relevant laboratory abnormalities or
11
relevant hepatic clinical events, or those who had
12 a
serious hepatic adverse event without meeting
13
flair criteria. These events were
infrequent among
14
both naive and refractory patients, with the number
15 of
individual cases summarized here.
16
Safety surveillance of the entecavir
17
development program involved the assessment of
18
comparative incidences for new or recurrent
19 malignancy diagnoses in entecavir- and
20
lamivudine-treated subjects. Use
of the larger
21
safety cohort database increases sensitivity in
22
this analysis of events that are infrequent. A new
56
1
diagnosis or a new recurrence of malignancy was
2
counted from the time of first study dose to the
3
time of the last patient contact regardless of
4
whether the event was diagnosed on or post
5
treatment. In the safety cohort
the
6
entecavir/lamivudine treatment groups differed in
7
size and the duration of observation.
8
Event rates are presented as incidences of
9
patients diagnosed per 1,000 patient-years of
10
observation. Hepatocellular
carcinoma is the
11
single most frequent type of cancer identified, not
12
unexpectedly, due to the underlying HBV disease.
13
Incidences across the treatment groups are
14
comparable whether assessed for any malignancy, any
15
malignancy excluding non-melanoma skin tumors or
16 the
category of great interest, non-hepatocellular
17
carcinoma, non-skin malignancies.
18
Further analyses in the entecavir program
19
demonstrate that the distribution of new or
20
recurrent non-skin malignancy diagnoses over time
21 is
comparable for entecavir and lamivudine.
In
22
both treatment groups the greatest number of new
57
1
diagnoses occurred between weeks 24 and 48. This
2
temporal clustering may reflect tumors that were
3
latent at the time of study enrollment.
There is
4 an
apparent leveling off for new diagnoses after
5
week 48.
6
In order to establish a comparative
7
context for the observed tumor rates in the
8
development program, Bristol-Myers Squibb provided
9
grants to two independent research groups. These
10
groups identified cohorts of chronic HBS antigen
11
positive patients within their established
12
databases. The results are
provided in the two
13
right-hand columns. The Taiwan
cohort had been
14
prospectively identified as part of an established
15
cancer incidence study which started in 1991 and is
16
sponsored by the Taiwan Ministry of Health. The
17
rates of malignancy in the entecavir-lamivudine
18
arms are comparable to the Taiwan and the Kaiser
19
observational cohorts.
20
In summary, the safety profile of
21
entecavir is consistently comparable to that of
22
lamivudine. Also, the safety of
entecavir is
58
1
comparable across the nucleoside-naive and
2
lamivudine-refractory populations, and across the
3 two
doses of 0.5 mg and 1 mg daily.
Importantly,
4 the
malignancy incidences among approximately 1,500
5
entecavir-treated patients are comparable among
6
those observed in the lamivudine-treated control
7
group. Dr. Richard Colonno will
now present the
8
resistance profile for entecavir.
9 Resistance
10
DR. COLONNO: Thank you. For all
11
antivirals there is a direct relationship between
12
potent viral suppression and absence of viral
13
resistance emergence because viruses require a
14
minimal threshold level of replication to select
15 for
resistant variants. Sustained
suppression of
16
viral DNA undetectable levels in the woodchuck
17
model, described earlier, resulted in the absence
18 of
virologic rebound and no evidence of resistance
19
over the 14- and 36-month treatment periods.
20
To ascertain whether the potent and
21
sustained suppression of viral replication achieved
22 by
entecavir in our clinical studies results in a
59
1
favorable resistance profile, a comprehensive
2
resistance evaluation was conducted that included
3
both in vitro and in vivo studies, along with
4
characterization of over 1,500 clinical samples
5
from entecavir-treated patients.
6
In vitro studies showed entecavir
7
susceptibility was reduced when viruses contained
8 the
two primary lamivudine-resistant substitutions,
9 a
leucine thymodin[?] change at residue 180 and a
10
methionine to valine or isoleucine change at
11
residue 204. Despite this
reduction, entecavir
12
remains greater than 50-fold more potent than
13
adefovir against lamivudine-resistant viruses.
14
There was no cross-resistance between entecavir and
15
adefovir since adefovir-resistant viruses
16
containing resistant substitutions at residues 181
17 or
236 remain fully susceptible to entecavir.
18
During Phase II studies two extensively
19
pretreated patients, designated as patient A and
20
patient B, exhibited virologic rebounds on
21
entecavir therapy. Following at
least 76 weeks of
22
entecavir, virologic rebounds noted in two patterns
60
1 of
genotypic resistance emergence were identified.
2
Entecavir resistance emergence in patient A
3
required two additional substitutions, an
4
isoleucine change at residue 169 and a valine
5
substitution at residue 250.
Patient B needed
6
glycine and isoleucine substitutions at residues
7 184
and 202 respectively, along with a subsequent
8
change at residue 169. In both
cases these changes
9
occurred in the background of preexisting
10
lamivudine-resistant substitutions.
Both isolates
11
were growth impaired and remained fully susceptible
12 to
adefovir.
13
The impact of substitutions at each of
14
these four residues of entecavir's susceptibility
15 are
shown on this slide. Recombinant viruses
16
containing the indicated substitutions at residues
17
169, 184 and 202 alone had no significant impact on
18
entecavir's susceptibility relative to wild type
19
virus, while a change at residue 250 reduced
20
entecavir's susceptibility levels by less than
21
10-fold, about the same as when
22
lamivudine-resistant substitutions alone are
61
1
present.
2
The 169 substitution appears to act as a
3
secondary mutation and did not further reduce
4
entecavir's susceptibility in the
5
lamivudine-resistant viruses.
However, when
6
lamivudine-resistant substitutions are combined
7
with the entecavir-resistant substitutions at
8
residues 184, 202 and 250 significantly higher
9
levels of entecavir resistance are observed.
10
Presence of multiple entecavir-resistant
11
substitutions further decreased entecavir's
12
susceptibility levels.
13
An extensive resistance monitoring program
14 was
undertaken. In the nucleoside-naive
trials all
15
available entecavir-treated e-antigen positive and
16
two-thirds of randomly selected e-antigen negative
17
patients were genotyped at study entry and at week
18 48,
a total of 550 pairs of patient samples.
For
19 the
lamivudine-refractory population all available
20
patient samples were genotyped.
All emerging
21
changes identified were tested for their potential
22
impact on entecavir susceptibility.
23
In addition, samples from all patients
24
experiencing a virologic rebound, defined as any
25
greater than or equal to 1 log increase from nadir
62
1
identified by PCR, were genotyped and subjected to
2
population phenotyping to determine if they
3
harbored circulating viruses resistant to study
4
drug. In nucleoside-naive
patients treated with
5
entecavir there was no evidence of genotypic or
6
phenotypic resistance by week 48.
7 The figure plots the distribution
of
8
patients with the HBV DNA levels indicated at study
9
entry and at week 48 for both entecavir and
10
lamivudine. The size of each
circle corresponds to
11 the
percentage of patients and each column of
12
circles adds up to 100 percent.
And, 81 percent of
13
entecavir-treated patients achieved viral DNA
14
levels of less than 300 copies/mL, represented by
15 the
bottom circle, compared to only 57 percent for
16
lamivudine-treated patients.
Overall, 88 percent
17 of
patients, represented by the bottom two circles
18 in
each case, achieved viral DNA reductions below
19
1,000 copies/mL on entecavir by week 48.
20
Genotyping identified 76 emerging changes
21 but
no distinctive patterns were observed, and no
22
change was present in more than three isolates,
23
representing 0.6 percent of those treated.
24
Phenotypic analysis of these emerging changes show
25
that their presence did not result in a significant
63
1
decrease in entecavir susceptibility.
There were
2 11
virologic rebounds on the entecavir arms of
3
these studies compared to 88 rebounds on lamivudine
4
therapy.
5
This slide shows the origin and frequency
6 of
rebounds by study. When genotyped,
nearly all
7 of
the observed virologic rebounds on lamivudine
8
therapy coincided with the emergence of resistance
9
substitutions at residues 180 and 204, yielding a
10
confirmed resistance frequency of 8-18 percent by
11
week 48. In contrast, none of the
entecavir
12
virologic rebounds observed in nucleoside-naive
13
patients could be attributed to emergence of
14
resistance.
15
A close examination of the individual
16
patient profiles showed that all 11 patients
64
1
exhibiting a rebound on entecavir had at least a
2
3-log reduction in viral DNA levels and 7 of the 11
3 had
greater than a 5-log reduction. Most
4
importantly, all patients had viral populations
5
that were full susceptible to entecavir at the time
6 of
rebound, and there was no evidence of emerging
7
genotypic changes that reduced entecavir
8
susceptibility.
9
From this comprehensive analysis we
10
conclude that there was no evidence of emerging
11
genotypic or phenotypic resistance to entecavir in
12 any
of the nucleoside-naive patients by week 48, a
13
result that is most likely due to the high degree
14 of
sustained viral suppression observed. We
15
continue to monitor these patients for resistance
16 in subsequent treatment years.
17
Let us now turn to the
18
lamivudine-refractory patient population where
19
previous studies indicated that entecavir
20
resistance emergence can occur.
Similar to
21
nucleoside-naive patients, entecavir was highly
22
effective in lamivudine-refractory patients
65
1
enrolled in study 026 and in the 1 mg arm of study
2
014.
3
The figure again plots the distribution of
4
lamivudine-refractory patients having the HBV DNA
5
levels indicated at study entry, week 24 and week
6
48. While reductions were
somewhat less than those
7
observed in nucleoside-naive patients, 22 percent
8 of entecavir-treated patients achieved viral
DNA
9
reductions below 300 copies/mL by week 48. There
10 was
a clear trend of sustained and increasing
11
reductions from week 24 to week 48, and superiority
12 to
continued lamivudine therapy.
13
As part of our comprehensive resistance
14
evaluation, all patients, regardless of treatment
15
arm, were genotyped at study entry and week 48.
16
There were 5 virologic rebounds among the
17
lamivudine-refractory patients treated with
18
entecavir.
19
The figure plots the HBV DNA levels for
20 the
first two patients, labeled 1 and 2.
Both
21
exhibited only modest reductions in HBV DNA levels
22 on
entecavir therapy. Evidence of entecavir
66
1
resistance substitutions at residue 184 were noted
2 in
both patients and population phenotypes
3
indicated a 15-19-fold decrease in entecavir
4
susceptibility, consistent with resistance
5
emergence.
6
In contrast, the three other patients,
7
labeled 3, 4 and 5, all experienced at least a
8
4-log reduction in viral DNA levels and further
9
reductions following rebound either on continued
10
therapy or off treatment, with no evidence of
11
genotypic or phenotypic changes beyond those
12
expected for lamivudine-resistant viruses.
13
Based on this evaluation, only two
14
patients or one percent of lamivudine-refractory
15
patients treated with entecavir experienced
16
virologic rebound due to resistance by week 48.
17
Entecavir-resistant substitutions were, however,
18
noted in 12 entecavir-treated patients by week 48,
19 all
with a background of lamivudine-resistant
20
substitutions. These patients
continue to be
21
monitored for virologic rebounds in subsequent
22
years. Emerging substitutions at
14 other residues
67
1
were also identified, but none were present in more
2
than 3 patients or reduced entecavir susceptibility
3
beyond those expected for lamivudine-resistant
4
viruses.
5
An unexpected finding was that lamivudine
6 can
preselect for entecavir-resistant
7
substitutions. This was further
supported by the
8
observation that lamivudine-treated patients showed
9
evidence of emerging changes at residues 169 and
10 184
in study 026. Among the greater than 360
11
lamivudine-refractory patients genotyped, at least
12 22
had detectable changes at entecavir-resistant
13
substitutions at study entry.
Nine were randomized
14 to
an entecavir treatment arm, where two progressed
15 to
have resistance-induced virologic rebounds
16
described earlier. Only 2/9
patients were able to
17
reduce viral DNA levels below 300 copies/mL. This
18
observation, along with the other results described
19 in
this presentation, indicate that extended use of
20
lamivudine will not only select for the primary
21
lamivudine-resistant substitutions at 180 and 204,
22 but
can also select for a number of secondary
68
1
substitutions that can significantly reduce
2
entecavir susceptibility and clinical efficacy.
3
This slide summarizes our current
4
understanding of the entecavir resistance profile
5 at
week 48. There was no evidence of
genotypic or
6
phenotypic resistance in any studied
7
nucleoside-naive patients treated with entecavir.
8
Entecavir did not select for lamivudine-resistant,
9 or
entecavir-resistant substitutions, or other
10
novel substitutions that result in decreased
11
entecavir susceptibility and there were no
12
virologic rebounds due to resistance.
13
Among the patients having primary
14
lamivudine-resistant substitutions at residues 180
15 and
204, 7 percent exhibited emerging
16
entecavir-resistant substitutions while on
17
entecavir therapy, and only 1 percent of
18
lamivudine-refractory patients exhibited a
19
virologic rebound due to resistance by week 48.
20 The
preexistence of entecavir-resistant
21
substitutions appears to be a marker for decreased
22
efficacy and potential virologic rebound.
23
In summary, the potent and sustained
24
suppression of viral replication by entecavir
25
likely accounts for the absence of resistance
69
1
emergence in nucleoside-naive patients.
An
2
extensive analysis of nucleoside-naive patients
3
showed no evidence or resistance.
Entecavir was
4
also effective in lamivudine-refractory patients
5
where only 1 percent of patients experienced a
6
virologic rebound due to resistance by week 48.
7
Substitutions correlated with entecavir resistance
8
were identified at primary residues 184, 202 and
9 250
and the secondary residue 169.
10
Lamivudine-resistant substations are a prerequisite
11 for
achieving high level entecavir resistance and
12
lamivudine treatment can preselect for some
13
entecavir-resistant substitutions.
14
We conclude that this virologic profile
15
provides critical information to physicians
16
regarding the placement of entecavir in the
17
armamentarium of drugs available to treat chronic
18
hepatitis B infection. Dr. Donna
Morgan Murray
19
will now conclude our presentation with
70
1
pharmacovigilance and final summary.
2 Pharmacovigilance and Summary
3 DR. MORGAN MURRAY: As you have heard this
4
morning, the entecavir clinical development program
5 was
extensive. It was the largest HBV
program
6
conducted to date and the only antiviral HBV
7
program to use an active comparator in Phase III
8
trials. That comparator was
lamivudine, the only
9
agent available at the time of initiation of the
10
trials and the most common HBV therapy used to
11
date.
12
Entecavir demonstrated substantial
13 clinical
benefit in Phase III and was superior to
14
lamivudine in the prespecified primary endpoint of
15
improved histology. Entecavir was
also superior to
16
lamivudine in most of the secondary endpoints.
17
Based on the rodent tumor findings,
18
entecavir is a rodent carcinogen.
The lung tumors
19
appear to be species specific, and the other tumors
20
occur at high exposure multiples.
The
21
investigative data submitted to the carcinogenicity
22
assessment committee do not definitively eliminate
71
1 a
risk for humans. With more than 2,300
patients
2
treated with entecavir, there is no safety signal
3
related to malignancy in the clinical development
4
program. While this is
reassuring, we recognize
5
that the observation period is short.
6
As Dr. Sigal mentioned, we are committed
7 to
continuously assessing the benefit versus risk
8
profile of entecavir, and have proposed a
9
post-marketing pharmacovigilance plan with three
10
main components. In addition to
routine
11
post-marketing surveillance, the pharmacovigilance
12
plan also includes real-time monitoring of special
13
events, specifically malignancies and hepatic
14
events. We have designed special
questionnaires to
15 aid
in collecting follow-up information for reports
16 of
both malignancies and hepatic events. We
will
17
periodically review post-marketing and clinical
18
trial adverse event data, using quarterly aggregate
19
frequency reports, and we will review these events
20 of
special interest.
21
There are three ongoing long-term safety
22
studies and we have proposed an additional large,
72
1
prospective, randomized safety study to be
2
conducted post-marketing. First
let's review the
3
ongoing studies.
4
The clinical development program included
5
one- to two-year treatment studies and long-term
6
safety studies with careful observation for the
7
development of malignancies.
Responders from the
8
Phase II/III trials were encouraged to enroll in an
9
observational study that was aimed to gather safety
10
data off treatment. Malignancy
was the primary
11
focus of this observational study.
Some patients
12
from the Phase II treatment studies were eligible
13 to
enroll in open-label treatment studies, and
14
these patients were also encouraged to enroll in
15 the
observational study.
16
To date, more than 80 percent of patients
17
from Phase III have enrolled in at least one of the
18
long-term safety studies, and the observational
19
study has more than 400 patients enrolled, with the
20
expectation that we will enroll up to 1,500
21
patients and all patients will be followed for 5
22
years. In addition to the ongoing
studies, we
73
1
propose initiating a large safety study post
2
approval.
3
Given the limitations of pre-approval
4
clinical studies, we recognize that we cannot rule
5 out
a cancer risk in patients treated with
6
entecavir. Pre-approval studies
do not provide
7
sufficient numbers of patients to rule out such
8
uncommon events. We considered
several options for
9
further assessment and concluded that a randomized,
10
prospective study would permit rigorous analysis of
11
these events of special interest--mortality,
12
neoplasms and progression of liver disease.
13
The draft protocol for this study calls
14 for
patients to be randomized 1:1 to entecavir
15
versus another standard of care nucleoside or
16
nucleotide; to be stratified as naive or previously
17
treated; and to be followed for at least 5 years.
18 It
is our intent to engage an external, independent
19
data safety monitoring board to conduct periodic
20
reviews of the data from this study.
21
We propose to conduct the study globally
22 and
to recruit patients via their own physicians.
74
1
Patients who are starting a new HBV therapy or are
2
changing their therapy will be eligible to enroll.
3 We
expect to enroll a total of 12,500 patients.
We
4
will report annually on rates of all-cause
5
mortality, malignancy and progression of liver
6
disease. While other common
nucleosides also have
7
rodent tumor findings, and the benefit-risk
8
assessment was favorably concluded based on the
9
serious nature of the disease, such as AZT for HIV,
10 few
have been the subject of the rigorous
11
assessment that we propose here.
12
However, the proposed study does have
13
several challenges. First, the
planned primary
14
analysis is intent-to-treat and, as patients will
15
inevitably switch therapies over the course of the
16
study, the primary analysis may be confounded.
17
However, we will not limit our review of the data
18 to
this analysis and we will look at the data in
19
several different ways.
20
Second, there may be limited ability to
21
detect treatment group differences for events of
22
variable latency. Since all
patients will be
75
1
studied for at least 5 years, and many may well be
2
studied for up to 8 years, we should detect a
3
signal if there is an increased risk.
4
Third, the study is designed to detect
5
differences in overall malignancy rates and in
6
rates of HCC, but is not designed to detect
7
treatment group differences for individual
8
malignancy types.
9
Finally, attrition will occur but this
10
does not mean that patients will be lost to
11 follow-up.
We will implement tactics to enhance
12
follow-up, and we have developed strategies to
13
address these challenges listed on this slide, and
14
conclude that the proposed study will provide
15
important data on both the benefits of entecavir
16 and
on further risk assessment.
17
Adequate data exist to demonstrate the
18
substantial benefit of entecavir over existing
19
therapies. Entecavir provides
superior viral
20
suppression in both nucleoside-naive and
21
lamivudine-refractory patients.
Specifically,
22
treatment with entecavir resulted in up to a 7-log
76
1
decrease in HBV DNA.
2
Entecavir results in superior
3
normalization of ALT in both nucleoside-naive and
4
lamivudine-refractory patients.
Up to 78 percent
5 of
patients achieve normal ALT.
6
Entecavir also provides superior
7
improvement in histology in both nucleoside-naive
8 and
lamivudine-refractory patients.
Treatment with
9
entecavir resulted in up to 72 percent reduction in
10
necroinflammation.
11
Entecavir has a favorable resistance
12
profile compared to lamivudine.
As you heard from
13 Dr.
Colonno, no resistance substitutions emerged in
14
nucleoside-naive patients and resistance
15
substitutions were uncommon in
16
lamivudine-refractory patients.
17
Given the demonstrated superiority of
18
entecavir in viral suppression, ALT normalization
19 and
improved histology, and the favorable
20
resistance profile both in nucleoside-naive and
21
lamivudine-refractory patient populations,
22
long-term benefits of entecavir might include a
77
1
reduction in disease progression, such as lower
2
rates of liver failure, liver cancer, liver
3
transplant and liver-related deaths.
4
We conclude that the demonstrated benefits
5 of
entecavir represent an important treatment
6
advance for HBV infection. The
demonstrated
7
benefits of entecavir against HBV, a known
8
carcinogen, are indeed substantial and outweigh the
9
theoretical risk posed by the rodent tumor data.
10
Thank you for you attention this morning.
11 Questions from the Committee
12
DR. ENGLUND: Thank you very much,
Dr.
13
Murray. I would like to thank the
Bristol-Myers
14
Squibb people for a very clear, concise and timely
15
presentation. It was very
nice. Thank you.
16
This is the time that we are going to open
17 up
for questions to the panel, but I would like to
18
caution people that the questions are supposed to
19 be
directly related to the information presented
20
today. We will have discussion
time later on but
21 if
there are clarifications or questions about
22
specific points related to the presentation we just
78
1
heard, now is the time to begin so I will open it
2 to
the panel for questions. Dr. DeGruttola?
3
DR. DEGRUTTOLA: Yes, I have two
4
questions. The presentations
mentioned that the
5
studies in dogs and rats did not find an increased
6
risk of lung cancer associated with entecavir. I
7 was
wondering how long those studies had gone on;
8
were they powered to be able to detect such an
9
effect? Then, regarding the
post-marketing study
10 to
try to determine an effect on cancer in humans,
11 I
was wondering what the power will be in that
12
study; what magnitudes of effects is the study
13
powered to detect?
14 DR. MORGAN MURRAY: First I will ask Dr.
15
Lois Lehman-McKeeman to address your first question
16
about the duration of studies in dogs and rats.
17
DR. LEHMAN-MCKEEMAN: I will speak
to the
18
rats first because they were, in fact, one of the
19
species used in the lifetime carcinogenicity study.
20 So,
in two years, for the lifetime of the rat,
21
there were no tumors in the lung that developed.
22
The dog the studies were not conducted to
79
1 be
carcinogenicity studies; they were chronic
2
toxicology studies and they were three months in
3
duration. However, what we
understand about the
4
lung lesion in the mouse is that it develops very
5
quickly and the early preneoplastic change that I
6
described occurs within the first two weeks of
7
dosing. In the course of a
three-month study in
8
dogs we saw no early preneoplastic change.
9 DR. DEGRUTTOLA: Thank you.
10
DR. MORGAN MURRAY: And for your
second
11
question about the power of our post-marketing
12
study to detect differences, Dr. Phil Pierce will
13
address that.
14
DR. PIERCE: The primary goal of
the large
15
safety trial is to investigate the potential
16
treatment effect on the development of non-HCC
17
malignancies. First we had to
establish what the
18
background rate in this population is, and we
19 utilized
the data from the Taiwan cohort that was
20
presented, as well as the background rates that we
21 saw
in the BMS studies.
22
The background rate was approximately 4
80
1
non-HCC cancers over 1,000 patient-years of
2
follow-up. We estimated from that
that there would
3 be
16 non-HCC malignant events per 1,000
4
patient-years per arm over 5 years.
Also, the
5
total accrual of time will be 65,000 patient-years.
6 Our
study was designed to show a 30 percent
7
increased risk of malignancy.
That translates into
8 5
additional cancers per 1,000 patient-years over
9 the
16 that I mentioned earlier. I believe
BMS
10 concludes
this is a reasonable assessment of that
11
risk.
12
Slide 1-520, please. I gave you a
lot of
13
numbers with that and I want to show the expected
14
events in the untreated population over the 5
15
years. The rate that I mentioned
for the non-skin,
16
non-HCC cancers is 16 as the expected rate and we
17
would have a power to detect, with this sized
18
population, an increase of 5 over that 16. The
19
additional benefit of this study is that we will
20
also be able to analyze the impact on the other
21
events of interest which, obviously because of the
22
large size of those, we are adequately powered to
81
1
show whether we have an impact on the rates of HCC
2 and
on the progression to cirrhosis.
3
DR. DEGRUTTOLA: Thank you.
4
DR. ENGLUND: Thank you. Dr. Washburn?
5
DR. WASHBURN: It is very
interesting that
6 the
study drug is chemotactic for mouse monocytes
7 but
not human monocytes. I wonder if there
is any
8
work that can be shared that would discuss some
9
mechanism of that difference.
Does it relate to
10
complement activation, or a macrophage chemotactic
11
peptide, or other? The question
is of potential
12
relevance in the carcinogenicity of disease.
13
DR. MORGAN MURRAY: Dr.
Lehman-McKeeman
14
will address that.
15
DR. LEHMAN-MCKEEMAN: At this point
in
16
time we don't know the molecular basis of that
17
difference. What we know is that
based on the fact
18
that macrophages were accumulating in the lung and
19
were not proliferating to accumulate, we looked
20
specifically for a chemotactic event and we tested
21
that in some standard in vitro systems.
When we
22 did
that work, there is clear chemotactic activity
82
1 to
the mouse with no effect in the human at all.
2
Now, to go further, we have looked, in
3
doing some investigative work, at whether or not
4
altering macrophage recruitment alters the
5
progression of this lesion. To do
that, we have
6
looked at a CCR2 knockout, so chemokine receptor to
7 a
knockout animal, and we found that that mouse
8
does, indeed, have a very different response to the
9
drug. It is no unequivocal proof
that this is
10
mediated through CCR2, but it suggests that it
11
plays a role.
12
I want to add one other factor though, and
13
that is that the lesion that we see involves
14
accumulation of macrophages but, based on our
15
assessment, those macrophages don't appear to be
16 activated. They are simply accumulating.
17
DR. WASHBURN: Thank you.
18
DR. ENGLUND: Dr. Fish?
19
DR. FISH: I didn't hear my name
earlier
20 in
the disclosure statement and I just need to add
21
that though I signed the disclosure waiver, I have
22
been on the speakers bureau for the sponsor and two
83
1
competitors.
2
The question that I have is on the study
3 were there pregnancies and, if so, the
outcomes of
4
those pregnancies in entecavir-treated patients?
5
DR. MORGAN MURRAY: I am going to
try out
6 Dr.
Brett-Smith's voice here. So, Helena?
7
DR. BRETT-SMITH: The studies were
8
designed that if pregnancy was determined to occur
9
during the course of the study the patient was to
10
immediately stop study drug.
Indeed, pregnancies
11 do
occur. The majority of these actually
resulted
12 in
elective termination of pregnancies.
13
If we could show slide 5-79, this includes
14 the
various treatment combinations that have been
15
used across our entire program to date with
16
entecavir alone, lamivudine alone, entecavir in
17
combination with lamivudine, for the initial period
18 of
the 901 long-term rollover study and also in
19
placebo.
20
As you can see, the majority of
21
pregnancies identified resulted in elective
22
termination. There was a small
number of
84
1
spontaneous abortions. There have
been 6 live
2
births. The 4 outcomes that are
listed as
3
"unknown" are progressions that are currently under
4 way
and for which we are actively pursuing
5
follow-up on those deliveries.
6
With respect to the live births, across
7
those live births there were no reported defects in
8 5
out of the 6 cases. There was, indeed, 1
live
9
birth where the mother had received entecavir 0.5
10 mg
for a total of 44 weeks but the diagnosis of the
11
pregnancy was made at approximately week 7 of
12
gestation. That had a fairly
complicated history.
13 The
child was born with what has been reported to
14 us
as a severe cerebral cortex defect.
15
Unfortunately, despite repeated contact with the
16
site, the family has not wished to provide us with
17
further data.
18
The details of the early pregnancy are a
19
little complex so let me walk you through those.
20 The
patient had discontinued entecavir immediately
21 at
the time that pregnancy was diagnosed, as I
22
said, about week 7. The patient
then experienced
85
1
what was clinically diagnosed as a spontaneous
2
abortion and was told by the gynecologist that no
3
fetus had been present. A
subsequent ultrasound
4
actually did reveal a live fetus, but in the
5
interim entecavir had been briefly restarted by the
6
clinician for 2 weeks and the moment the ultrasound
7
became available it was discontinued.
So, that
8
represents the sum of our experience to date in the
9 program with pregnancy.
10
DR. ENGLUND: Dr. Haubrich?
11
DR. HAUBRICH: It is clear that
emergence
12 of
viral resistance to therapy is dependent on the
13
degree of viral suppression and, clearly, drugs
14
that have greater suppression will have less
15
emergence of resistance. It is
also clear from
16
extensive experience in AZT that after 15-20 years
17 of
nucleoside therapy we are still identifying new
18
mutations. So, perhaps I didn't
follow it well,
19 but
if you could clarify the emergence of mutations
20
that may have occurred with entecavir.
Although
21
they may not lead to phenotypic susceptibility
22
since the number of mutations is few at this point,
86
1 you
know, they may in the future be defined when
2
greater numbers of samples are available.
3
So, just a comment that it is clear that
4 the
resistance profile is better with greater
5
suppression, but it seems a little premature to be
6
saying that there is no resistance that develops on
7
therapy when the number of specimens is low and it
8 may
be a bit early. So, if you could comment
on
9
that I would appreciate it.
10
DR. MORGAN MURRAY: I will ask Dr.
Colonno
11 to
comment but first I would like to note that the
12
original NDA and the safety update--at that time we
13
only had 48-week data available and that is the
14
only data that have been submitted for review. But
15
very recently we did complete the analysis on
16
patients who have been treated for two years and
17 Dr.
Colonno can perhaps share those data as well.
18
DR. COLONNO: Let me just deal
with the
19
first part first in terms of the number of
20
mutations, just to give you a sense of what
21
mutations were found.
22
Can I have slide 1-315, please?
This is a
87
1
list of all the mutations that have been found or
2
identified in all patients examined that have taken
3
entecavir--as you can see, a very wide range. The
4
vast, vast majority of these, again, have occurred
5 at
polymorphic sites. We call them new
emerging
6
substitutions because they have not been described
7
previously at those particular sites.
8
Again, I will point out that these
9
mutations do not occur in any more than three
10
patients. Most of these occur in
a single patient,
11
again, representing less than one percent. We have
12
tested all of these different mutations and
13
substitutions not only by themselves but also in
14 the
context of their preexisting clinical
15
background and, as you can see by the EC
50s that are
16
present, they really do not alter the normal wild
17 type
susceptibility.
18
Now if I can just move to your statement,
19
which I think is a correct one and, again, as a
20
virologist having worked in resistance for many,
21
many years, there is no such thing as no
22
resistance. So, we have gone out
to the second
88
1
year, and this is real-time data and the data
2
continues to come in, and I would like to just
3
share with you some very encouraging data for the
4
second year.
5
This is the second year data as it
6
currently stands. On the
left-hand side, again,
7 are
the bubble charts and the first thing I want to
8
point out is this is study 022 where we have the
9
most data. You can see that the
continued
10
progression in decreasing DNA from week 48 to 96,
11
where we have 65 undetectable now, we continue to
12
drive viral load down with 81 percent of patients
13 now
with undetectable virus.
14
That correlates with the table on the
15
right where, again, despite the fact that we have
16
treated now for 2 years, we have a very similar
17
profile to what we saw in year 1.
In year 2 we
18
have a total of 7 rebounds, virologic rebounds
19
using the definition I described earlier but,
20
again, looking at their genotypes and phenotypes we
21 see
no evidence of any genotypic or phenotypic
22
resistance. So, out to 2 years in
the
89
1
nucleoside-naive population with that type of viral
2
suppression we have not observed any resistance to
3
entecavir.
4
DR. ENGLUND: Dr. Johnson, do you
have a
5
specific question about that?
6
DR. JOHNSON: Victoria Johnson,
University
7 of
Alabama at Birmingham. As a virologist
and
8
viral resistance person, I share concerns that
9
despite the elegant data presented, given this
10
compound's potency, as you realize, two years may
11 not
be enough, and I want to just ask is this part
12 of
the pharmacovigilance monitoring plan?
That is
13 one
question.
14
The second question is, if you can go to
15
your second to last slide of your previous
16
presentation--
17
DR. MORGAN MURRAY: Let me answer
your
18
first question first around the pharmacovigilance
19
plan. Several of our studies are
ongoing, as I had
20
mentioned, and in all of the ongoing clinical
21
studies we do continue to monitor for resistance.
22
Acknowledging that the pharmacovigilance plan is
90
1
very large, we will have many centers and it will
2 be
usual practice, we feel it will be impossible
3 for
us to get resistance data on all of the 12,500
4
patients. But what we do propose
is to have a
5
sub-study, a subset of patients, a center in the
6
U.S., a center, you know, here and there that we
7
will get much more data including resistance data.
8 I
will let Dr. Colonno address your second point.
9
DR. COLONNO: We will continue to
look for
10
resistance until we find it.
Again, there is
11
always going to be resistance at some point. But
12 the
key point of this slide, which we don't have
13
with HIV, unfortunately, even with combination
14
therapy, is the ability to drive viral load down by
15 6
or 7 logs, 8 logs in some cases and to maintain
16
that for a very long period of time.
Those viruses
17
require a minimal amount of replication to give
18
rise to resistance. So, we are
encouraged. Again,
19
that is not to say there will never be resistance
20 but
we are highly encouraged with that kind of
21
suppression and with the limited ability of the
22
virus to actually replicate that a large amount of
91
1
resistance will all of a sudden come up.
We will
2
continue to monitor these patients for the
3
foreseeable future.
4
Another interesting point is that these
5
particular patients do not give rise to any
6
evidence of resistance substitutions being
7
selected. We know lamivudine
resistance is a
8
stepping stone to becoming clinically relevant
9
resistance to entecavir. But the
fact that we,
10
again in that population, see none of those changes
11
really coming up again is encouraging but, again,
12 it
is only two-year data for a large number of
13
patients, but not a tremendous amount, so we will
14
continue to monitor in subsequent years.
15
DR. JOHNSON: My second question
is on
16
your second to last slide, just for clarification.
17
DR. COLONNO: My second to last
slide?
18
DR. JOHNSON: Yes, from your
earlier
19
presentation. It was called
summary of viral
20
resistance data at week 48. So,
just to clarify,
21 and
I think part of this got answered, the title is
22
week 48 but the bottom data are presented on two
92
1
patients who had greater than 76 weeks.
2
DR. COLONNO: Those two patients
were from
3 the
Phase II study. They are not included
here;
4
they were Phase II.
5
DR. JOHNSON: So, they are
different than
6 the
two on this slide that are on the bottom?
7
DR. COLONNO: These two are from
the Phase
8 III
evaluation.
9
DR. JOHNSON: At week 48?
10
DR. COLONNO: At week 48.
11
DR. JOHNSON: And that is
different than
12 the
other two patients you described with virologic
13
rebound resistance?
14
DR. COLONNO: That is
correct. One was in
15 the
015 study which was a transplant study, and the
16
other one was in 014.
17
DR. JOHNSON: But they appear to select
18 the
same signature mutations?
19
DR. COLONNO: They select the same
20
signature mutations. Those three
mutations appear
21 to
be the key primary resistance markers for
22
entecavir.
23
DR. ENGLUND: Dr. Sherman?
24
DR. SHERMAN: The presentation
indicated
25
that phosphorylation was required for this product.
93
1
Could you comment on any data you have regarding
2 interactions with anti-retrovirals that also
3
require phosphorylation in vitro?
I know you have
4
limited in vivo HIV-positive patients, but is there
5 any
pharmacokinetic analysis and any issues of
6
changes in resistance to HIV or susceptibility
7
because of the interaction?
8
DR. MORGAN MURRAY: I will let Dr.
Colonno
9
follow up on that.
10
DR. COLONNO: We have done an
extensive
11
analysis of the interactions because it is a
12 nucleoside
analog and there are many nucleoside
13
analogs that are used in HIV, interactions based on
14 the
phosphorylation patterns of these various
15
combinations. What I can tell you
is that because
16 the
concentration of entecavir is so low relative
17 to
other nucleoside analogs and the efficiency is
18 so
high, when one does in vitro cell culture
19
combination studies to look for the effect of
94
1 entecavir on the antiviral potency of the HIV
2
nucleoside analogs, or in the opposite direction in
3 the
presence of the HIV and RTIs and does it have
4 an
impact on entecavir activity, we find, using
5
concentrations of both sets of compounds up to five
6
times their C
max,
clinical
Cmax, we see no
7
interactions whatsoever; no antagonism; and no
8
decrease in the activity. Again,
that is a big
9
plus for entecavir because entecavir is very
10
selective for hepatitis B and so it literally also
11 can
be used in a co-infected patient but not having
12 to
worry about any kind of selective pressure on
13
HIV.
14
DR. ENGLUND: I am going by the
order that
15 I
saw the hands come up, which may be wrong, and we
16 are
only going to have time for about four or five
17
more questions. But the first
question was Mr.
18
Grodeck's.
19
MR. GRODECK: In terms of marketing
20
antivirals, one of the biggest games I have seen
21
pharmaceutical companies play is the sequencing
22
game--my drug should come before your drug. In
95
1
your description of the resistance profile of
2
entecavir, it seems to me that you are setting up
3 the
drug to be positioned as a first-line
4
treatment. Is that your
position? How does it fit
5 in
terms of the range of other treatments available
6 to
chronic hepatitis B patients today?
7
DR. MORGAN MURRAY: I will ask Dr.
8
Dienstag to comment on how entecavir might fit into
9
current treatment guidelines and the physicians'
10
armamentarium. I will just remind
you, from our
11
data, that we have demonstrated that entecavir is
12
superior to lamivudine. We have
substantial
13
benefits in both nucleoside-naive and
14
lamivudine-refractory patients.
15
DR. DIENSTAG: Jules Dienstag,
16
Massachusetts General Hospital. I
think if we
17
consider hepatitis B a viral disease, then the drug
18
that suppresses HBV most profoundly is likely to
19
have the most benefit. That has
been shown in this
20
study for histology, biochemical markers and
21
especially for the profundity of suppression of HBV
22
DNA. In almost 90 percent of
patients you can
96
1
achieve an undetectable level of HBV DNA, which no
2
other antiviral comes close to at this point.
3
So, it is not unreasonable to suggest that
4
this would be a first-line therapy.
When you add
5 the
resistance profile and when you consider the
6
potential that, for example, a drug like lamivudine
7
sets you up for lamivudine resistance in the future
8 and
also sets you up for resistance to any other
9
nucleoside, it makes sense to start with this drug.
10 It
is a very reasonable suggestion.
11
DR. ENGLUND: Dr. Paxton, did you
get your
12
question answered?
13
DR. PAXTON: Yes, it was. Thank you.
14
DR. ENGLUND: Dr. Wood, or were
you first,
15 Dr.
Seeff or Dr. Schwarz?
16
DR. SCHWARZ: I have two questions
17
relative to future applications of entecavir. You
18
said that in the animal carcinogenicity models in
19 the
organ involved with the tumor there were
20
ETV-induced dNTP pool perturbations.
In either the
21
animal studies or in the human studies, was there
22
evidence of peripheral blood lymphocytes--the same
97
1
phenomenon occurring in peripheral blood
2
lymphocytes that might be a useful non-invasive
3
surrogate marker for malignant potential?
4
Then the second question is I assume in
5
these lifetime exposure studies that the drug was
6 not
started in the immediate newborn period.
So,
7 at
what age of the animal was it started, and can
8 you
make an educated guess about the human
9
equivalent age?
10
DR. MORGAN MURRAY: I will ask Dr.
11
Lehman-McKeeman to address the data that we have in
12
animals around dNTP pool perturbations and also
13
about the rodent studies. I will
just comment that
14 we
do not have any human data around dNTP pool
15
perturbations. As Dr.
Lehman-McKeeman will
16
describe, these perturbations in animals occur at
17
much higher doses than we administer in humans.
18
DR. LEHMAN-MCKEEMAN: I will
actually
19
address the second question first for you. The
20
studies that are conducted in rodents basically
21
start when they are approximately 5-6 weeks of age.
22 For
perspective, that is when a rodent reaches
98
1
sexual maturity. So, in a 2-year
life span, if I
2 had
to extrapolate, I will just say at sexual
3
maturity so it would be roughly teenage.
4
To your first question about the dNTP
5
pools, in the work that we did we specifically
6
looked at target organ effects related to
7
carcinogenicity. So, we
specifically looked at the
8
liver and we don't have any data on another system.
9
Those analyses are actually quite, I will say,
10
difficult to do, as it were, simply because the
11
pools themselves are really quite fleeting. So, it
12
really is prohibitive for us to collect more then
13 one
sample and we targeted the liver.
However,
14
what we know, based on the work we have done, is
15
that that is a high dose phenomenon.
So, at
16
dosages where we saw carcinogenic activity we saw
17
perturbations in pools, and at a dose below a
18
carcinogenic effect we did not seriously disrupt
19
pools. So, I think it is a
function, again, of the
20
maximum tolerated dosage that we are administering
21 in
the carcinogenicity studies.
22
DR. ENGLUND: Dr. Wood?
23
DR. WOOD: My question has to do
with
24
analysis of rates of malignant neoplasms according
25 to
ethnicity. This is related to the fact
that I
99
1
believe I read that Asians have a higher
2
pharmacokinetic exposure to entecavir and I was
3
wondering whether or not an analysis had been done
4 on
that basis.
5
DR. MORGAN MURRAY: I will ask Dr.
6
Brett-Smith to come up again. I
will try and spare
7 her
voice a bit and comment that while we have not
8
seen PK differences on the basis of race in
9
particular, the differences that we do detect are
10
related to weight more than to race.
Dr.
11
Brett-Smith, on the malignancies?
12
DR. BRETT-SMITH: At this point we
have
13
chosen not to look at any subpopulations in terms
14 of
the overall rates in malignancies because the
15 total
numbers remain low, and we believe that the
16
rates would be sort of unreliably variable. That
17 may
become an option later in terms of the
18
pharmacovigilance.
19
DR. ENGLUND: Dr. Seeff?
20
DR. SEEFF: I thought that the
efficacy
21
data that were presented were fairly impressive but
22
there are a couple of questions that I just need
23
some clarification on. Perhaps
you presented them
24 and
I missed them.
25
The primary endpoint for your study was
100
1
histologic using the Knodell score.
I gather that
2
this is not unusual; this is fairly routine. Is
3
this the 18-point HAI score?
4 DR. MORGAN MURRAY: Yes.
5
DR. SEEFF: In other words, the
drop for
6
example from 10 points to 8 points would represent
7 an
endpoint having been achieved.
8
DR. MORGAN MURRAY: Correct.
9
DR. SEEFF: What was the average
drop? Do
10 you
know what the average decline in points was,
11
just to get a sense of how much improvement there
12 was
in histology? Do you have those data by
any
13
chance? I mean, you have the
percentage of people
14 who
achieved a 2-point reduction, but what I am
15
interested in knowing is by how much of a
16
reduction.
17
DR. MORGAN MURRAY: Dr.
Brett-Smith?
18
DR. BRETT-SMITH: Yes, we do have
data and
19 I can
present it for you if we can show slide 2-66.
20
Overall, in the naive patients it was approximately
21 a
4-point drop in the mean score, and in the
22
refractory patients it was approximately a 3-point
23
drop.
24
DR. SEEF: That is fine. Thank you.
The
25
second thing is your secondary endpoints,
101
1
essentially a reduction in HBV viral load and
2
normalization of ALT, do you have a composite score
3
taking into account the virologic, histologic,
4
biochemical reduction? Do we have
a score of using
5
those three parameters?
6
DR. MORGAN MURRAY: Dr.
Brett-Smith?
7
DR. SEEFF: And is it the same between
8
entecavir and lamivudine for example?
9
DR. BRETT-SMITH: If I can just
repeat the
10
factors that you are interested in, you are
11
interested in combining histology with virology--
12
DR. SEEFF: And with biochemical
response.
13
DR. BRETT-SMITH: With ALT.
14
DR. SEEF: ALT.
15
DR. BRETT-SMITH: Those
three. We have
16
looked at a number of ways of combining virology
17
with ALT. I will ask my colleagues
to confirm
18
whether we have yet completed the analysis
19
combining with histology. I do
not have that at
20
this time.
21
DR. MORGAN MURRAY: So, we will
confer
22
during the break and see if we can quickly pull
23 something
together to answer that.
24
DR. ENGLUND: Last question, Dr.
So?
25
DR. SO: There is a common belief
by many
102
1
clinicians that, you know, if you have e-antigen
2
seroconversion you pretty much, you know, have a
3
good response and you might be cured.
So, I notice
4
that earlier in this handout to us, the committee
5
members, you did describe some follow-up on the
6
patients in your study 22 where they have so-called
7
complete response. Some of the
patients were taken
8 off
drugs. Do you have two-year follow-up
9
information regarding how many of those patients
10
have so-called sustained response and what
103
1
sustained response means?
2
DR. MORGAN MURRAY: I will ask Dr.
3
Brett-Smith to comment, and I need to make the
4
statement that in the NDA and the NDA update we
5
only had the 48-week data so, again, these data
6
have not been submitted for review.
7
DR. BRETT-SMITH: I heard a
two-part
8
question there. Let me just
clarify. I heard
9
first for patients who, at the end of year one,
10
went off dosing--you were interested in the
11
sustained response off treatment.
12
DR. SO: Right.
13
DR. BRETT-SMITH: Also, did I hear
an
14
interest in what happens to the portion of partial
15
responders who have a virologic response--
16
DR. SO: No, I am just interested
in your
17
so-called complete responders.
18
DR. BRETT-SMITH: Let me first
summarize
19 for
you the design of the studies at the week 52
20
endpoint. A clinical decision was
made based on
21
laboratory results from week 48 as to the
22
management of the patient, which was simply a
104
1
management algorithm that was modeled on guidance
2 at
the time and it differs for each population.
In
3 the
e-antigen positive population we required, in
4
order to go off therapy, that patients have lost
5
e-antigen and have an HBV DNA less than the bDNA
6
assay level of detection, so less than 0.7. In the
7
e-negative population patients had to meet the
8
virologic requirement of bDNA less than LOQ, and
9
they had to have an ALT less than 1.25 times the
10
upper limit of normal. In the
refractory antigen
11
positive patients we again required that the
12
patients achieve the virologic endpoint in
13
association with e-loss. In that
last group there
14
were very small numbers of patients going off
15 treatment,
therefore, we will not discuss that
16
further; the numbers were substantially small.
17
With respect to the two naive patient
18
populations, if we could show slide 2-380, the
19
studies were designed to follow people out to 24
20
weeks of off-treatment follow-up.
If during that
21
time patients went on alternative therapy or into
22 the
rollover study they were considered failures to
105
1 maintain that endpoint. These represent the
2
respective percentages in the naive e-antigen
3
positives on the left, 82 percent for entecavir and
4 73
percent for lamivudine, who maintained their
5
study-defined response rate at week 24 off
6
treatment. Likewise, in the naive
e-antigen
7
negative population we had 48 percent for entecavir
8 and
35 percent for lamivudine.
9
DR. SO: But I don't think you
answered my
10
question. How many of those patients
who were off
11
treatment actually were followed up, like actually
12 48
weeks off treatment, are still off treatment?
13 You
know, it could be very misleading for a lot of
14
clinicians when you say sustained response, not
15
knowing, you know, for how many of those patients
16
actually their histologic improvement was
17
sustained? Was the virologic
improvement sustained
18 at
48 weeks? So, I feel that the 24-week
off
19
treatment, so-called sustained response, could be
20
misleading.
21
DR. BRETT-SMITH: Point taken, 24
weeks is
22
what had been agreed upon with regulatory
106
1
authorities in the design of the original study.
2 All
patients are encouraged to enroll on completion
3 of
the original study in the 049 long-term rollover
4
study which remains currently enrolling at this
5
time and has not undergone its initial analysis.
6
DR. SO: Just one last question,
how does
7
your company plan to talk to those clinicians who
8
say, you know, if my patient seroconverted--these
9 are
naive patients before treatment, if they
10
seroconverted I am planning to stop the treatment?
11 How
do you plan to advise those clinicians?
12
DR. MORGAN MURRAY: Our current
proposed
13
labeling reflects how the studies were conducted,
14 and
in that regard, for those patients who were
15
determined to be responders therapy was stopped at
16 48
weeks and they were monitored. Patients
who
17
were partial responders continued on therapy. Our
18
current trials cannot define the definitive
19
duration of dosing for entecavir, which is in
20 general
in flux for HBV therapy. Dr. Dienstag,
do
21 you
have any further comments?
22
DR. DIENSTAG: Jules Dienstag,
Mass.
107
1
General Hospital. No one really
knows what the
2
sustained responsiveness or the durability of an
3
e-antigen response is, but in the experience we
4
have for interferon, lamivudine and adefovir if a
5
person maintains that serologic response for 6
6
months after stopping therapy the durability is 80
7
percent. That is the experience
in Asia and in the
8
West. I assume that that will be
repeated in this
9
experience but that remains to be seen.
10
DR. ENGLUND: Thank you, everyone,
for
11
asking questions, answering questions.
We will now
12
take a 15-minute break. We will
be back at 10:25
13 to
resume the FDA portion of this morning's
14
presentation.
15
[Brief recess]
16
DR. ENGLUND: Thank you. Welcome back
17
from coffee. We are now going to
have an FDA
18
presentation led by Dr. James Farrelly, the
19
pharmacology team leader, and he will begin his
20
presentation.
21 FDA Presentation
22
Carcinogenicity
Issues
23
DR. FARRELLY: Good morning. My name is
24 Jim
Farrelly. I am the pharmacology team
leader in
25 the
Division of Antiviral Drugs.
108
1
Today our purpose is to present some of
2 the
data relating to the genetic toxicity and the
3
animal carcinogenicity of entecavir.
Entecavir is
4 a
nucleoside analog and, as such, is a member of a
5
class of molecules which are in general expected to
6 be
genetically toxic. Its 5-prime hydroxyl
can be
7
phosphorylated to the nucleotide triphosphate and
8 as
a guanosine triphosphate analog can be
9
incorporated into the growing DNA chain.
It has
10 the
three-prime hydroxyl group and is, therefore,
11 not
an obligate chain terminator as are many other
12
nucleoside analogs.
13
However, after incorporation of entecavir
14
into the growing DNA chain, it halts DNA synthesis
15
after the addition of a small number of subsequent
16
bases. Its mechanism of action is
essentially as a
17
chain terminator, which is consistent with its
18
being a clastogenic compound or having the ability
19 to
break chromosomes. Indeed, entecavir has
been
109
1
shown to be clastogenic in an in vitro assay in
2
human lymphocytes.
3
It is negative in a number of genetic
4
toxicity tests both in vitro and in vivo. These
5
include an Ames test, an in vitro assay in Chinese
6
hamster ovary cells, in the Syrian hamster embryo
7
cell transformation assay, and in an in vivo rat
8
micronucleus assay, and in an unscheduled DNA
9
synthesis assay. In general, most
of the battery
10 of
genotoxicity tests can be used only for hazard
11
identification. They are not used
for risk
12
assessment but have indicated that entecavir can be
13 a
possible genetic toxicity hazard.
14
In an effort to place the results of the
15
genetic toxicity studies into perspective, one can
16
compare the outcome of the studies used to evaluate
17
entecavir with the outcome of the studies used to
18
evaluate the genetic toxicity of the three entities
19
approved for the treatment of hepatitis B. The
20
three are adefovir, lamivudine and interferon.
21
Adefovir is a nucleotide analog rather
22
than a nucleoside analog, and was found to be
110
1
mutagenic and to induce chromosomal aberrations in
2 two
in vitro genetic toxicology studies.
3
Lamivudine, or 3GC, is a nucleoside analog and was
4
found to be mutagenic in two in vitro assays as
5
well. Interferon was not an
active genetic toxin.
6
Since it is a protein one would not expect
7
interferon to be positive in the screening battery
8
used to test for genetic toxicity.
However, most
9 of
the nucleoside analogs approved as antiviral
10
antigens are positive in genetic toxicology
11
batteries of tests.
12
Now, as is usual for a drug that is going
13 to
be administered chronically to humans, entecavir
14 was
evaluated in two-year carcinogenicity studies
15 in
rats and mice. The design and outcome of
the
16
study in rats can be seen in the next slide where
17 the
data for male rats are shown.
18
Entecavir was administered by gavage to
19
rats at four doses, 0.003, 0.02, 0.2 and 1.4
20
mg/kg/day. They were administered
for 96 weeks.
21
There were two identical vehicle controls in the
22
study. The doses in male rats
represent the human
111
1
equivalent exposure of much less than 1, 0.3, 5 and
2 35
times the clinical dose at the 1 mg proposed
3
clinical dose, which you see under MHD.
4
In male rats at an exposure 35-fold that
5 in
the clinic entecavir caused the appearance of a
6 low
level but significant incidence of brain
7
gliomas. A no-level of tumors was
seen, or very
8 low
level, at 5-fold the exposure, and below no
9 significant
number of tumors was seen in the study.
10
The next slide shows the results in female
11
rats. As can be seen from this
slide, entecavir
12 was
administered at doses of 0.01, 0.06, 0.4 or 2.6
13
mg/kg/day for two years. Dosing
was again by
14
gavage and drug groups as well as two identical
15
vehicle control groups were treated for 104 weeks.
16 As
can be seen in the slide, entecavir again
17
induced the appearance of brain gliomas at the high
18
dose. It also induced the
appearance of skin
19
fibromas at the high dose, and increased the
20
incidence of liver tumors at the high dose from 1-8
21
adenomas and from 0-3 carcinomas.
The exposure to
22
entecavir at the high dose in which these tumors
112
1
were seen was approximately 24-fold higher for
2
females than that measured in the clinic at the 1
3 mg
dose.
4
Mention should be made regarding the
5
exposure multiples at which tumors were seen in the
6
study. Although a multiple of 24
in exposure is a
7
high multiple of the human exposure, it should be
8
remembered that there were no significant induction
9 or
increase in tumors at the 4-fold for females and
10
5-fold level for males. The real
cutoff,
11
therefore, is somewhere between the high dose and
12 the
next lower dose, and the no-observed effect for
13
tumors was at the 4- and 5-fold human dose.
14
The results of the mouse carcinogenicity
15
study were more complicated. In
the next slide it
16 is
shown that male mice were treated in a similar
17
manner as were the rats. The
doses of entecavir
18
used actually in both the males and the females
19
were the same on a milligram per kilogram per day
20
basis. The doses were 0.004, 0.04, 0.4 and 4
21
mg/kg/day.
22
As seen here, entecavir caused a
113
1
dose-related increase in common bronchoalveolar
2
adenomas in the males, significant at the three
3
higher doses. The lowest of the
three doses
4
produced an exposure only 3-fold higher than the
5
clinical exposure. Also increased
in the males was
6 the
incidence of hepatocellular carcinoma at the
7
high dose, going from 1 in one of the controls to 8
8 at
the high dose. The exposure in the
latter case
9 was
42-fold higher than the clinical exposure.
For
10 the
hepatocellular carcinomas no increase was seen
11 at
an exposure 40-fold the clinical dose, very low;
12 not
significant.
13
The next slide shows the female mice in
14
which entecavir induced a significant increase in
15 the
lung tumors only at the high dose, giving an
16
exposure in the animal study 40-fold the exposure
17 in
the clinic. There was no significant
increase
18 at
11-fold the exposure. Also in female
mice there
19 was
an increase in ovarian and uterine vascular
20
tumors, again at the high dose.
If one combined
21 all
the vascular tumors, as is commonly done, there
22 was
a significant increase in combined hemangiomas
114
1 and
hemangiosarcomas at the high dose.
2
We have heard the sponsor make a good case
3 for
the proposition that the pulmonary tumors seen
4 in
the mouse are mouse specific. No
cellular
5 proliferation
was seen in the lungs of rats and no
6
lung tumors in rats, as well as no cellular
7
proliferation in the dog and monkey studies. If,
8
indeed, the tumors were mouse specific the outcome
9
would be that the only tumors seen in the two
10
studies were at the high dose only.
11
Again, putting the results of the
12
carcinogenicity studies into perspective with the
13
other approved regimens for hepatitis B, no
14
carcinogenicity studies were carried out with
15
interferon. Studies were carried
out with adefovir
16 and
lamivudine; they were not carcinogenic.
17
However, because of kidney toxicity in the
18
carcinogenicity studies, the exposures of the
19
animals in the adefovir studies relative to the
20
clinical exposures were 10-fold for mice and 4-fold
21 for
rats. The maximum tolerated dose cannot
go any
22
higher than those. So, if
entecavir was examined
115
1
only at those exposures, it would have been
2
positive only for the lung tumors in mice and for
3 no
other tumor types.
4
The exposures in lamivudine studies were
5
high relative to the exposures in the clinic, up to
6
34-fold in the mice and 200-fold in the rats. At
7
those exposures the entecavir results would have
8
been at least identical to those which we have seen
9 in
these studies. However, many nucleoside
analogs
10
approved as antivirals have been positive in
11
carcinogenicity studies.
12
The results of the two carcinogenicity
13
studies were presented to the CDER Executive
14
Carcinogenicity Assessment Committee, which we call
15 the
executive CAC, as well as to the full CAC for
16
evaluation. The CDER CAC
committees were formed in
17 the
late 1980s to examine the protocols of
18
carcinogenicity studies, as well as to examine the
19
outcomes of the same studies. The
committees were
20
founded so that the interpretation of the
21
carcinogenicity data would not be inconsistent
22
depending on which division reviewed them. Two
116
1
committees exist, the executive CAC, as I said, and
2 the
full CAC.
3
The executive CAC consists of four
4
members, the associate director for
5
pharmacology/toxicology in the center; one
6
permanent expert in the evaluation of
7 carcinogenicity studies; the supervisor whose
8
division is presenting the data; and another
9
supervisor from another division chosen on a
10
rotating roster. The executive
CAC meets every
11
Tuesday and evaluates a great number of protocols
12 and
studies in a year, usually somewhere between
13 150
and 200 either protocols or carcinogenicity
14
studies in a year.
15
The next slide shows the makeup of the
16
full CAC which is empowered to review the studies
17
when members of the executive CAC cannot
18
unanimously agree on the interpretation of the
19
data, or when requested by the sponsor of the drug.
20 The
full CAC consists of the associate director for
21 the
center; three associate directors for the
22
offices; and each of the supervisors from the
117
1
individual divisions in the center.
The full CAC
2 is
a fairly large committee and meets only rarely.
3 In
fact, the meeting for this drug was the first
4 one
in over a year for the full CAC.
5
Both the executive CAC and the full CAC
6
agreed that the tumors seen in the studies were
7
probably relevant to a safety evaluation for
8
humans. The full CAC in general
voted that the
9
tumors seen in the carcinogenicity studies were
10
relevant to human safety evaluation.
11
The questions asked of the committee were
12
does the CAC agree that the lung tumors in mice
13
were relevant to human safety evaluation? The
14
committee voted yes, 16; no/probably not, 2; and 2
15
answered they don't know.
16
Does the CAC agree that, one, the liver
17
tumors in male mice and, two, the vascular tumors
18 in
female mice are relevant to human safety
19
evaluation? The vote was 17 yes;
3 no.
20
Does the CAC agree that, one,
21
hepatocellular adenomas and carcinomas in female
22
rats, two, the skin fibromas in female rats and,
118
1
three, the brain gliomas in male and female rats
2 are
relevant to human safety evaluation? The
3
answer was yes, 17; 3 no.
4
Now, in our division many carcinogenic
5
nucleoside and nucleotide analogs have been
6
approved for the treatment of viral diseases.
7
Among these are ganciclovir which gives rodent
8
tumors at very low doses relative to the human
9 exposure;
zidovudine; abacavir and cidofovir.
10
Cidofovir causes palpable mammary adenocarcinomas
11 in
rats after as few as six weekly doses and is
12
closely related in chemical structure to adefovir.
13
Some of the reverse transcriptase inhibitors as
14
well as the HIV protease inhibitors are positive
15 for
animal carcinogenicity. Other drugs,
such as
16
8-methoxy psoralen, which has been approved for the
17
treatment of psoriasis, are carcinogens.
In fact,
18
this compound has been identified as a human
19
carcinogen in epidemiology studies.
Dr. Linda
20
Lewis will continue the division presentation.
21
Thank you.
22 Clinical Issues
23
DR. LEWIS: Good morning. My name is
24
Linda Lewis, and I was the lead clinical reviewer
25 for
the entecavir review team. I would like
to
119
1
give you the perspectives of the entire team on our
2 review of entecavir for the treatment of
chronic
3
hepatitis B.
4
My presentation is outlined in this slide.
5
First I will go over a little bit of the
6
development program for entecavir, which you have
7
heard presented earlier by Bristol-Myers Squibb.
8
Then I would like to go over the results of our
9
reviews of the efficacy, safety and
10
virology/resistance data that were contained in the
11 NDA
submission. At that point I will turn my
12 discussion
to an assessment of the risk-benefit of
13
entecavir and the applicant's proposed
14
pharmacovigilance plan. I will
end the
15
presentation with a preview of the questions that
16 we
would like the advisory committee to consider
17
later this afternoon.
18
As you heard this morning, the treatment
19
options for chronic hepatitis B are somewhat
120
1
limited. Interferon was approved
for treatment of
2
hepatitis B in 1992. Its
requirement for
3
parenteral administration and its significant side
4
effect profile have somewhat limited its use.
5
Lamivudine was the first effective oral therapy,
6 and
it was approved in 1998. Its usefulness
has
7
been limited by the predictable emergence of
8
resistance in relatively short periods of time. A
9
most recent addition, adefovir, was approved in
10
2002. It has known renal toxicity
that may limit
11 its
use in some populations.
12
The entecavir development program included
13 a
diverse patient population. The clinical
studies
14
were drawn from multinational sites in North and
15
South America, Europe and Asia.
Among these
16
studies, patients from the United States made up
17
about 10 percent of the pivotal trials.
The
18
entecavir studies were made up of about 20 percent
19
women. There was a good mix of
Asian and non-Asian
20
patients in the populations.
However, Black or
21
African American patients were under-represented in
22 the
clinical trials, making up only 2 percent of
121
1 the
pivotal studies. The development program
2
enrolled patients at different stages of disease
3 and
treatment. Although there is a study in
4
progress, the data were insufficient to review the
5 use
of entecavir in patients with decompensated
6
liver disease during this review cycle.
7
BMS submitted study reports and electronic
8
data sets for the four key studies that they have
9
mentioned in their presentation earlier.
To go
10
over these again, study 022 was the Phase III study
11 enrolling
nucleoside-naive, e-antigen positive
12
adults. Study 027 enrolled
nucleoside-naive
13
e-antigen negative adults. Both
of these studies
14
used a dose of 0.5 mg of entecavir given once
15
daily. Study 026 enrolled
patients with persistent
16 HBV
viremia despite lamivudine treatment.
These
17 are
termed lamivudine-refractory subjects.
18
Patients in this study were e-antigen positive and
19
received a dose of 1 mg of entecavir given once
20
daily.
21
In order to expand the safety
database for
22
lamivudine-refractory patients we included in our
122
1
review patients from study 014, the dose-finding
2
study in that patient population, and used the
3
cohorts that received either 1 mg of entecavir or
4 the
standard dose of lamivudine. As has been
5
pointed out, all of the pivotal trials were
6
compared to the standard dose of currently approved
7 lamivudine.
8
For all of the Phase III studies, studies
9
022, 027 and 026, the primary endpoint was the
10
overall histologic improvement in liver biopsy
11
after 48 weeks of treatment. This
histologic
12
improvement was defined as greater than or equal to
13 a
2-point decrease in the Knodell necroinflammatory
14
score, with no worsening in the Knodell fibrosis
15
score compared to the baseline biopsy.
A series of
16
secondary endpoints were also evaluated and
17
included a number of virologic, serologic,
18
biochemical and composite endpoints.
19
The applicant also submitted data from
20
several important studies in special populations.
21
These included study 015. This
was a small pilot
22
trial in post-liver transplant patients who had
123
1
recurrent hepatitis B. Study 038
enrolled a cohort
2 of
HIV/HBV co-infected patients. Study 048
3
compares the use of entecavir to adefovir in
4
patients we decompensated liver disease.
This
5
study is still enrolling and the data were not
6
sufficient for us to conduct any meaningful interim
7
analysis during this review cycle.
In these
8
studies histologic endpoints were not used. They
9
relied on a series of virologic, serologic and
10
biochemical endpoints.
11
Now I would like to turn to the efficacy
12
review of entecavir. You will
probably notice in
13
these slides that many of our slides look very
14
similar to those presented by the applicant earlier
15
this morning.
16
The FDA statistical review, conducted by
17 Dr.
Tom Hammerstron, confirmed the applicant's
18 primary efficacy analysis. A review of secondary
19
efficacy analyses, using the virologic, serologic
20 and
biochemical endpoints, was also in agreement
21
with BMS's conclusions. Multiple
sensitivity
22
analyses and subgroup analyses were performed and
124
1 all
supported the primary analysis.
2
This table displays the results of the
3
primary efficacy analysis and some of the other
4
histologic endpoints for each of the Phase III
5
studies, study 022, 027 and 026.
The top line of
6 the
study shows the primary analysis, the overall
7
histologic improvement after 48 weeks.
As you can
8
see, in each of the three studies entecavir
9
performed better than lamivudine in each study, as
10
highlighted--these are supposed to be pink I don't
11
know exactly how it projects.
12
The next two lines display the two
13
individual components that make up the overall
14
histologic improvement score.
Again, you can see
15
that patients receiving entecavir achieved that
16
endpoint significantly more often than those who
17
received lamivudine. The last
line of the study
18
shows the secondary histologic endpoint of the
19
Ishak fibrosis score. This is
another method of
20
evaluating liver histology. In
this analysis
21
entecavir was superior to lamivudine only in the
22
lamivudine-refractory study, study 026.
In the
125
1
treatment-naive studies the proportion of patients
2
achieving an improvement in their Ishak fibrosis
3
score was similar across the treatment arms.
4
This table displays some of the
5
sensitivity analyses that were done by our
6
statistical reviewers. The top
line is a carryover
7
from the previous slide and shows the primary
8
analysis. In the primary analysis
the only
9
subjects who had evaluable baseline biopsies were
10
included in the analysis.
Subjects with missing or
11
inadequate week 48 biopsies were counted as
12
treatment failures. The
sensitivity analyses, done
13 by
Dr. Hammerstron, included a series of different
14
methods to impute the missing data for each of the
15
Phase III studies. I am going to
show you just two
16 of
the many analyses that he did.
17
In FDA sensitivity analysis C, missing or
18
inadequate baseline or week 48 biopsies were
19
excluded from the analysis. In
this analysis, in
20
study 022, the results were similar between
21
entecavir and lamivudine and this is due primarily
22 to
the fact that more patients in the lamivudine
126
1 arm
were excluded because they did not have week 48
2
biopsies. In the other two
studies, again,
3
entecavir achieved the primary endpoint
4
significantly more often than patients who received
5
lamivudine.
6
In sensitivity analysis D, this analysis
7
includes all patients who were treated, not just
8
those who had evaluable biopsies, but missing or
9
inadequate week 48 biopsies were still counted as
10
failures. Although the numbers
are lower for all
11 of
these analyses, the difference between entecavir
12 and
lamivudine remains evident in each of the three
13
pivotal trials.
14
This slide displays some of the analyses
15 of
secondary virologic, serologic and biochemical
16
endpoints for the three pivotal trials.
Again, the
17
significant values are highlighted in the pink
18
cells. In the Phase III studies a
greater
19
proportion of patients receiving entecavir than
20
lamivudine achieved an HBV DNA PCR less than 400
21
copies/mL. Similarly, patients
who received
22
entecavir had a greater mean log decrease in PCR
127
1
from baseline to week 48 than did patients who
2
received lamivudine. In the two
studies that
3
included e-antigen positive patients, studies 022
4 and
026, the proportions of patients who had a
5
seroconversion were roughly the same.
You will
6
notice that in study 026 a relatively small number
7 of
patients actually met this criteria.
Finally,
8 in
terms of the proportion of patients who reached
9 a
normalized ALT, again, entecavir was shown to be
10
superior to lamivudine in each of the three pivotal
11
trials.
12
We also conducted a number of subgroup
13
analyses for baseline covariates of demographic or
14
disease characteristics. The
treatment effect of
15 the
primary endpoint was comparable for the
16
covariates gender, race, age, geographic region,
17 HBV
subtype, baseline ALT, baseline bDNA or PCR, or
18 by
prior treatment with lamivudine or interferon.
19
Similarly, more limited subgroup analyses
20
were performed to assess some of the key secondary
21
endpoints. The treatment effect
measured by the
22
proportion of patients of subjects who achieved a
128
1 normalization of HBV DNA or those who
achieved a
2
viral load less than 400 copies/mL at weeks 24 and
3 48
were similar according to gender, race and age.
4
This slide displays a composite of the
5
subgroup analysis for the Phase III studies. I
6
really show you this for pattern recognition more
7
than to display any kind of specific results. This
8
slide plots the mean difference in treatment effect
9 for
the primary endpoint between entecavir and
10
lamivudine, with 95 percent confidence intervals,
11 for
the three pivotal trials. This cluster
12
represents study 026. This is 022
and this cluster
13 is
027. In this display the horizontal line
at
14
zero percent represents no difference between the
15
entecavir and the lamivudine arms for each of the
16
baseline covariates that were evaluated.
The
17
cross-hatch mark is the mean, and as you can see,
18 the
vertical line is the 95 percent confidence
19
interval.
20
In this analysis, every instance where the
21
cross-hatch is above the zero line indicates an
22
analysis that favored entecavir.
Those with
129
1
cross-hatches below the zero line are an analysis
2
that favors lamivudine. What I
will show you
3
though is that in all of these the confidence
4
intervals are very wide and overlap, and this is
5
what was seen in the subgroup analyses.
There were
6 no
discernible differences but there were very wide
7
confidence intervals between the different
8
subgroups.
9
Now I would like to turn to our review of
10 the
safety conclusions. I would like to
remind the
11 committee that these were very large
databases and
12
there are minor differences in the analysis results
13
between what you may have seen this morning in the
14
applicant's presentation and in the numbers you may
15 see
in my presentation. These results and
minor
16
differences are due to slightly different methods
17 of
capturing different study windows and defining
18
values that are used when there are multiple values
19
within a study window.
20
In general, the FDA clinical review
21
confirmed the safety and tolerability of entecavir
22 as
compared to lamivudine. No significant
130
1
differences in the rates or patterns of common
2
adverse events or laboratory abnormalities were
3
identified in entecavir-treated subjects compared
4 to
lamivudine-treated subjects. The rates
of
5
serious adverse events, discontinuations due to
6
adverse events and deaths were very low across all
7 of
the studies.
8
Acute exacerbations of hepatitis as
9
demonstrated by marked elevations of ALT, called
10 ALT
flares, are an important complication of HBV
11 and
its treatment. These were evaluated in
more
12
detail. Also, because central
nervous system
13
adverse events and malignancies were identified as
14
possible toxicities from the animal studies, these
15
events were also evaluated in detail.
I will
16
present some of the results of these analyses in
17 the
next few slides.
18
For this NDA, one interesting feature is
19
that ALT levels were used as both a marker of
20
efficacy and as a safety parameter.
ALT flare was
21
defined as an ALT value that was at least 2 times
22 the
patient's baseline value and also 10 times the
131
1
upper limit of normal. In
discussing these ALT
2
flares, one must remember that, particularly in the
3
nucleoside-naive subjects, mean ALT values
4
decreased from baseline to week 48 in both
5
treatment groups. The mean
decrease was about 100
6
international units from baseline to week 48 if the
7
groups are taken as a whole.
8
In the nucleoside-naive subjects ALT
9
flares occurring on study treatment were uncommon,
10
15/679, or about 2 percent, of entecavir subjects
11
compared to 27/668 lamivudine subjects, or about 4
12
percent, experienced an ALT flare while on
13
treatment. Though the numbers are
very small, this
14
analysis does favor the entecavir arm.
15
In studies 022 and 027 the study design
16
allowed only subjects who met the protocol-defined
17
response criteria to discontinue treatment and be
18
then be followed off therapy. In
these studies
19
more subjects met that protocol-define response
20
criteria in study 027 than in 022.
Consequently,
21 the
analysis of off-treatment ALT flares represents
22 a
very selected subgroup of the patients enrolled.
23
That being said, compared to on-treatment
24 ALT
flares occurred slightly more often in both
25
treatment groups, 15/414, or 4 percent, of
132
1
entecavir patients compared to 30/377, or about 8
2
percent, of lamivudine-treated patients.
This
3
analysis also favors the entecavir arm.
4
In lamivudine-refractory subjects,
5
on-treatment flares were documented in 4/183, or 2
6
percent, of entecavir subjects compared to 19/190,
7 or
about 10 percent, of lamivudine subjects.
8
Again, this favors the entecavir arm.
In this
9
study, 026, smaller proportions of the
10
lamivudine-refractory subjects met the
11
protocol-defined response criteria, discontinued
12
therapy, and were followed of treatment.
So,
13
again, this represents a very selected subgroup in
14 the
study population. Off-treatment flares
15
occurred in 3/56 entecavir subjects compared to
16
0/31 lamivudine subjects.
17
Central nervous system adverse events were
18
identified in preclinical animal toxicity studies
19 of
entecavir. These events were closely
monitored
133
1 in
the Phase I and Phase II studies. In the
Phase
2 II
dose-finding study 005, which was conducted in
3
nucleoside-naive subjects, the incidence of grouped
4
neurologic events increased with increasing doses
5 of
entecavir. Compared to a 7 percent rate
of
6
neurologic events reported in the lamivudine group,
7
there were 11 percent of subjects in the 0.01 mg
8
entecavir group; 19 percent in the 0.1 mg entecavir
9
group and 0.5 percent in the 0.5 mg entecavir group
10
reporting a neurologic event.
There appeared to be
11
trends but not statistically significant toward
12
events of increased dizziness and insomnia in the
13 0.5
mg dose of entecavir.
14
However, in the Phase II
15
lamivudine-refractory dose-finding study 014 a dose
16
relationship with neurologic events was not
17
identified, and in that study doses ranged up to 1
18 mg
of entecavir.
19
We evaluated these events in all of the
20
primary studies that were submitted, both
21
individually and pooled as nucleoside-naive and
22
lamivudine-refractory groups.
This table displays
134
1 all
neurologic events and individual events from
2 the
pooled study data. The rates of central
3
nervous system events were roughly similar across
4 the
treatment groups of nucleoside-naive and
5
lamivudine-refractory patients.
These proportions
6
represent patients who reported any central nervous
7
system adverse event and selected events that are
8
called psychiatric events. It is
kind of an
9
arbitrary cutoff in the currently used dictionary
10 of
adverse event terms.
11
However, if you look at the individual
12
events, events such as anxiety, dizziness,
13
headache, insomnia, migraines, paresthesia,
14
somnolence and syncope were no different
15
statistically across either the treatment groups or
16
between the nucleoside-naive and
17
lamivudine-refractory patients.
If only subjects
18 who
were reporting grades 2-4 events, and those are
19
moderate to severe events, were tabulated there was
20 a
slightly higher proportion of entecavir patients
21 in
the lamivudine-refractory study who reported
22
grade 2-4 events compared to those patients
135
1
receiving lamivudine.
2
In looking at these patients individually,
3
these differences can be accounted for by single
4
patients who reported a variety of different
5
moderate CNS events. It should
also be noted that
6 in
all of these primary studies there was only a
7
single subject who reported a grade 4 neurologic
8
event.
9
Because entecavir was identified as a
10
potential carcinogen in animal studies, the
11
occurrence of malignancies has been tracked through
12 all
of the entecavir clinical trials. As of
the
13
last safety update during the NDA review cycle, 37
14
subjects had been diagnosed with a malignancy while
15
participating in entecavir clinical trials. Most
16 of
these subjects were enrolled in the primary NDA
17
studies, and these are 19/1,497 entecavir subjects,
18 and
9/899 lamivudine subjects. In addition,
there
19
have been 9 subjects developing malignancies while
20
enrolled in the special population studies. These
21
studies include 038, the HIV/HBV co-infected
22
subjects; 048, the subjects with decompensated
136
1
liver disease who contributed a disproportionate
2
number of malignancies; and study 901, the large
3
rollover continuing study. In
these special
4
populations there were 3 malignancies among
5
patients receiving entecavir alone; 2 among
6
subjects receiving adefovir alone; and 4 in the
7
large group receiving a combination of entecavir
8
plus lamivudine in the rollover study.
9
As might be expected, hepatocellular
10
carcinoma was the most commonly reported
11
malignancy. Malignancies that
were reported in
12
more than one subject in either treatment group in
13 the
NDA safety database included hepatocellular
14
carcinoma in 7 entecavir subjects and 4 lamivudine
15 subjects;
basal cell carcinoma in 2 entecavir
16
subjects and 1 lamivudine subject; breast cancer in
17 1
entecavir subject and 2 lamivudine subjects, 1 of
18
whom had carcinoma in situ; and prostate cancer in
19 2
entecavir subjects. Of these patients
who
20
reported malignancies during the clinical trial, 6
21 of
them were known to have had previous
22
malignancies prior to entering the studies.
23
Now I would like to shift attention to our
24
review of the virology resistance data.
These data
25
were reviewed by Dr. Lisa Nagra and Julian O'Rear
137
1 in
our microbiology group. I will point out
that
2 the
data that was reviewed in our NDA review
3
included only data through 48 weeks so the numbers
4 of
patients that we have evaluated are somewhat
5
smaller than the numbers that were presented in the
6
applicant's presentation earlier this morning.
7
In our review, no genotypic or
phenotypic
8
evidence of entecavir resistance has been detected
9
among 434 nucleoside-naive subjects analyzed at 48
10
weeks of entecavir treatment.
These are patients
11 in
study 022 and 027. In that time period
there
12
were 2 subjects in study 022 who experienced a
13
confirmed virologic rebound, but no genotypic or
14
phenotypic evidence of entecavir resistance was
15
identified in their HBV isolates.
Follow-up data
16 are
needed after 48 weeks to determine the
17
emergence of resistance of mutations in these
18
patients and determine the pathway to entecavir
19
resistance in treatment-naive subjects.
20
Lamivudine-refractory subjects are much
21 less
likely than treatment-naive subjects to
22
achieve an HBV DNA less than 400 copies.
Although
23
this is true, reductions in viral load less than 2
24
logs and suppression below a viral load of 400
25
copies/mL can occur in subjects with
138
1
lamivudine-resistant HBV at baseline when they are
2
treated with entecavir 1 mg.
Lamivudine-resistance
3
substitutions L8OV, L180M and M204V or I can emerge
4 in the
HBV of some patients receiving 1 mg of
5
entecavir by week 48. These
substitutions often
6
arise in the context of mixtures at these sites and
7
other lamivudine-resistance mutations at baseline.
8
Substitutions at amino acids I1169, T184,
9
S202 and/or M250 are associated with entecavir
10
resistance both individually and in combination.
11 In
all cases these entecavir-associated resistance
12
substitutions emerged when lamivudine resistance
13
mutations at L180 and/or M204 were present at
14
baseline. And 14/189, or 7.4
percent, of evaluated
15
lamivudine-refractory subjects treated with
16
entecavir developed resistance mutations at 48
139
1
weeks. These entecavir-associated
resistance
2
substitutions were associated with virologic
3
rebound in 3/14 subjects by 48 weeks and additional
4
subjects experienced rebound with prolonged therapy
5
beyond that time.
6
Lamivudine-resistant HBV clinical isolates
7 at
baseline and from studies 015, the transplant
8
study, and 026 showed a 3-51-fold reduced
9
susceptibility to entecavir by in vitro assays.
10 HBV
developing entecavir-associated resistance
11
substitutions in the clinical trials were
12
susceptibility to adefovir in vitro but remained
13
resistant to lamivudine. Finally,
14
adefovir-resistant hepatitis B was susceptible to
15
entecavir by in vitro assays.
16
Our virologists' conclusions were that no
17
entecavir resistance has been detected in
18
nucleoside-naive subjects treated with entecavir
19
through 48 weeks, but longer-term follow-up data
20 are
needed.
21
Entecavir resistant mutations can emerge
22 on
entecavir treatment when lamivudine mutations
140
1 are
present. These emerge at a rate of less
than
2 10
percent at 48 weeks. These entecavir
resistance
3
mutations are associated with virologic rebound
4
and, finally, entecavir is cross-resistant with
5
lamivudine but not adefovir by in vitro assays.
6
Now I would like to turn attention to the
7
risk-benefit assessment of entecavir and the
8
proposed pharmacovigilance plan.
I would like the
9
committee members to consider these issues very
10
carefully and provide feedback to us during the
11
discussions this afternoon.
12
In the evaluation of risk-benefit we must
13
balance the potential benefit of an effective drug
14 for
a serious disease against an unknown risk of
15
cancer. It has been well
documented that patients
16
with chronic hepatitis B have increased risk of
17
hepatocellular carcinoma and new cohort studies
18
suggest that they may have an increased risk of
19
other malignancies as well.
20
There is accumulating evidence that
21
treatment of chronic hepatitis B may decrease the
22
rate of progression of liver disease and may delay
141
1 or
prevent hepatocellular carcinoma.
Entecavir has
2
demonstrated efficacy in the treatment of chronic
3
hepatitis B as measured by liver histology, HBV DNA
4 and
other endpoints. Its efficacy was better
than
5 or
equivalent to lamivudine in all of these
6
analyses through 48 weeks of treatment.
The
7
general safety and tolerability profile of
8
entecavir was similar to that of lamivudine.
9
Positive carcinogenicity findings in
10
animal studies are not rare and they are usually
11
described in the product label, usually in a
12
special section for carcinogenicity, mutagenicity
13 and
impaired fertility. Animal
carcinogenicity
14
studies identify a hazard signal, as Dr. Farrelly
15
pointed out earlier, and cannot be directly
16
extrapolated to a level of risk in humans.
17
Quantifying this level of human risk is very
18
difficult. The mechanism of
carcinogenicity is
19
likely to be different for each different drug.
20
Consequently, the FDA has traditionally considered
21
these risk-benefit assessments on a case-by-case
22
basis. Higher perceived risk is
tolerated among
142
1
drugs for diseases with serious and
2
life-threatening consequences.
3
BMS has proposed a comprehensive
4
pharmacovigilance plan for entecavir.
This plan
5
includes increased monitoring and analysis of
6
post-marketing safety reports and regular reporting
7 of
the results of these analyses to the FDA.
It
8
also includes continued tracking of subjects in
9
clinical trials through the ongoing rollover and
10
observational studies. Finally,
BMS has proposed a
11
large simple safety study to evaluate the
12
occurrence of major events as entecavir moves into
13
broader clinical use.
14
We have reviewed a draft protocol for this
15
post-marketing safety study and discussed the
16
proposal with our colleagues in the Division of
17
Drug Risk Evaluation, Office of Drug Safety. We
18
agree that the proposed study has a number of
19
strengths and represents a good effort on the
20
applicant's part to collect important safety data.
21
The strengths of the study include the
22
fact that the study design is randomized. It
143
1
includes an active control group; stratification by
2
prior treatment; pertinent endpoints and
3
pre-planned analyses. The study
will evaluate an
4
international population who are using the drug in
5 a
real-life setting. it will allow
enrollment of
6
patients with concomitant hepatitis C and HIV, and
7
enroll a patient population with a broader spectrum
8 of
hepatitis B disease than was seen in the
9
clinical trials. The size of the
study, 12,500
10
patients, and enrollment through many local
11
physicians, each following a relatively small
12
number of their own patients will be advantageous.
13
However, we also recognize the potential
14
limitations of the proposed study.
The length of
15 the
study may not be adequate to identify
16
malignancies with a long latent period.
There may
17
need to be some mechanism of ascertaining events
18
over a longer period than is currently proposed.
19
Results may be confounded as subjects may switch
20
from the originally assigned treatment to the
21
comparator group over time.
Certainly, the number
22 of
patients lost to follow-up may be higher than
144
1
anticipated. In this case, no
specific tumor type
2 can
be targeted for surveillance and, clearly,
3
there is no way to stratify for all the other
4
possible co-factors for malignancies that might be
5
encountered in the study population.
6
That being said, the study would be
7
similar in size and scope to some others that have
8
been requested by the FDA or that have been used to
9
identify other risk factors. The
study might
10
identify changes in 5-8-year risk of hepatocellular
11
carcinoma or other tumors in patients receiving
12
treatment for hepatitis B.
Importantly, however,
13
negative findings at the end of the study may not
14
equate to a conclusion that there is no risk.
15
I would like to put the entecavir animal
16
carcinogenicity findings in context of other drugs
17
that have been reviewed in our division.
As Jim
18
pointed out, we see nucleoside analog drugs on a
19
fairly regular basis. We have
made risk-benefit
20
assessments for drug approvals and for the need for
21
follow-up on a case-by-case basis based on the
22
robustness of the animal data and the disease being
145
1
treated.
2
Zidovudine, the first approved
3
anti-retroviral drug, was shown to result in
4 vaginal
tumors in rodents. The division
considered
5 the
devastating consequences of untreated HIV to
6 far
outweigh the potential risk of cancer in this
7
population. However, in the
setting of zidovudine
8
being used for the treatment or for the prevention
9 of
perinatal transmission of HIV, many of the
10
infants exposed to zidovudine will not be infected.
11 In
this case, infants exposed to zidovudine
12
perinatally are being followed in a long-term
13
prospective outcome study conducted by the NIH.
14
This is in PACTG study 076 and 219.
15
Many of the nucleoside reverse
16
transcriptase inhibitors and a number of the
17
protease inhibitors, such as ritonavir, have shown
18
positive findings in animal carcinogenicity
19
studies. A similar rationale led
to the acceptance
20 of
this risk in humans using these drugs.
21
Ganciclovir and cidofovir, both approved
22 for
the treatment of serious CMV infections, are
146
1
also among the drugs with positive animal
2
carcinogenicity findings. The
division again
3
considered the consequences of untreated CMV to
4
outweigh the potential for human cancer.
However,
5
both of these drugs contain in their labels a boxed
6
warning that includes the animal carcinogenicity
7
findings.
8
In the case of famciclovir, a drug used
9 for
the treatment of less serious herpes simplex
10
infections, the animal findings were considered a
11
very weak signal and not relevant for human
12
clinical use.
13
The Division of Antiviral Drugs is not the
14
only review division to debate the clinical
15
relevance of positive animal carcinogenicity
16
findings. Drugs with positive
findings have been
17
approved for a variety of other indications,
18
including but not limited to lipid-lowering drugs,
19
anticonvulsants, and drugs for osteoporosis, ADHD
20 and
gastroesophageal reflux. For some of
these
21
drugs long-term clinical trials have shown no
22
imbalance in cancer rates. Some
of the drugs were
147
1
approved many years ago, before animal
2
carcinogenicity studies were available, and have
3
subsequently had significant long-term use
4
experience. In some cases
completed epidemiologic
5
linking studies have given conflicting results.
6
In some cases, however, the FDA has
7
requested post-marketing studies to further assess
8 the
risk of human cancer in approved drugs.
Some
9 of
the types of requested post-marketing
10
evaluations include a long-term prospective
11
observational study of a drug compared with an
12
appropriate control; registries of patients using a
13
drug long term; post-marketing surveillance
14
program; and a retrospective cohort study to
15
measure the incidence of a specific tumor in the
16
contribution of drug.
17
In conclusion, we will like to say that we
18
believe that in well-conducted clinical trials
19
entecavir was shown to provide efficacy compared to
20
lamivudine for the treatment of chronic hepatitis B
21 as
measured by multiple histologic, virologic,
22
biochemical and composite endpoints.
The treatment
148
1
benefit of entecavir over lamivudine was greatest
2 in
lamivudine-refractory subjects. The
general
3
safety and tolerability of entecavir was similar to
4
lamivudine in all populations studied.
Similarly,
5 the
safety and tolerability profile of entecavir
6 was
similar in nucleoside-naive subjects who
7
received 0.5 mg dose and lamivudine-refractory
8
subjects who received 1. mg dose.
9
Nonclinical studies have identified
10
entecavir as carcinogenic in mice and rats.
11 However, the clinical relevance of these
animal
12
carcinogenicity studies are unknown.
To date, no
13
increase in human malignancies has been identified
14 in
the clinical trials. BMS has proposed a
large
15
simple safety study designed to identify increased
16
cancer risk in patients receiving entecavir as part
17 of
a comprehensive pharmacovigilance program.
18
We believe that entecavir fits in a unique
19
position. Based on the animal
carcinogenicity
20 studies, it may pose some increased risk of
cancer.
21
However, its treatment effect in chronic hepatitis
22 B
may actually lead to a reduction in
149
1
disease-related hepatocellular carcinoma. The
2
review team believes that the proposed
3
post-marketing study and pharmacovigilance plan may
4
provide a good opportunity to evaluate the
5
long-term effects of entecavir, and we are looking
6
forward to hearing the discussion from members of
7 our
committee and consultants this afternoon.
8
I would like to finish with just a quick
9 run
through of the questions we will pose to the
10
committee this afternoon so that you can keep these
11 in
mind if you have other questions you would like
12 to
pose to either me or Bristol-Myers Squibb.
13
Question 1, how would you assess the
14
risk-benefit of entecavir in the context of the
15
available clinical safety, efficacy, resistance and
16
nonclinical carcinogenicity data?
17
Question 2, does the risk-benefit
18
assessment for entecavir support the approval of
19
entecavir for the treatment of chronic hepatitis B
20 in
adult patients? If the answer to 2A is
no, what
21
additional information would be needed to support a
22
resubmission?
23
If the answer to 2A is yes, discuss
24
whether the results of the rodent carcinogenicity
25
studies should impact the indication and usage
150
1
section of the product labeling.
2
B, based on the available data, discuss
3 the
potential role of entecavir in the HBV
4
treatment armamentarium.
5
Question 4, assess the potential risks and
6
benefits of proceeding with development of
7
entecavir for the treatment of chronic hepatitis B
8 in
pediatric patients.
9
B, what, if any, additional information is
10
needed in order to proceed in this age group?
11
Question 5, discuss the applicant's
12
proposed pharmacovigilance plan to address human
13
cancer risk, including comments on the design of
14 the
proposed large simple study.
15
Finally, question 6, are there other
16
issues that you would like to see addressed through
17
post-marketing commitments?
18
Thank you, and I will take questions along
19
with Dr. Farrelly.
20 Discussion
21
DR. ENGLUND: Thank you, Dr. Lewis
and the
22 FDA
committee for giving us a nice summary,
23
succinct and pretty clear.
24
At this point, from the committee, we are
25 going to entertain questions directed only to
the
151
1
presentations you have heard this morning. We are
2 not
going to discuss the questions that were laid
3 out
for us. That is for this afternoon and
we are
4
going to have a whole afternoon in which to do that
5 so
this is a relatively limited and focused
6
discussion and I am happy to ask for questions from
7 the
floor. Dr. Paxton?
8
DR. PAXTON: I have a very brief
question.
9
Could you just explain for me what is the FDA's
10
criteria for having a boxed warning versus a
11
mention?
12
DR. LEWIS: I am actually going to
defer
13
that question to Dr. Birnkrant, our division
14
director.
15
DR. BIRNKRANT: When we helped to
16
construct the labels for cidofovir and ganciclovir
152
1 we
took into account, with regard to a box warning,
2 the
effects of the drug in the animals such that in
3
those two drugs in particular the tumors appeared
4 at
multiples of human dosage either less than 1 or
5
very close to 1. So, we thought
that was highly
6 significant. Whereas, in this drug the tumors
7
appear at much higher multiples of human dose. So,
8
based on those findings, in the ganciclovir and
9
cidofovir carcinogenicity studies were placed in a
10
boxed warning.
11
DR. ENGLUND: Dr. Haubrich?
12
DR. HAUBRICH: This may be a
question for
13 the
applicant, but in the pharmacovigilance program
14 how
will you address the issue if patients either
15
drop out or refuse to be randomized, given the
16
efficacy data which clearly shows this drug is
17
better than certainly lamivudine?
18
DR. MORGAN MURRAY: Dr. Pierce
will
19
address the questions on enrollment and dropout and
20 how
we intend not to lose patients to follow-up.
21
DR. PIERCE: Thank you. There are several
22
mechanisms of handling dropouts or of switching
153
1
really in this. The way we have
thought through
2 this--and certainly as mentioned this is a
draft
3
proposal and we are willing to take other
4
suggestions to modify this plan--our plan, in the
5
worst-case scenario, if people are dropping out at
6
high rates, is that we will then be left with an
7
observational study which, in and of itself, will
8
have great power to give us a rate which we can
9
then compare to a background rate of malignancies.
10
We concur with you that there may be
11
difficulties in randomization. We
do, however,
12
plan in this study to have randomization against
13 the
standard of care so whatever alternative
14
therapies are available within that country,
15
patients will have access; it is not randomized to
16
lamivudine only for example.
17
DR. HAUBRICH: Just a quick
follow-up, is
18
drug going to be provided for either arm?
19
DR. PIERCE: Those levels of
details have
20 not
been really worked out.
21
DR. ENGLUND: Dr. Wood?
22
DR. WOOD: In the sponsor's
proposed
154
1
post-marketing study, the FDA comments that the
2
study might identify changes in a 5- to 8-year risk
3 of
hepatocellular carcinoma and other tumors.
I
4 was
wondering, from the FDA, from the experts that
5 are
present or from the sponsor, do we have any
6
current estimates of the 5- to 8-year risk of
7
hepatocellular carcinoma and tumors in patients
8
with HBV who are untreated and then those who are
9
treated, so that we might have an assessment of
10
what that risk is.
11
DR. LEWIS: BMS actually does have
data
12
that they can present according to that.
13
DR. MORGAN MURRAY: Dr. Pierce?
14
DR. PIERCE: I think to respond to
that we
15
will go back to that slide I showed this morning,
16 the
15-20 slide. This slide used projections
of
17 the
rates of HCC based on the experience in the
18
Taiwan data set. These are
similar patients to
19
those that meet treatment guidelines.
These are
20
individuals who have a viral load of greater than
21
10
5, greater than or equal to 105.
So,
that
is why
22 you
may see this particular estimate of the number
155
1 of
HCCs that you would see over a five-year period
2
that may be higher than what you see in other
3
cohorts because this is dependent on the treatment
4
guidelines essentially.
5
DR. WOOD: Do we have any data in
treated
6
patients at all? The duration of
treatment with
7
lamivudine has been somewhat more limited and maybe
8 not
as extensive but it would be interesting to see
9
whether or not--I don't know if any data exists
10
regarding treated patients and whether or not that
11 is
significantly lower because that might impact
12 the
ability to detect this excess incidence of
13
cancers since everyone would be treated in the
14
post-observational study?
15
DR. MORGAN MURRAY: Dr. Wilber,
please?
16
DR. WILBER: Richard Wilber. The study
17
referenced this morning in the original background
18
presentation, and I am sure a number of you are
19
familiar was the Liaw study which compares,
20
according to the question, treatment versus
21
placebo. It does not give you the
range of time
22
that you asked about since the study was terminated
156
1 at
32 months. Within that study there was adequate
2
time to assess the difference in HCC in
3 lamivudine-treated
patients versus placebo.
4
Although a number of the HCCs appeared to have
5
occurred early, and when those are dealt with not
6
simply as events on study but when they are
7
assessed whether they might have actually been
8
antecedent to study beginning, the significance
9
drops off between the two. There
were many other
10
endpoints in disease progression and the treatment
11
benefited those far more noticeably, if you will,
12
than the event of HCC. Dr.
Dienstag, do you have
13
anything else to add? You are
probably a little
14
closer to those data.
15
DR. DIENSTAG: Jules Dienstag,
16
Massachusetts General Hospital.
One of the things
17 to
keep in mind about the study is that it was a
18
prospective study designed to monitor differences
19
between the treated and untreated groups. The
20
study had to be terminated at 72 weeks because the
21
difference was so substantially different. Had
22 they
been able to continue the study, then the
157
1
marginal difference--I mean, hepatocellular
2
carcinoma almost certainly would have been more
3
statistically significant, but that is the
4
limitation of having a data safety monitoring board
5 to
protect patients.
6
DR. MORGAN MURRAY: Dr. Di
Bisceglie,
7
anything else to add about hepatocellular
8
carcinoma?
9
DR. DI BISCEGLIE: Adrian Di
Bisceglie,
10 St.
Louis University. I think that I would
fully
11
expect a reduction in hepatocellular carcinoma over
12
time. I think your question is
how long would it
13
take before we begin to see that.
I think it will
14
take at least two or three years.
We may begin to
15 see
a difference at that time, but the difference
16
will become more and more evident with time with an
17
agent that suppresses virus to a great degree and
18 is
not associated with resistance. One of
the
19
points in the Liaw study was that with lamivudine
20 as
resistance began to appear, so the clinical
21
benefit began to be lost.
22
DR. ENGLUND: Thank you. Dr. Bartlett?
23
DR. BARTLETT: Do you have any
plans to
24
study this drug in pediatric populations or during
25
pregnancy?
158
1
DR. LEWIS: We will get into this
a little
2 bit
later as we discuss the questions, but based on
3 the
preliminary animal carcinogenicity data and
4
uncompleted Phase III adult trials, the FDA asked
5 BMS
to delay starting studies in pediatrics until
6 we
had a fuller understanding of the risk-benefit
7
before starting.
8
DR. ENGLUND: Dr. Paxton?
9
DR. PAXTON: Yes, I had a question
about
10
decompensated patients. It looks
to me like in the
11
previous studies most of the patients were
12
compensated. What are your
plans? Will
13
decompensated patients be included in the
14
pharmacovigilance studies that are going on? Do
15 you
have plans to look at them in any other form as
16
well?
17
DR. MORGAN MURRAY: Yes, we will
include a
18
broader patient population and, as Dr. Lewis
19
alluded to, we do have an ongoing study in patients
159
1
with decompensated liver disease with comparison of
2
entecavir and adefovir. We have,
as Dr. Lewis
3
mentioned, conducted an interim analysis on 50 or
4 so
of those patients that have completed 24 weeks
5 of
treatment. The study is intended to
enroll 270
6
patients and we would be happy to share those
7
interim data, again recognizing that it is a very
8
small number of patients.
9
DR. PAXTON: And as a follow-up,
do you
10
expect to see a markedly different malignancy rate
11
between the compensated and the decompensated
12
patients in the trial?
13
DR. MORGAN MURRAY: As Dr. Lewis
alluded
14 to,
these patients in general will have a higher
15
malignancy rate.
16
DR. ENGLUND: Dr. Bell?
17
DR. BELL: I have one other
question for
18
Bristol-Myers Squibb on some of these cancer data.
19 You
previously showed on your slide 62--you
20
referred to a U.S. cohort and a Taiwan cohort in
21
which you were estimating the incidence of HCC and
22
other tumors. I wonder if you
could, please, give
160
1 us
a little more information about the source of
2
those data and who the people are in these cohorts.
3 DR. MORGAN MURRAY: Yes.
Dr. Brett-Smith,
4 can
you provide some more information, please?
5
DR. BRETT-SMITH: Let me take the
U.S.
6
cohort first. The U.S. cohort is
actually based on
7 a
historical database derived from Kaiser in
8
northern California, so primarily the Oakland
9
system there, and the Henry Ford Hospital system in
10
Detroit. This was, again,
sponsored with a grant
11 to
the independent people who manage those
12
databases, and they conducted a review of their
13
historical patient data from 1995 to 2001. They
14
identified a cohort of confirmed surface antigen
15
positive patients within that database.
Then they
16
cross-referenced it with their entire medical
17
record database, and also with the cancer
18
registries and with death certificates.
From that
19
data set they developed a rate of cancer incidence
20
over the entire cohort. This is a
cohort that we
21 do
not have good information about the proportion
22
treated, non-treated, the mix.
23
The Taiwan cohort is structurally quite
24
different. This was a
community-based prospective
25
observational study sponsored by the Taiwan
161
1
Ministry of Health. It was
actually looking at
2
overall cancer incidence. Because
of the
3
demographics of the population locally, obviously,
4
hepatitis B infection and HCC were important
5
issues. They enrolled subjects
over 1991 to 1992,
6 and
they actually evaluated them and have continued
7 to
follow them to the current time. Our
data cut
8 was
taken in June of 2004. Again, they
performed
9 all
analyses and maintained the database.
10
In that data set there are a couple of
11
important factors to note. The
first opportunity
12 or
the first availability for hepatitis B
13
nucleoside treatment was in 2003.
So, this is
14
essentially more of an untreated cohort.
There was
15
more specific and directed screening for HCC within
16 the
general surface antigen positive population,
17 and
specifically for patients who were identified
18 as
having cirrhosis. So, there are caveats
around
19
these comparisons. They are the
best ballpark
162
1
estimates for comparison that we were able to have.
2
DR. ENGLUND: Before you step
down, I have
3
just one quick related question.
Did that study
4
cohort then include children, or was it just adults
5 for
both of those studies?
6
DR. BRETT-SMITH: Both are adults
only.
7
DR. ENGLUND: Mr. Grodeck, you had
a
8
question?
9
MR. GRODECK: This question is for
Dr.
10
Lewis. So that we can get some
context in terms of
11 the
cancer, potential cancer risk, you showed us a
12
slide on adefovir. I noticed that
there were some
13
limitations in dosing adefovir.
To give us some
14
perspective how it might compare to similar dosing
15 for
entecavir, can you talk a little bit about
16
those limitations?
17
DR. LEWIS: Well, I think Dr.
Farrelly
18 pointed
out the major limitations. These studies
19 are
generally conducted at the MTD, maximum
20
tolerated dose that the animals will tolerate over
21 a
period of the two-year study. In many
cases a
22
pilot study is done to identify that MTD but with
163
1
adefovir, because of its known renal toxicity, the
2
study could only achieve a certain level of dosing
3 in
the rodents which was modest compared to the
4
levels that could be achieved in either the
5
lamivudine carcinogenicity studies or the entecavir
6
carcinogenicity studies. It is
very different,
7
even with using relatively standardized animal
8
models, to directly compare across studies because
9 the
general toxicity of the different compounds is
10
quite different and the target organs may be
11
different.
12
MR. GRODECK: So can a similar
cancer risk
13 be
eliminated for adefovir in the same arena?
14
DR. LEWIS: I would imagine that
you would
15
have to look at people who are on hemodialysis to
16 try
and figure that out. I really don't
know. I
17
don't think you can say it is eliminated; it just
18
can't be studied.
19
DR. ENGLUND: Dr. Wood had a
question.
20
DR. WOOD: My apologies, it is
going back
21 to
the post-observational study and this is really
22 a
question for the statisticians. Since we
don't
164
1
know the exact diminishment of what the risk for
2
hepatocellular carcinoma may be in treated
3
patients, is there a lower threshold number below
4
which the 12,500 projected participants would be
5
insufficient to detect an excess cancer risk? So,
6 if
it is 8 is 12,500 still going to be adequate to
7
detect that excess cancer risk potentially, or is
8 it
going to have to expand to 15,000? That
is what
9 I am
looking for, some lower threshold.
10
DR. MORGAN MURRAY: Dr. Pierce can
speak
11 to
what our power to detect will be with that
12
patient population.
13
DR. PIERCE: I want to make sure
this
14
powering that I mentioned is principally for the
15
non-HCC malignancy because really I think that is
16 the
question on the table. So, that is
really the
17
primary goal of this study.
However, what I had
18
wanted to point out, and I think your previous
19
question hinted in that direction, is that those
20
rates that I showed for the HCC were in the
21
non-treated group so that may shrink since both
22
groups will be on treatment to show a diminution in
165
1
those rates between arms. But the
primary
2
objective of this study is those non-HCC cancers.
3
DR. ENGLUND: Thank you. Dr. Seeff?
4
DR. SEEFF: I wonder if I can get
back to
5 the question I posed this morning to see
whether,
6 in
fact, we have the information about the
7
relationship between the primary and the secondary
8
endpoints, and specifically the composite outcome,
9 and
maybe FDA has done that as well. I did
see the
10
composite review but it did not include I think the
11
histology. So, what I am asking
is what happens
12
histologically, virologically and biochemically
13
when you treat with entecavir, and how does it
14 compare
to lamivudine?
15
DR. MORGAN MURRAY: We are doing
those
16
analyses. I am just going to
double check, are we
17
ready to discuss them or do we need some time over
18
lunch? I mean, literally, they
are plugging away
19 as
we are sitting here. Dr. Lewis said she
will
20
start and then Dr. Brett-Smith is prepared to show
21 you
what we have.
22
DR. LEWIS: In the FDA analysis we
did not
166
1
include histology in our composite endpoints. We
2
compared virologic and biochemical analyses,
3
serologic and biochemical analyses.
We did not
4
include histology in that.
However, we are in the
5
midst of actually a larger project using both the
6
adefovir database and this entecavir database to
7
look at many different combinations of outcomes and
8
predictors of outcomes but at this point we have
9 not
completed that because of the time frame
10
required for this review.
11
DR. SEEFF: Let me just be sure
that my
12
question does not impugn this drug.
There is no
13
question that it is a very effective drug in
14
reducing the viral load. But it
seems to me that
15
ultimately the FDA, I think, is going to have to
16
re-think the way it analyzes outcome.
I feel sure
17
that in the future we are going to have to have a
18
composite score to be able to be sure that we
19
understand. If we don't look at
histology and yet
20
histology is the primary endpoint, I don't quite
21
understand why we don't, in fact, include that in
22 the
composite score. It just doesn't make
sense to
167
1
me. Obviously, this is not the
place to discuss
2
this. We are going to have other
meetings to come
3 up
with perhaps better ways of assessing outcome,
4 but
histology is just not in it at the moment.
5
DR. LEWIS: I think we will
probably be
6
discussing this in great detail at a future meeting
7 to
discuss consensus hepatitis B treatment and
8
study design.
9
DR. ENGLUND: One last question?
10
DR. MORGAN MURRAY: Dr.
Brett-Smith is
11
prepared to show that composite analysis.
12
DR. BRETT-SMITH: We actually did
two
13
analyses for you looking at both virologic
14
endpoints. We used the PCR data
in both. So, if
15 we
could show slide 17-1? The 022 naive
e-antigen
16
positive study is on the left, naive e-negative is
17 in
the middle, and refractory is on the right.
The
18 top
line presents those who have histologic
19
improvement and ALT normalization and a DNA less
20
than 400, so the most rigorous virologic endpoint.
21 The
lower line is related more to the current
22
management guidelines and our own management
168
1
guidelines within the study, and does the same
2
analysis, this time with the PCR database, not the
3
bDNA database but using a cutoff of less than 10
5
4
copies/mL.
5
Again, the relationship and the pattern of
6
results for entecavir versus lamivudine is
7
consistent. Overall, the total
response rates are
8
obviously lower by this criterion, and I think it
9
reflects some of what you see in the background
10
document around this sort of issue of correlation
11
across those week 48 endpoints.
12
DR. MORGAN MURRAY: Dr. Cross, do
you have
13
something to add?
14
DR. CROSS: Just in case the
second
15
question is are the differences significant, yes,
16
they all support superiority for entecavir.
17
DR. ENGLUND: Could you state your
full
18
name?
19
DR. CROSS: Anne Cross,
Bristol-Myers
20
Squibb.
21
DR. ENGLUND: Thank you. One last
22
question from Dr. Fish.
23
DR. FISH: For the applicant,
returning to
24 the
pregnancy question, if I may, you reported I
25
think a low number of 41 pregnancies and 1
169
1
unfavorable outcome. The first
question, is there
2
animal pregnancy data? Second, I
was surprised by
3 the
termination rates and I am just wondering if
4 this
is similar to rates seen in other hepatitis B
5
studies, or perhaps related to culture differences
6 and
regional differences where the terminations
7
were occurring, or whether these were perhaps
8
encouraged by the investigator out of fears of the
9
drug.
10
DR. MORGAN MURRAY: First I will
ask Dr.
11
Lois Lehman-McKeeman to address data in animals.
12
DR. LEHMAN-MCKEEMAN:
Nonclinically, as
13
part of the development of entecavir, it was
14
evaluated for embryo toxicity and teratology
15
endpoints in both rats and rabbits.
Essentially,
16
what those data indicated is that in rats there was
17
evidence of some embryo toxicity only at dosages
18
that were maternally toxic. When
we interpret
19
these studies that is an important finding relative
170
1 to
the presence of maternal toxicity. Those
2
dosages that were associated with that effect were
3 at
least 180 times the human exposure. In
rabbits
4
there was again little evidence of embryo fetal
5
toxicity. It was at an exposure
of about 800 times
6
human exposure when it first presented.
So, the
7
nonclinical data suggests no signal for teratologic
8 or
adverse developmental outcome.
9
DR. MORGAN MURRAY: And Dr.
Brett-Smith
10
will address your question on the clinical outcomes
11 and
how they compare with other studies.
12
DR. BRETT-SMITH: In our database and in
13 our
pregnancy CRF forms we do not collect actual
14
data as to the reason for a termination.
15
Therefore, what I am saying is somewhat speculative
16 is
but based on our global experience in the
17
virology group of conducting multinational trials.
18 And
it is important to recognize that, again, there
19 are
many different factors involving, you know,
20
areas outside the U.S. and what is contributing to
21
these termination rates. In a
global sense, as an
22
individual looking at these results across some of
171
1 our
other virology programs including HIV, these
2
early termination rates did not strike us as
3
concerning. I am sure that there
are multiple
4
individual factors for the woman who is pregnant,
5
including some concern about uncertainty.
6
DR. ENGLUND: Well, thank you,
everyone.
7
There will be some more time for questions after
8
lunch. Before we leave, I would
like to remind the
9
committee to refrain from discussing any agenda
10
items or meeting-related questions with each other
11 or
with the sponsor during the lunch hour.
There
12 is,
in fact, a table reserved in the restaurant in
13 the
lobby of the hotel for the committee members
14
where you can have a seat and pay for yourself.
15
Thank you. The meeting is
adjourned for lunch.
16
[Whereupon, at 11:57 am., the proceedings
17
were adjourned for lunch, to reconvene at 1:05
18
p.m.]
19 - - -
172
1
A F T E R N O O N P R O C E E D I
N G S
2
DR. ENGLUND: Welcome back to the
3
continuation of the new drug application 21-797 and
4
21-798 for entecavir tablets and oral solution. At
5
this point we have an opportunity for an open
6
public hearing, and no one has previously
7
registered to have themselves heard, and I would
8
just like to make sure that there is no person
9
present that would like to have a discussion as
10
part of this open public hearing.
If not, then we
11 won't
have it and we will go on to the next
12
discussion and at this point I
would like to ask
13 Dr.
Debra Birnkrant to come up and give us our
14
charge.
15
DR. BIRNKRANT: Good afternoon and
welcome
16
back to the advisory committee meeting.
What did
17 we
hear this morning? We heard that chronic
18
hepatitis B infection is a serious disease, with
19
very limited treatment options.
You also heard I
20
believe that the agency and the applicant agree on
21 the
safety and efficacy findings. We also
heard
22
about issues related to animal carcinogenicity
173
1
findings.
2
Now, this is a very unique situation
3 because
we have a disease caused by hepatitis B
4
virus which, in and of itself, has been
5
characterized as a carcinogen, and we have a
6
treatment that appears to be highly effective and
7
safe but happens to have positive animal findings.
8
There is also literature that was mentioned, and
9
those references support that treatment with
10
decreasing hepatitis B virus DNA may actually
11
translate into perhaps a decreasing cancer risk.
12
So, what is the bottom line? The
bottom
13
line is that the relevance to humans with regard to
14 the
animal findings is unknown and at this point in
15
time we can't really quantitate the risk. But what
16 can
be done is further study and then we will
17
specifically be asking you about the applicant's
18
proposed pharmacovigilance study which is a part of
19
their pharmacovigilance program.
20
So, with that, I would like to turn it
21
back to Dr. Englund for the discussion period prior
22 to
the question and answer period. Thank
you.
23
DR. ENGLUND: Thank you. I just want to
24
make sure, before we go to the specific questions
25 for
the committee--we have one or two minutes if
174
1
there are short questions that anyone has that we
2
didn't address before lunch. Dr.
Sun?
3
DR. SUN: Yes, I have a question
for Dr.
4
Farrelly which he may or may not be able to answer,
5 but
to the extent that he can describe the
6
rationale of the CAC committee opinion, why did 16
7 or
17 members--what was the rationale for the
8
opinion on the mouse lung tumor findings? Why was
9 the
vote so positive in terms of the clinical
10
relevance? My question is did
they not find the
11
mechanistic explanation that the sponsor proposed
12 to
be compelling?
13
DR. FARRELLY: Yes, most of us did
I
14
think. Most of us felt the
explanation was quite
15
compelling. Some said it wasn't
proven but in
16
general it was pretty good. There
was some concern
17
about people who smoke taking entecavir who don't
18
have the same lungs as people who don't smoke.
19 They
will have some cells that are turning over in
175
1 the
lung. They may have some macrophage
invasion.
2 I
think the point was that most of the people on
3 the
committee felt that, yes, there was some human
4
concern about a drug that does induce tumors in an
5
animal models whose cells are proliferating. I
6
think if you look at some of the drugs that induce
7
cytochrome p450, many of those drugs are liver
8
carcinogens and one of the reasons may be because
9
what they are doing is they are making the liver
10
turn out these enzymes and for the lifetime of an
11
animal whose liver cells are turning over, and
12
over, and over, one sees tumorigenesis.
So, I
13
think most people felt that for the people who
14
might be smokers there might be some risk, but in
15
general I would think there is very little risk for
16
folks who aren't smokers. Now, in
Asia there is a
17
very high percentage of people who smoke. I think
18
that was much of the reasoning, although I can't
19 get
inside the head of everybody.
20
DR. ENGLUND: And one other
question by
21 Dr.
Bell?
22
DR. BELL: Yes, just another brief
176
1
question, you mentioned earlier the difference in
2 the
magnitude of how carcinogenic some of the other
3
antivirals were compared with this drug--
4
DR. FARRELLY: Right.
5
DR. BELL: --and to the extent
that you
6 can
help us even further put that into context, at
7
least that would be helpful to me, you know, how
8
"bad" is this in comparison to other similar
9
compounds?
10
DR. FARRELLY: Most of the tumors
that
11
arise here arise at fairly high multiples of the
12
human exposure. We usually go by
three different
13
ways: The comparison of nominal
dose between the
14
animals and humans, which is usually the worst way;
15
body surface area, body surface area is pretty good
16 for
drugs that are not metabolized and that are
17
eliminated by body surface area phenomena. So, for
18
drugs that are not metabolized and are passed
19
through the kidney body surface area is usually a
20
very good way to do it. But the
exposures in the
21
animals and the exposures in the clinic are known
22 for
this drug so we use the exposures. For a
lot
177
1 of
the other drugs we have done the exposures.
2
To give an example of two of the drugs
3
that we have boxed warnings for, one of them is
4
cidofovir and this is the drug that is approved for
5
hepatitis--no, it is adefovir; it is a relative of
6
adefovir. It is a nucleotide
analog that is fairly
7
similar in structure. When the
drug was being
8
developed for CMV retinitis in AIDS patients the
9
studies were stopped for a while because it was
10
found in a three-month study in rats that after six
11
doses, one dose a week for six doses, palpable
12
mammary adenocarcinomas could be found in the
13
animals. The argument was made
that they are
14
probably there because the drug actually was given
15 to
the animals subcutaneously and it was felt that
16
mammary tissue was being flooded by higher
17
concentrations of the drug. So,
we asked that a
18 different
route of administration be used so the
19
sponsor did intravenous administration and, lo and
20
behold, the same tumors showed up again.
21
When we looked at the exposure in the
22
animal studies compared to the exposure in the
178
1
clinic, it was much lower than 1.
I mean, it was
2
very difficult to calculate; it was about 0.1. So,
3 we
felt that there was great concern over that drug
4 because it gave tumors that killed all the
rats in
5
really short-term studies. So,
there are no
6
carcinogenicity studies carried out on cidofovir.
7
Although we do have in the label that in a one-year
8
study in monkeys there were no tumors seen, but
9
there were only a few monkeys in that study so it
10 is
hard to say. That is not a
carcinogenicity
11
study and that is pointed out.
12
Ganciclovir is very similar. It
is a CMV
13
retinitis drug. It is interesting
that ganciclovir
14 and
cidofovir are for the same indication.
15
Ganciclovir gave a very high incidence of tumors in
16
lots and lots of tissues in the mouse at a tenth of
17 the
exposure in the clinic or at 1.-something the
18
exposure, about 1-fold the exposure.
There were a
19 lot
of tumors, a lot of mouse specific tumors in
20
tissues that don't exist in the human.
Rats don't
21
have a gallbladder so you will never see a
22
gallbladder tumor in rats--you know something is
179
1
wrong if somebody examined the gallbladder. But we
2
were very concerned that a lot of different tumors
3
showed up and many of the tumors were vaginal
4
tumors but at very, very low doses, and those are
5 the
things we look for when we are trying to get a
6
comparison between the animal studies with the
7
clinical studies.
8
As was mentioned earlier, we do the same
9
thing for the reproductive toxicity studies so that
10
when entecavir was looked at in reproductive
11
toxicity studies you only saw really bad results
12
when there was lots of toxicity to the dams. What
13 we
usually look for is at doses lower, where there
14 is
no toxicity to the dams even though it is maybe
15
50-fold or 10-fold or, probably in this case,
16
100-fold and if we see nothing that indicates the
17
type of things that we saw with the toxicity in the
18
dams we are much less concerned.
19
So, as Debby or Linda said, on a
20
case-by-case basis you look at the studies. This
21
drug gives tumors. The studies
were good. The
22
studies were carried out very nicely.
It gave
180
1
tumors, but most of the tumors were at fairly high
2
doses and, like I said and like Dr. Sun said, it
3
looks like the company made a pretty good case for
4
lung specificity in mice although it is not proven.
5
Does that help?
6
DR. ENGLUND: Thank you. Dr. Munk?
7
DR. MUNK: Yes, I have a question
about
8 the
distribution over time of the malignancy
9
diagnosis. There is a figure in
our binder on page
10 84,
figure 7.5.2--
11
DR. ENGLUND: This is the sponsor
12
background.
13
DR. MUNK: --saying that the
greatest
14
number of new diagnoses was made between weeks 24
15 and
48 showing a similarity between entecavir and
16
lamivudine and that they levelled off and go
17
essentially almost down to zero after 72 weeks. I
18
guess I would just like some explanation of that.
19 It
says "may reflect the on-study diagnosis of
20
tumors that were latent at the time of enrollment."
21
Now, does this imply that it took a while for the
22
drugs to have an anti-tumor effect, or does it
181
1 imply
somehow that the treatment stimulated the
2
tumors into a state of activity where they could be
3
diagnosed?
4
DR. MORGAN MURRAY: I would like
Dr. Di
5
Bisceglie to comment on that, please.
6
DR. DI BISCEGLIE: Adrian Di
Bisceglie.
7
What I can comment on are the hepatocellular
8
carcinomas, not the other cancers.
To look at
9
this, I had done an analysis of the tumors that
10
developed in the study cohort.
There were 11
11
patients with HCC. Of those 11,
there were 6 in
12
whom the tumor size was known at the time of
13
diagnosis.
14
Is that slide available, my slide?
15
Thanks, if you could put that up for me.
What I
16 did
with those tumor sizes is, based on these known
17
data of growth rates of HCC--this is from published
18
data in Taiwan based on increased tumor diameter by
19
ultrasound--you see that the median doubling time
20 of
HCC is 117 days. The range is from 29
days up
21 to
about 400 days. So, first, there is a
broad
22
range. But what I did was I took
the worst-case
182
1
scenario, what if this was the most rapidly
2
doubling tumor, 29 days, and I looked at these 6
3
tumors and tried to figure out when they may have
4
arisen.
5
Each of those lines represents 1 of the 6
6
cases. They are numbered, 1, 2,
3, 4, 5, 6 whether
7
they were receiving lamivudine or entecavir, and
8 the
top diamond shows the tumor volume, not the
9
tumor diameter but the tumor volume.
If we take
10
tumor doubling time of 29 days, that worst-case
11
scenario, and then backtrack to when the tumor
12
arose when it was about 1 mm in diameter, you will
13 see
that in 5/6 cases we would predict it would
14
have arisen many months prior to the onset of
15
therapy.
16
Next slide. Finally, this one
tumor that
17 was
the latest developing, if you take the median
18
doubling time, not the worst-case scenario but the
19
median doubling time, you can see that tumor might
20 be
predicted to have arisen nearly two years prior
21 to
the onset of therapy. So, that is what I
can
22
address.
23
DR. MUNK: I guess my question is
why are
24
they not detected when patients enter the studies,
25 and
is this perhaps an issue of them being
183
1
monitored more closely after they are in the study,
2 or
what is going on her?
3
DR. MORGAN MURRAY: Dr.
Brett-Smith?
4
DR. BRETT-SMITH: The entecavir
studies
5
actually did minimal monitoring for tumors prior to
6
study entry in the sense that we wanted to see
7
all-comers. Therefore, we did
have alpha
8
fetoprotein criteria but, beyond that, and if
9
people were over an alpha fetoprotein of 100 you
10 had
to have an ultrasound to screen. Other
than
11
that, there was not routine ultrasound screening
12
done so many of these patients came in with no
13
screening particularly for HCC.
14
The point of the comment about some of the
15
tumors, whether HCC for which I think you have
16
heard a nice argument, or non-HCC might precede the
17
onset of enrollment to the study is, I think, an
18
issue in any cohort that sort of comes into medical
19
care and then is followed.
20
DR. ENGLUND: Thank you. This is
21
absolutely the last question but I know you didn't
22 get
a chance before.
23
DR. GERBER: It is a very short
question,
24
just related to the post-marketing surveillance for
25
ganciclovir. Is there any signal
that caused
184
1
increased tumors in people or not?
2
DR. LEWIS: There was no specific
3
post-marketing study required after the approval of
4 ganciclovir. At the time, there was no other
5
treatment approved for CMV retinitis in HIV
6
patients and those patients' survival was very
7
limited after that period. So,
there has been no
8
formal study but there has clearly been more
9
extensive use of the drug and, as far as we know,
10
there has not been any report of an epidemiologic
11
study linking increased tumors.
12 Questions to the Committee
13
DR. ENGLUND: Well, thank you, everyone.
14 We
are now going to proceed to our questions.
For
15 at
least the first two questions I will read the
16
question and I would like to have us go around the
185
1 table
just to make sure everyone has time to say or
2 ask
a question or give an opinion. This is
not a
3
vote. This first phase is the
discussion phase for
4
question number 1.
5 Question No. 1
6
Question number 1 is how would you assess
7 the
risk-benefit of entecavir in the context of the
8
available clinical safety, efficacy, resistance,
9 and
nonclinical carcinogenicity data?
10
For this period you really only get two
11
minutes so it is not that you get to expound a
12
whole lot but we would like to hear your opinions,
13
your concerns. We have some
experts in different
14
fields on the committee and it would be really
15
helpful to have people address some of the things
16
that their expertise addresses.
So, with that, I
17
think I am going to take the chairman's prerogative
18
and, Dr. Schwarz, you are going to be nominated to
19 go
first, if you don't mind.
20
DR. SCHWARZ: Well, I have
prepared a
21
series of comments for the specific role of
22
possible future pediatric studies so I think I will
186
1
defer to that.
2
DR. ENGLUND: Great, and we need
those but
3 why
don't we go on? Dr. Bell?
4
DR. BELL: I am also not sure that
I am
5 the
right first person to comment on the answer to
6
this question in that a lot of my expertise is more
7 in the epidemiologic aspects of this rather
than
8 the
clinical aspects.
9
DR. ENGLUND: You can come back
later.
10 Dr.
So?
11
DR. SO: I guess I have to say
something,
12
right? I think the sponsor has
demonstrated that
13
this is a very effective drug in suppressing HBV
14
replication. Based on the data
presented, I think,
15
apart from the potential carcinogenicity problem,
16 it
seems like a pretty safe drug for treatment of
17
this problem.
18
I agree with some of my colleagues that,
19 you
know, with these drugs over time, even though
20 at
the moment you don't see any development of
21
resistance or mutants at one year, with time I am
22
sure you are probably going to find more of that.
187
1 If
you look at the group where entecavir was used
2 in
the treatment of lamivudine-refractory patients,
3 you
can already see that at one year. The
FDA data
4
show about 7.4 percent already showing some
5
entecavir-resistant mutants, although only about
6 one
percent caused a rise in the DNA level.
But
7
overall I think I am pretty favorable on this drug.
8 DR. ENGLUND: Dr. Seeff?
9
DR. SEEFF: I agree that this is a
very
10
good drug. This is a bad disease
and we need
11
treatments. We have three other
treatments and I
12
think that this drug has some advantages that the
13
others don't have, namely at least at this point,
14 the
lower rate of mutant strains developing and no
15
different toxicity. There is the
potential of
16
malignancy and I think that that is an issue that
17
needs to be addressed, but I think that in the
18
context of where we are I believe this is a good
19
drug, worth supporting and should be used.
20
I do believe that the concerns that have
21
been expressed, even though there is some
22
information that has gone some way to allay my
188
1
original anxiety because I was really concerned
2
about the malignant potential, I do think that,
3
obviously, the pharmacovigilance studies that have
4
been suggested are critically important and need to
5 be
done, looking both for outcome with respect to
6
malignancy and to the issue of the development of
7
mutagenic strains. So, I agree
that I would
8
support the approval of this drug.
9
DR. ENGLUND: Dr. Munk?
10
DR. MUNK: I agree that this drug
appears
11 to
represent a significant addition to the
12
armamentarium against hepatitis B.
One of the
13
factors that impresses me is the lack of
14
interactivity with HIV medications, the fact that
15
there is no cyp3A involvement which should make it
16
easier for a physician to prescribe in a
17
co-infected patient.
18
I guess I am concerned about the
19
implementation of the long-term follow-up study. I
20
have some concerns about that for carcinogenicity
21 and
I am assuming that there will be inevitable
22
clinical follow-up of emergence of resistance
189
1
mutations as there has been for every other
2
antiviral drug.
3
DR. ENGLUND: Dr. Haubrich?
4
DR. HAUBRICH: The risk-benefit
for any
5
drug is clearly dependent upon the disease being
6
studied. If entecavir was an
anti-retroviral that
7 had
7 logs reduction with little development of
8
resistance by 48 weeks we probably would all be
9
home now.
10
[Laughter]
11
Even accounting for the fact that it is 2
12
logs better than a previously approved drug, you
13
would have the same conclusion.
So, I think that
14 the
efficacy data, the safety data, the resistance
15
data, although I might characterize it perhaps a
16
little bit differently, clearly show the drug has
17
great activity, and the only negative, the only
18
thing that is even a question at all is these
19
animal data. So, given the need
for further
20
therapies for hepatitis, as well as the greater
21
demonstrated efficacy, I think a plan of use of the
22
drug with careful monitoring should be done. When
190
1 we
get to the questions about monitoring I will
2
have some comments on that.
3
DR. ENGLUND: Dr. Bartlett?
4
DR. BARTLETT: As an HIV clinical
5
investigator, I have a few comments.
I am
6
impressed that the safety of this drug is similar
7 to
lamivudine. I am impressed that its
antiviral
8
efficacy is better than lamivudine.
In the short-
9
term the resistance appears to be less than with
10
lamivudine. I think there may be
an opportunity
11
here with lamivudine-resistant virus to look at
12
some of the challenges in treating those patients,
13 and
it may be that in that arena some form of
14
combination therapy for hepatitis B may be
15
necessary.
16
I am still a bit uncertain about
17 interactions between anti-retroviral drugs and
18
entecavir. It appears, based on
in vitro studies,
19
that there shouldn't be any problems but the proof
20 of
the pudding is always what happens in patients,
21 and
I will be keen to see what happens in
22
co-infected patients as that data set matures.
23
The context of the animal carcinogenicity
24
data is reassuring and I am reassured to hear Dr.
25
Farrelly's comments. I think the
proposed
191
1
pharmacovigilance study is reasonable although
2
there are a lot of details that remain to be worked
3
out, and I think it would really be crucial to have
4
diligent follow-up of those patients in order to
5
achieve the desired goal.
6
DR. DEGRUTTOLA: Victor
DeGruttola. From
7 the
information that has been developed to date,
8 the
risk-benefit profile of entecavir appears very
9
favorable. The issue has been
discussed about
10
uncertainty regarding future risk of malignancy.
11 So,
it will be important to discuss and develop an
12
appropriate plan to evaluate that risk over time.
13
DR. ENGLUND: Mr. Grodeck?
14
MR. GRODECK: As a person who wakes up
15
every morning with the very real threat of liver
16
cancer, I think that the risk-benefit of entecavir
17
right now is positive. It is a
hypothetical cancer
18
threat of the future and a very real threat of
19
liver cancer from the virus itself.
Now, ten years
192
1
from now will I feel the same way?
It is unknown
2 but
today, given the drugs that are out there, I
3
think the benefits outweigh the risks.
4
DR. ENGLUND: Dr. Wood?
5
DR. WOOD: I would have to concur
with the
6
comments of all of my previous colleagues regarding
7 the
favorable risk-benefit profile for this drug
8
regarding specifically the efficacy, clinical
9
safety and the resistance data.
Given this signal
10
that has been detected in preclinical animal model
11
carcinogenicity studies, I do think that we have to
12 say
that that signal is significant. I do
think
13
that the sponsor's explanation of the signal
14
attributed to pulmonary tumors in mice is
15
satisfactory.
16
My major concerns are that since this
17
signal is significant, we do know that it is
18
impossible and it is unknown as to how this
19
significant signal may translate into a clinically
20
significant risk or hazard. So,
since the risk is
21
unknown and can't be known, my major concerns are
22
being able to detect excess non-HCC malignancy, if
193
1 it
occurs, as soon as possible, which really
2
relates to the post-marketing study and monitoring.
3
The second issue is something that we have
4 not
discussed really, and that relates to the
5
duration of exposure to the drug.
Since
6
presumably, if there is increased risk associated
7
with exposure to the drug--I don't really have a
8
sense or a handle on how long people are going to
9 be
treated. And, if it is a recommended
period or
10 if
it is indefinite the presumption would be that
11 if
the exposure is going to be very, very long it
12
might carry with it an increased risk.
So, that is
13 an
issue if we can address possibly that I would
14
like to try.
15
DR. ENGLUND: Dr. Paxton?
16
DR. PAXTON: I just want to add my
17
thoughts. As an HIV
epidemiologist, I am more
18
accustomed to thinking on the population level and
19 I
am impressed by what I have seen today about the
20
potential of cost benefit analysis for this drug,
21
particularly given the limited options that are
22
currently available to us and the strong efficacy
194
1
results from this drug.
2
In my mind, and I think in the minds of
3
other people, there really is no other way to
4
resolve this issue of the potential malignancies
5
except to do the post-marketing vigilance study.
6 So,
it is going to be in our best interest to make
7
sure that that is done to the best possible
8
standards within the limitations, like the possible
9
crossover of drugs during the study.
But my
10
general comment is that I think I would recommend
11
approval for this particular drug.
12
DR. ENGLUND: Dr. Johnson?
13
DR. JOHNSON: I am not going to
echo what
14 has
already been said. I will focus my
comments on
15
resistance. I agree that the
risk-benefit profile
16 is
positive in all aspects of what was in question
17
1. I think the company is to be
commended for the
18
thoroughness of the available data to date but, as
19 I
mentioned earlier as a cautionary note, given its
20
superb potency and its durability of response over
21
such a long time, I think we have an incomplete
22
resistance story and I think follow-up will be
195
1
needed in both the treatment-naive and the
2
treatment-experienced subjects to really understand
3
what the resistance pathways are for this drug. We
4
know that if we were meeting in two years and we
5
were presented data sets of the virologic
6
breakthrough at the highest baseline HBV subjects,
7 the
company would have that data set and we will be
8
eager to see that in their vigilance surveillance
9 of drug
resistance, and we encourage them to keep
10
putting out the data. Thank you.
11
DR. ENGLUND: Dr. Sherman?
12
DR. SHERMAN: First, I would like
to also
13
commend the sponsor of this drug and the agency for
14 their detailed and thorough analysis. As a
15
hepatologist, I think this drug will add
16
significantly to the tools we have available to
17
treat patients with liver disease, and overall the
18
risk-benefit ratio is clearly in favor of moving
19
forward with approval of this drug, particularly in
20 the
e-antigen positive and e-antigen negative naive
21
population. I think that it will
probably come up
22
under the question of the role of this drug in
196
1
terms of the lamivudine-resistant population and
2 the
best way to manage those patients, and that
3
discussion will follow.
4
DR. ENGLUND: Dr. Herbert?
5
DR. HERBERT: I am a veterinary
6
pathologist and my expertise with the National
7
Toxicology Program is in rodent carcinogenicity
8
studies so my comments are going to be based on
9
that expertise. I agree, and I
want to applaud the
10
applicant. The rodent studies
were thorough and
11
well conducted. Although the drug
seems to be
12
carcinogenic at several sites, I think that the
13
carcinogenicity is shown at multiples of doses that
14 are
significantly higher than in human exposure.
15 In
my estimation, based on those results, I think
16 the
benefits of this drug outweigh the risk and I
17
would be in favor or approval.
18
DR. ENGLUND: Thank you. Dr. Fish?
19
DR. FISH: As a clinician and
clinical
20
researcher who takes care of HIV-infected
21
individuals, many of our patients are co-infected
22
with hepatitis B and hepatitis C, as you know.
197
1
This is a disease that does have and can have
2
devastating consequences, including the significant
3
potential for malignancies which is a reality for
4
these folks on a daily basis. I
think that the
5
breadth of the trial data that was presented was
6
very impressive and highly convincing.
Certainly,
7 the
7-log drop that Dr. Haubrich mentioned is quite
8
impressive. The breadth, in terms
of its
9
multinationality, the differing populations that
10 have
been studied and studies that are ongoing, I
11
find impressive.
12
Also, I think the collaboration, the
13
briefing document--and I wonder about that name;
14
they are not so brief--have lots of good
15
information where there was obvious collaboration,
16
back and forth between the sponsor and the agency
17
that really seemed to culminate in having a good
18
product in the end. So, in my
opinion the
19
risk-benefit ratio is favorable, highly favorable.
20
DR. ENGLUND: Thank you. Dr. Washburn?
21
DR. WASHBURN: As an antifungal
22
investigator, I am a fish totally out of water--
23
[Laughter]
24
--but I do have ears and I have been
25
listening carefully all day, and my response is
198
1
that the risk-benefit ratio appears acceptable, and
2 I
will be looking forward over the coming years to
3
learning more about drug interactions, a topic on
4
which we haven't heard much today.
5
DR. ENGLUND: Dr. Gerber?
6
DR. GERBER: Yes, I am a clinical
7
pharmacologist as well as a clinical infectious
8
disease specialist, and I think this drug, in terms
9 of
nucleoside analogs, has an extremely favorable
10
risk-benefit ratio. I was quite
impressed with all
11 the
data.
12
Unlike Dr. Bartlett, I am much less
13
concerned about drug interactions.
The in vitro
14
data seem extremely convincing that we shouldn't be
15
expecting drug interaction with HIV drugs.
16
Overall, I think if you look at other nucleoside
17
analogs--famciclovir as an example and
18
ganciclovir--that have tumor producing properties,
19 I
think this drug actually performs better overall.
199
1 So,
I feel that this is very favorable.
2
DR. ENGLUND: Dr. Sun?
3
DR. SUN: Actually, I thought that
the
4
answer to this question is best stated by a single
5
sentence in the FDA briefing document on page 22,
6
which I was just going to read, not that there
7
weren't other good sentences in the document--
8
[Laughter]
9
--it says, "these positive findings from
10 the
entecavir studies must be weighed against
11
findings that are less clearly understood." I
12
think you will notice the word "risk" does not
13 appear in there and I think this is carefully
14
worded to indicate that what we are talking about
15
that is of potential concern is a finding that is
16 of
questionable clinical relevance. I think
the
17
benefit of the drug is very clear.
It is a very
18
clear and very clean win in all the studies they
19
have done. It is clear in a
disease with high
20
morbidity and high mitochondria.
But the answer to
21 the
question, unfortunately, can only be answered
22 by
the kind of post-marketing surveillance study
200
1
that they have decided to undertake, which I would
2 say
is a very significant undertaking but,
3
unfortunately, there is really no other way to
4
answer the question.
5
DR. ENGLUND: Thank you. Before I
6
summarize, are there any questions or additions
7
from Dr. Schwarz or Dr. Bell?
8
DR. BELL: No, I pretty much agree
with
9 what
everybody has said. The one small point
I
10
would make is on the topic of the various patient
11
populations that have been studied, which certainly
12 is
a very extensive study but just, for example, to
13
remind people of Dr. Lewis' point about the very
14
small proportion of African American patients in
15
these populations. I am sure
there are a lot of
16
potential explanations for why this might be the
17
case, but it is something that I think we don't
18
want to forget about and perhaps will need to be
19
dealt with as we go forward.
20
DR. ENGLUND: Well, thank you,
everyone.
21 If
I may take the prerogative of just doing a brief
22
summary, and then we are actually going to put this
201
1 to
a vote for question 2. But to summarize,
I
2
think I have heard quite universal opinion that
3
there is a favorable risk-benefit for the drug
4
entecavir. The enthusiasm perhaps
is relatively
5
high. There remain concerns about
resistance,
6
well-founded concerns and well-founded concerns
7
about details of the pharmacovigilance study which
8 I
think we are going to be able to address later on
9
this afternoon.
10
I think that we all have appreciated the
11
input on the carcinogenicity story from both the
12 FDA
and from Dr. Herbert also. It is very
good to
13
have more input in this as many of us, clinicians,
14
don't have expertise in this, and it is reassuring
15 to
hear similar stories from the company, the FDA
16 and
from our own independent person here.
17
As was stated by our--what are you?
18
Civilian representative?
19 MR. GRODECK: Patient representative.
20
DR. ENGLUND: I think that we are
dealing
21
with very real risks of hepatitis B.
I see the
22
patients. If we don't see the
patients, some of us
202
1 are
evaluating the numbers and looking at the
2
outcomes of these patients and the very, very real
3
risk versus theoretical concerns which do need to
4 be
followed up. I hear there are cautionary
notes
5
concerning resistance and concerning how we are
6
going to do post-surveillance, but that overall, as
7 a
group, we are finding quite good benefit of this
8
particular compound.
9
So, that is what I have heard as a group.
10 At
this point I would like to move to question
11
number 2, and this part is only for the voting
12
representatives, which is most of us.
I am just
13
going to call you off in the order that you are
14
listed, and I don't know what order it is but it is
15
nothing personal. Dr.
Gerber? You need to say yes
16 or
no.
17 Question No. 2
18
The question is, number 2, does the
19
risk-benefit assessment for entecavir support the
20
approval of entecavir for the treatment of chronic
21 HBV
in adult patients? And you are allowed
to
22
answer yes, no or abstain.
23
DR. GERBER: Yes.
24
DR. ENGLUND: Dr. Washburn?
25
DR. WASHBURN: Yes.
203
1
DR. ENGLUND: Dr. Fish?
2
DR. FISH: Yes.
3
DR. ENGLUND: Dr. Herbert?
4
DR. HERBERT: Yes.
5
DR. ENGLUND: Dr. Sherman?
6
DR. SHERMAN: Yes.
7
DR. ENGLUND: Dr. Johnson?
8
DR. JOHNSON: Yes.
9
DR. ENGLUND: Dr. Paxton?
10
DR. PAXTON: Yes.
11
DR. ENGLUND: Dr. Wood?
12
DR. WOOD: Yes.
13
DR. ENGLUND: Dr. Grodeck?
14
MR. GRODECK: Well, I am not a
doctor but
15 I
would still vote yes.
16
DR. ENGLUND: Dr. DeGruttola?
17
DR. DEGRUTTOLA: Yes.
18
DR. ENGLUND: Dr. Bartlett?
19
DR. BARTLETT: Yes.
20
DR. ENGLUND: Dr. Haubrich?
21
DR. HAUBRICH: Yes.
22
DR. ENGLUND: Dr. Munk?
23
DR. MUNK: Yes.
24
DR. ENGLUND: Dr. Seeff?
25
DR. SEEFF: Yes.
204
1
DR. ENGLUND: Dr. So?
2
DR. SO: Yes.
3
DR. ENGLUND: Dr. Schwarz?
4
DR. SCHWARZ: Yes.
5
DR. ENGLUND: Dr. Bell?
6
DR. BELL: Yes.
7
DR. ENGLUND: And I am Dr. Englund
and I
8 am
going to vote yes, and that makes it a unanimous
9
vote so we do not have to address question 2B so we
10
have already eliminated some of our work.
11 Question No. 3
12
For question 3 I would like to have a
13
little bit more discussion, particularly from those
14
people who have the expertise. We
have kind of
15
addressed this already but I would like to formally
16
answer the question.
17
Question 3A states, if the answer to
18
number 2A is yes, which it is, discuss whether the
19
results of the rodent carcinogenicity studies
20
should impact the indication and usage section of
21
product labeling.
22
That is 2A, and 2B is discuss the
23
potential role. But I think
question A really is
24
important. I guess I would ask
first from the FDA
25 if
you could explain does this mean either a black
205
1 box
or a warning? Could you explain
specifically
2
what you want?
3
DR. BIRNKRANT: I will clarify
that
4
question. What we were interested
in was, given
5
that the presentation appeared as though the drug
6 was
being presented such that it would be
7
first-line therapy, given the findings of the
8
animals, we wanted somewhat of a discussion on
9
whether or not the committee would consider
10
anything else other than a first-line indication.
11 We
specifically asked about indications in the
12
usage sections of the product labeling.
We can
13
talk about other sections of the labeling as well
206
1 but
first I would like to address the indication
2 and
usage section which we can expand with
3
additional information that will be helpful to
4
practitioners with regard to use of this drug in
5
various populations.
6
DR. ENGLUND: So, this first part
is
7
indications and usage and then the carcinogenicity
8
could actually be a little discussion.
9
DR. BIRNKRANT: Right.
10
DR. ENGLUND: I would like to ask
some of
11 our
hepatologists to comment first on this, if I
12
may.
13
DR. SHERMAN: There are two of us.
14
DR. ENGLUND: Good.
15
DR. SHERMAN: I think that the
drug should
16 be
labeled for first-line therapy, and I think that
17 it
will be an important addition for the treatment
18 of
those patients. The carcinogenicity
listings
19 and
what should be put into that label--I think
20
that a black box warning is not indicated at this
21
stage, based on what type of reporting has been
22
used for other drugs. Until we
see a clinical
207
1
signal of some sort in humans, or at least a
2
primate, it is not a reason to go ahead and issue a
3
specific warning in that regard.
All of these
4
patients need to be monitored for malignancy,
5
particularly hepatocellular carcinoma, and I don't
6
know if the label is the place to do that but that
7
certainly should be part of the standard of care of
8 the
management of patients with chronic hepatitis B
9
infection.
10
The patients that have lamivudine
11
resistance, which means second-line therapy, I
12
think represent a group that I would turn and ask
13
first the agency and then the company to provide
14
information about comparisons with other available
15 products in terms of efficacy prior to stating
that
16
that is a group. It is clearly
safe; it is clearly
17
efficacious relative to lamivudine but is it the
18
best first-line therapy or second-line in a sense
19
that the patients who are lamivudine-resistant
20
already have been on lamivudine.
21
DR. ENGLUND: Dr. Seeff?
22
DR. SEEFF: I agree with Ken that
this
208
1
should be labeled a first-line drug.
I do think
2
though that there should be mention, not in a black
3
box, of the fact that studies have shown that there
4 has
been development of cancer in animals, and I
5
think it is fair enough, if it possible to do this,
6 to
discuss the issue that this is at a much higher
7
dose than one would normally use and there is
8
little concern. But the other
side of the coin is
9
that, in fact, this drug may lower the rate of
10
liver cancer by, in fact, reducing disease
11
progression and may be beneficial with respect to
12
liver cancer and not harmful. But
I cannot see
13
that there could not be at least mention of this in
14 the
insert but I don't think a black box is needed.
15
DR. ENGLUND: I am going to call
on people
16
unless people want to volunteer.
Dr. Bartlett?
17
DR. BARTLETT: Well, certainly I
would
18
agree that it seems that it is indicated for
19
first-line treatment. I would
share Dr. Sherman's
20
question back to the agency about second-line
21
treatment, whether it needs to be compared to
22
adefovir or tenofovir to have that indication. But
209
1 I
agree with the comments previously made.
2
DR. ENGLUND: Dr. Gerber?
3
DR. GERBER: I also agree with
everything
4
that has been said. This should
be a first-line
5
treatment. I think in most viral
diseases-and I
6
have a lot of experience treating HIV--we try to
7 use
the most effective therapy that doesn't result
8 in
resistance and this seems to be the case right
9 now
for all the drugs that are available.
So, I
10
think it should be first line.
11
DR. ENGLUND: Dr. Johnson?
12
DR. JOHNSON: I agree with the
first-line
13
label. I think, as was written in
the materials,
14 we
saw data presented for second-line indication
15
versus lamivudine and other drugs out there. So, I
16
think the agency and sponsor should be encouraged
17 to
further study second-line therapy in comparative
18
studies; combination drugs, because of the
19
likelihood of emergence of further resistance
20
across resistance within the nucleoside class but,
21
clearly, first-line therapy could be put in the
22
label.
23
DR. ENGLUND: Dr. Haubrich?
24
DR. HAUBRICH: Well, I was going
to play
25
devil's advocate and say that, in fact, the best
210
1
efficacy, although in smaller numbers, is with
2
patients that have lamivudine failure.
If you are
3
looking at the risk-benefit, people that need it
4 the
most have the most benefit so any potential
5
risk from cancer is lower.
6
On the other hand, I think that arguments
7
from members of the committee have convinced me
8
that that risk is fairly low so I would then agree
9
with the first-line indication and I probably would
10 say
that it has shown good efficacy in second-line
11
failure as well and would not restrict it based on
12
that. So, I would probably allow
both.
13
DR. ENGLUND: Dr. Wood?
14
DR. WOOD: I concur that there is
clearly
15 an
indication for first-line therapy. I
also agree
16
that there appears to be very strong evidence for
17 its
efficacy as second-line treatment. I do
think
18
that in the indications and usage one of the
19
phenomena that occurs is that once a new drug is
211
1
licensed and approved and it is highly potent--7, 9
2
logs is head-spinning for many individuals so there
3 is
a tendency to put individuals who are the
4
sickest and rush them to the new agent and I think
5
there would need to be some comment about the fact
6
that individuals with decompensated liver function
7
actually had higher SAEs than individuals with
8
compensated liver function. So,
there would be
9
that kind of precaution in the clinical sphere. I
10
also agree that based on the FDA's historical data
11
about what has been done on a case-by-case basis
12 for
ganciclovir and other drugs the carcinogenicity
13
signal that came from the animal studies does not
14
warrant a black box warning.
15
DR. LEWIS: Janet, could I answer
some of
16 those
questions to the FDA?
17
DR. ENGLUND: Sure, Dr. Lewis.
18
DR. LEWIS: The question was asked
about
19
comparisons in second-line therapy after lamivudine
20
failure. The one thing that I can
say is that if
21 you look at the current adefovir product label
22
there is a very small study in
212
1
lamivudine-refractory patients that is listed in
2
that label. The endpoints were
not really similar
3 and
it is hard to do cross-study comparisons but
4 the
study that Bristol-Myers Squibb has completed
5 is
a much larger study and looked at a good number
6
more endpoints, including histology.
So, there is
7 the
evidence that was presented today in the 026
8
study that would support that kind of an
9
indication.
10
The other question that came up about
11
alternatives to putting in carcinogenicity data,
12
almost every product label that is issued has a
13
section that is devoted to carcinogenicity and
14
mutagenicity. What those sections
do is they
15
describe the findings in the studies with the
16
ranges of multiples over which the studies are
17
conducted so that you can determine whether it is
18
very close to the human dose or many, many times
19 the
human expected exposure, and puts it in some
20
context without trying to make a correlation to a
21
particular human level of risk.
So, that is kind
22 of
a given for any of the drugs that come out of
213
1 our
division.
2
DR. ENGLUND: Thank you for the
3
clarification. Dr. Munk?
4
DR. MUNK: Yes, just picking up on
the
5
last comments in terms of the label and the
6
discussion of carcinogenicity, I would urge the
7
agency to go a little bit further in terms of
8
putting those comments and data in context so that,
9
beyond a recitation of the data from the existing
10
studies, perhaps there could be a statement of the
11 CAC
findings; perhaps there could be a statement,
12 as
was made here, that clearly this is a patient
13
population for whom monitoring of emerging cancers
14 and
tumors is standard of care. I am
concerned
15
that some physicians and certainly some patients
16
reading it either will be too reassured by the
17
multiples of human dosage and simply ignore the
18 risk
or, on the other hand, given the number of
19
column inches devoted to it, will be concerned
20
about it. So, I would just like
to see more
21
context rather than less.
22
DR. ENGLUND: Dr. So?
23
DR. SO: I pretty much agree with
all that
24 has
been said. I think it should be approved
for
25
first-line treatment. I also
agree the insert
214
1
should have something mentioning the risk of rodent
2
carcinogenicity. I think, you
know, the data
3
actually shows also that it could be effective in
4
cases of patients who are lamivudine-resistant,
5
although, you know, since we don't have any uniform
6
outcome assessment we really can't compare whether
7 it
is better than adefovir. You know, there
is
8
really no data to compare.
9
DR. ENGLUND: Dr. Fish?
10
DR. FISH: I would agree with the
11
first-line indication and also would agree with the
12
second-line indication in the treated population
13
that was presented for these three pivotal trials,
14 the
lamivudine-treated individuals as second-line
15
therapy. The others, the studies
and work is
16
ongoing. I would also agree with
the comment in
17
terms of future studies and looking at combination
18
therapies of some of these drugs, and I think that
19 has
a bright future.
20
DR. ENGLUND: Any other person who
hasn't
21 commented? Dr. DeGruttola?
22
DR. DEGRUTTOLA: I would just
comment that
23 I
agree with the indication for both first-line
24
therapy and second line for lamivudine failures,
25 and
also with the FDA's discussion about how they
215
1
handle the carcinogenicity information.
2
DR. ENGLUND: I would actually
like to
3
call on Mr. Grodeck to make sure that we have your
4
opinion too.
5 MR. GRODECK: Well, I think I always have
6
something to say here. Right now
it seems the
7
benefits outweigh the risks, today.
I am thinking
8 to
myself where will I be in ten years. I
will
9
have survived the risk of liver cancer and where I
10
don't want to end up is that I get lung cancer ten
11
years from now. We encountered
the same problems
12
with HIV. You eliminate a lot of
the risk from the
13
virus only to see emerging--I guess it is called
14
co-mortalities [sic]. So, I guess
I want to see
15
some mechanism, some strong mechanism that goes
16
into place and holds accountable the reporting
216
1
system so I am aware, as a patient, that I am
2
taking this risk because I am afraid after it is
3
prescribed, you know, while we have suppressed the
4
virus and go on about your day, but I think what we
5
will probably see is an increase, slow but steady
6
increase of cancer over time, cancer risk. So, I
7
just want everyone to be thinking long term.
8
DR. ENGLUND: Thank you.
9
DR. BIRNKRANT: As was mentioned,
we have
10 a
section in our labeling for carcinogenesis,
11
mutagenicity findings and impairment of fertility
12 so,
in addition to putting wording in that section,
13
which is an obvious section to place wording
14
although it may not be the section where physicians
15
tend to go to when they are reading labels, it is
16
possible to put it in another section of the label,
17
perhaps in the precautionary section and then we
18 can
always refer treating physicians to the
19
carcinogenicity section of the label as well. But
20 I
agree with what was said, that it doesn't really
21
rise to the level of a boxed warning.
22
DR. ENGLUND: Have we answered
your
217
1
question 3 to the satisfaction of the agency?
2
DR. BIRNKRANT: Your discussion
has been
3
quite helpful.
4
DR. ENGLUND: Great!
5
DR. BIRNKRANT: There is 3B
though.
6
DR. ENGLUND: Well, we kind of
discussed--
7
DR. BIRNKRANT: A little bit.
8
DR. ENGLUND: --but let's more
formally
9
discuss 3B. We pretty much
discussed 3B.
10
[Laughter]
11
The potential role of entecavir in the
12
treatment armamentarium--I think we had several
13
questions which were discussed with a little bit of
14 a
difference of opinion. I think there was
15
universal acclamation for this drug for the
16
treatment of HB e-antigen negative and positive.
17
That was uniform. The question
was whether this
18
committee felt that there was sufficient data in
19
indications for labeling it for lamivudine
20
resistant or not naive patients.
There was a
21
little bit of waffling and then I think Dr. Lewis
22
gave us a little bit of background too.
But I
218
1
think that is something that we could discuss a
2
little bit further. Yes, Dr.
Paxton?
3
DR. PAXTON: Again as a non-hepatologist,
4
actually I found the data for the
5
lamivudine-resistant, the effects in that group, to
6 be
pretty striking so it appears to me that this
7
would be--I don't know how it compares to adefovir
8 but
it looked pretty striking, what was presented
9
today, so I would say, from what we saw, that it
10
would be recommended for treatment of
11
lamivudine-resistant HBV.
12
DR. ENGLUND: Dr. Gerber?
13
DR. GERBER: No, I agree that this
drug
14
should be approved for lamivudine-resistant HBV
15
virus as well. Based on what Dr.
Lewis said, I
16
mean, it seems to be that we have more data. It
17
would be great to get a comparative study with
18
adefovir and entecavir but we don't have that and
19 it
seems to be that we have a wealth of data on
20
lamivudine-resistant virus so I think it needs to
21 be
approved for both indications.
22
DR. ENGLUND: Dr. Bell?
23 DR. BELL: I am not a clinician and pardon
24 my
ignorance. Is adefovir labeled for
treatment of
25
lamivudine failures?
219
1
DR. LEWIS: Yes, it is, and I
would like
2 to
remind the committee that, while we didn't
3
discuss the data today, there is an ongoing, still
4
enrolling study, comparing adefovir and entecavir.
5
These are very advanced patients.
They are
6
patients with decompensated liver disease. What we
7 may
not have for quite some time is any data
8
comparing entecavir and adefovir in less advanced
9
patient populations in first treatment failure or
10
treatment naive patients. But
there is more data
11
coming and we are expecting that data to be very
12
useful.
13
DR. BELL: I would just say that
it seems
14 to
me that the level of information that we have
15
about how entecavir behaves in patients who have
16 failed
lamivudine is better than the data that we
17
have for adefovir and that, therefore, whether we
18 are
completely satisfied with all the data is
19
perhaps a different issue than whether it rises to
220
1 the
level of meriting labeling for that indication.
2
DR. ENGLUND: Dr. Johnson?
3
DR. JOHNSON: I don't think we
were
4
waffling. I think we all agreed
about the
5
second-line therapy and I don't want my earlier
6
comments of desiring the studies that Debra just
7
mentioned to cloud that. I
personally thought that
8
second-line data was beautifully presented and
9
sufficient for that label. But,
again, I would
10
love to see in the studies they have mentioned
11
further studies of earlier stages of treatment
12
experienced patients and further development of
13
drug resistance profiles and cross-resistance
14
profiles in patients so we better get a handle on
15
that because I still think we are headed toward
16
combination therapy based on what we saw this
17
morning. Thank you.
18
DR. ENGLUND: Thank you. I think that
19
clarifies that. I don't think we
need to go around
20 the
table to get everyone's opinion unless Dr.
21
Birnkrant wants that.
22
DR. BIRNKRANT: No, that is
fine. I am
221
1
satisfied for now.
2 [Laughter]
3
DR. ENGLUND: If she is happy
perhaps we
4 can
move on. Does anyone else have any
questions
5 on
question number 3? I guess I would like
to add
6 one
statement. As a clinician, I want to be
able
7 to
use entecavir in my lamivudine-resistant
8
patients and for that I need labeling because I am
9
dependent on getting reimbursement and things like
10
that. So, I really think that it
is going to be
11
done. I think they have good data
and I would
12
support that.
13 Question No. 4
14
Question number 4--aha, Dr. Schwarz, you
15 are
still with us! this question is
specifically
16
addressing the issues with pediatric patients and
17 Dr.
Wood is a pediatrician too. The question
18
states assess the potential risks and benefits of
19
proceeding with development of entecavir for the
20
treatment of chronic HBV in pediatric patients.
21
Part B, what, if any, additional information is
22
needed in order to proceed?
23
DR. SCHWARZ: Well, first of all,
I would
24
like to express my gratitude for inviting a
25
pediatrician, and I am honored to be the
222
1
pediatrician to try to give the most balanced
2
assessment I can of what I believe is a very
3
important problem.
4
So, in terms of the risks, I think we
5
understandably are extra conservative when it comes
6 to
giving any drugs to children. We do need
more
7
data on carcinogenicity potential before we proceed
8 too
much further, and I was interested to learn
9
that the so-called lifetime animal exposure studies
10
started with teenage rats and, as I will try to
11
articulate, there are reasons to consider treating
12
hepatitis B in fairly young children.
So, I think
13 it
would be important to do some more studies in
14
post-weaning rodents and, in particular, young
15
primates.
16
I am not a molecular biologist but I am
17
worried that this drug is not an obligate chain
18
terminator. So, the possibility
of site-directed
19
mutagenesis is something that I at least need to
223
1
raise. I also wonder about the
risk of exposure to
2
ovulating females. I thought I
heard that it was
3 not
integrated in mitochondrial DNA and that there
4 was
no risk of lactic acidosis but I would just
5
like to make sure that I understood that correctly.
6
Then, of course, another risk that is
7
unknown is the risk of long-term exposure to the
8
injured liver. It was interesting
to me that
9
almost all of the toxicology and carcinogenicity
10
animal studies were done in animals with a normal
11
liver, whereas patients with hepatitis B, including
12
even young children, have an injured liver. I am
13
actually excited about the woodchuck studies in
14
which, of course, the drug is given to animals with
15 an
injured liver and it looked beneficial in that
16
regard but I think we need a little bit more data.
17
In terms of the potential benefits for an
18
addition of a safe and effective hepatitis B drug
19 for
the pediatric hepatitis B clinical problem, I
20
think that is an enormous benefit.
There are some
21
thousands of children in the United States with
22
hepatitis B, probably falling in two camps, urban
224
1
adolescents and also international adoptees, and I
2
should say that the urban adolescents who are
3
probably at the highest risk for the infection have
4 the
lowest hepatitis B vaccine coverage.
Then,
5
there are millions of children worldwide with
6
perinatal transmission of hepatitis B.
7
There are two FDA approved drugs for
8
hepatitis B in children.
Interferon is approved
9 for
hepatitis B-infected children one year and up,
10 but
it does have a significant side effect profile.
11
Lamivudine is approved for children three years and
12 up,
but as is the case with adults, even at one
13
year of treatment there is a 20 percent resistance
14
rate. And, the pediatric adefovir
trials are
15
proceeding at the present time.
16
So, newborns who have acquired hepatitis B
17
from their mother probably have the highest
18
lifetime risk of morbidity and mortality from liver
19
disease and liver cancer. In some
studies it is as
20
high as 40 percent lifetime risk.
So, this is a
21
very significant problem.
22
This has not been said, but there is also
225
1 a
very significant social stigma of having
2
hepatitis B, including in a young child.
This is a
3
very real problem so it is one of the factors that
4
motivates pediatric hepatologists to be eager to
5
identify effective drugs. Parents
also are eager
6 to
find therapies for their infected children.
7
Finally, there is some data from the interferon
8
studies that it may actually be more effective to
9
treat hepatitis B in young subjects.
So, I am very
10
glad to be here for that reason.
11
Finally, I should say that we might as
12
well be realistic. There is an
oral suspension of
13
entecavir for consideration on the table today, and
14 the
minute the FDA approves that drug there will be
15
off-label use in children. So,
that being the
16
case, I think to the question should there be
17
pediatric development studies, the answer is yes
18
because if there aren't we are just not going to
19
know what is going to happen when young children
20
take this drug.
21
In terms of the recommendations, I have
22
talked about doing the carcinogenicity studies in
226
1 the
very young animals, including primates.
I am
2
excited about the post-marketing adult studies that
3 are
planned, and I agree with the comments that
4
there really has to be built into that effective
5
monitoring for cancers because I think the human
6
carcinogenicity studies we have heard about to date
7
have been in clinically manifest tumors.
There
8
hasn't been, for the most part, much screening.
9
Also, I think in studying this large cohort of
10
treated adults, it will be a chance to get
11
reproductive history in a systematic fashion.
12
If it does turn out that there is an
13
increased risk of cancer long term, as a
14
pediatrician who is always looking for non-invasive
15
markers of cancer potential, I would love at least
16 to
see the peripheral blood lymphocytes of the
17
cancer patients frozen so that those DNTP pool
18
studies could be done maybe on a case control
19
basis.
20
I would like to put up for discussion
21
consideration of holding approval of the oral
22
solution until we have a little bit more
227
1
carcinogenicity data from both young animals and
2 the
adults. Then, if these studies are
reassuring,
3 I
would like to argue for doing PK studies in young
4
children and then, finally, the Phase II safety and
5
efficacy studies.
6
DR. ENGLUND: Dr. Paxton?
7
DR. PAXTON: I would just ask a
8
clarification question. You are
advocating that
9 the
approval for the oral suspension be held up
10
simply to guard against the off-label use in
11
children? Is that the reason?
12
DR. SCHWARZ: I think it should be
13
discussed because there will be off-label use if it
14 is
available, particularly given the limited number
15 of
alternatives.
16
DR. LEWIS: Just one comment about
the
17
oral suspension solution, that product is being
18
considered in order to be able to dose entecavir
19
appropriately in patients with renal insufficiency,
20 and
without the oral solution that won't be able to
21 be
done.
22
DR. ENGLUND: Dr. Wood, I am going
to take
228
1 the
liberty of calling on you.
2
DR. WOOD: Well, I want to thank
Dr.
3
Schwarz for answering one of my questions. I was
4 not
aware what the specific risks were for
5
long-term disease progression as far as
6
hepatocellular carcinoma disease in very young
7
children who had hepatitis B. It
clearly is
8
significant. I would have to echo
all of your
9
comments and the fact that we clearly will need, I
10 do
believe, for carcinogenicity purposes animal
11
studies in the neonatal rats up until adolescence
12 to
see whether or not there is any excess tumor
13
incidence which would be very important.
14
Given all the limitations regarding dose,
15
particularly since the drug is 75 or 80 percent
16
renally excreted, there is the need for the
17 suspension clearly and there is tremendous
renal
18
co-morbidity in patients commonly who have
19
hepatitis B or HIV and hepatitis B.
20
I will have to echo though that the
21
urgency to conduct those preclinical animal
22 toxicity
studies and then move into pediatric
229
1
studies very efficaciously is going to be necessary
2
because when you have drugs that are very potent it
3 is
going to be a hot drug. It has a
favorable
4
resistance profile. It has a
favorable safety
5
profile. We are going to be
recommending it not
6
only for first-line therapy but second-line
7
therapy. People will use it in
children if there
8 is
a suspension without any safety or efficacy data
9 in
that population. The safety issues in
children
10 and
in neonates can definitely be very, very
11
different, and I will put forth the example of a
12
nucleotide analog, adefovir, for the indication of
13 HIV
infection. We have seen significant
14
musculoskeletal, bone toxicity in preclinical
15
animal models which has also been seen and observed
16 in
human clinical studies. So, that is an
argument
17 for
pediatric studies to be done promptly.
18
DR. ENGLUND: Dr. Johnson?
19
DR. JOHNSON: I am also an HIV
treater and
20 I
am an infectious disease adult clinician who
21
takes care of a large number of older African
22
Americans particularly men but also women in
230
1
Alabama who are on dialysis or near dialysis, who
2
have HIV and hepatitis B co-infection; not many
3
tri-infected HCV, HBV, HIV infected, but I need the
4
oral formulations. I can't always
get the patients
5 to
pick them up at the pharmacy but we won't go
6
there. But I need all
formulations of this
7
compound once it is approved for adult care. Thank
8 you.
9
DR. ENGLUND: Dr. Bartlett?
10
DR. BARTLETT: Yes, I just wanted
to echo
11
what Dr. Johnson said. The
availability of a
12
liquid formulation is really helpful in adult
13
practice, not just for dose titration in patients
14
with renal failure but also for patients who have
15
difficulty in swallowing pills.
So, I think having
16 it
is really important for adult medicine.
17
DR. ENGLUND: I would like to
interject my
18
feeling as a pediatrician also, Dr. Schwarz. I
19
think one population that is relatively small but
20
that should be encouraged for studies to begin
21
urgently, especially PK studies, is our transplant
22
population. We do pediatric
transplants, many of
231
1
them in my institution, but we do pediatric
2
transplants with a mean age of nine months. So,
3
many of these children are young.
And, if there is
4 an
HBV risk we don't even potentially need all the
5
animal studies to be done. If one
were to target a
6
target group that you would want to start doing
7
pediatric research on, it could potentially be
8
patients at very high risk which could include
9
transplant patients. Most of
them, of course,
10
don't have HBV.
11
DR. SCHWARZ: I was going to say
with all
12 due
respect, and I am the medical director of our
13
pediatric liver transplant program, there are very
14 few
children in the United States with hepatitis B
15 who
have at least a liver transplant; it may be a
16
little more common with kidney transplants. But I
17
still think, all in all, there are many more
18
children who might benefit from the studies and if
19 you
had an increased prevalence of a malignancy in
20 a
transplant patient--since when cyclosporin was
21
introduced we learned that there was a 100-fold
22
increased risk of all kinds of malignancies, I
232
1
think I personally wouldn't want to begin the
2
studies there. I would rather
proceed with a more
3
established population.
4
DR. ENGLUND: Well, I am concerned
that we
5
really don't even know how to dose--I am concerned
6
about malignancy but I am concerned the drug is
7
going to be used inappropriately because we don't
8
know how to dose them also.
9
DR. SCHWARZ: Right, but I
wouldn't start
10
with the transplant patients.
11
DR. ENGLUND: Okay. Dr. Haubrich?
12
DR. HAUBRICH: Just a quick
comment, when
13 I
first looked at this question I really had a hard
14
time making up my mind about it, but the discussion
15 by
my colleagues here has answered it.
Clearly if
16 the
oral suspension is needed that will lead to use
17 in
kids, it needs to be studied and I wouldn't
18
wait.
19
DR. BIRNKRANT: So, what we heard
then,
20
just to clarify, is that the committee feels as
21
though this could be an important drug for the
22
pediatric population, however based on the animal
233
1
findings, they want further animal studies before
2
conducting a formal trial in children.
Is that
3
correct?
4
DR. LEWIS: You know a
carcinogenicity
5
study in animals is going to take at least two
6
years.
7
DR. ENGLUND: I think that was Dr.
8
Schwarz's opinion, and in my opinion, I think that
9
limited PK studies could be done concomitantly with
10 the
animal studies--
11
DR. SCHWARZ: And I agree with
that.
12 DR. ENGLUND: --because I don't think
13
waiting two years to start PK studies--it is not
14
going to work.
15
DR. SCHWARZ: Right, and you
pointed out
16
correctly that the dosing is important in children
17 and
the PK may be different, and it would be most
18
different in the youngest subjects.
19
Then, I did want to ask the FDA a question
20
about labeling issues when it comes to safety in
21
pediatrics since there is no data.
I think that
22
most drugs in the Physician's Desk Reference have
234
1 not
been specifically approved for pediatric use.
2 So,
to be honest, I think many pediatricians simply
3 ignore
the warnings when it comes to children.
But
4 in
this case, where at least I think we all agree
5
that the same kind of careful studies that have
6
already been talked about should be done to a
7
certain extent in children, I just wonder if there
8 is
some special way to put a warning that people
9
will read and pay attention to that it is not for
10
pediatric use.
11
DR. LEWIS: I am a pediatrician so
I am
12
particularly aware of this issue.
When there is no
13
data in a particular age group, whether it is
14
pediatrics or geriatrics, we put that very clearly
15 in
the label and say there is no pharmacokinetic
16
data in this age group in the pharmacokinetic
17
section and in the other sections; there is no
18
safety and effectiveness data in this age group.
19
That clearly doesn't keep people from using the
20
drug off-label but we do try to indicate where
21
there is a lack of data.
22
DR. BIRNKRANT: Then just to
clarify one
235
1
more time, what we are hearing is that there should
2 be
concurrent development, that is, a Phase I study
3 in
young children at the same time as animal tox
4
studies looking at carcinogenicity in younger
5
animals. Is that correct?
6
DR. SCHWARZ: And I also think
that
7
planning for a Phase II safety and efficacy
8
pediatric trial can begin. That
always takes a
9
while.
10
DR. BIRNKRANT: So, then we will
be
11
expecting protocols from Bristol-Myers Squibb over
12 the
next few weeks. Right?
13
[Laughter]
14
DR. LEWIS: Maybe in the next few
months.
15 Question No. 5
16
DR. ENGLUND: With that, we are
going to
17
move on to our next question, which I think
18
actually might be the most discussion prone
19
question. Question number 5,
discuss the
20 applicant's proposed pharmacovigilance plan
to
21
address human cancer risk, including comments on
22 the
design of the proposed large simple study.
23
I think we have already briefly addressed
24
this but I think this is the time for us to
25
specifically say what we, the committee, would
236
1
recommend to the agency to request.
Dr. Haubrich?
2
DR. HAUBRICH: I think the biggest
risk to
3
this study--well, number one, I think that a
4
randomized study design is the right way to do it
5 and
is probably the best study design.
Number two
6
though, I think that the biggest risk to this study
7 is
either lack of enrollment because people just
8
won't do it--why would they want to be randomized
9 to
a drug that has already been shown to be
10
inferior? Or, two, that if they
enroll, they
11
enroll and then cross over. So, I
think it has to
12
have built in a prior contingency plans if
13
recruitment goals are not met and the design
14
changes or if certain pre-calculated proportions of
15
patients cross over before, again, a certain time
16
period that the study design changes as well so
17
then it just becomes a cohort study which, of
18
course, is less desirable but is certainly better
19
than having no study at all. So
that two years
237
1
from now we don't come back and hear that, well, we
2
started this study; we got 6,000 investigators and
3 we
enrolled 35 patients.
4
DR. ENGLUND: Dr. Bell?
5
DR. BELL: Yes, I would like to
echo that
6
sentiment and just say a little bit more about it.
7 I
mean, I kind of laugh at the idea of calling this
8 a
large simple study because it is about as
9
non-simple as you can imagine. I
think that while
10 we
all believe in the best of all possible worlds
11
that a randomized trial is the best way to address
12 a
research question, if it is a randomized trial
13
that can't be conducted appropriately it has the
14
potential to give the wrong answer.
For example,
15
this issue of loss to follow-up is not a small
16
problem. For a study like this
you are likely to
17
have differential loss to follow-up so that the
18
patients that you lose are different than the
19
patients that remain in the study.
I think there
20 is
certainly the potential not to detect the
21
endpoints of interest differentially because of the
22
people that have been lost to follow-up.
23
So, I think there are some potential
24
methodologic dangers in a poorly conducted
25
randomized trial, not from any lack of trying on
238
1 the
part of the sponsor but because of the
2
logistical difficulties involved with trying to
3
mount a randomized trial of this nature--some of
4 the
comments that were just made. So, I
think
5
there really needs to be a very careful and quick
6
attempt to determine the actual feasibility of
7
doing a study like this, as good as it looks on
8
paper, and move to something else fairly quickly if
9 it
doesn't look like it is going to work.
10
I think, you know, while these concerns
11
about cancer risk are somewhat theoretical at the
12
moment, it is also true that we actually haven't
13
studied patients on this drug the way it is going
14 to
be used, which is over a long period of time,
15 and
that is another reason to be very serious about
16
really keeping track of what is happening with
17
other cancers besides HCC, in addition to HCC, in
18
this population.
19
I also think that we should not downplay
239
1 too
much the relative usefulness of observational
2
studies and using large databases such as, for
3
example some of these Kaiser databases, to address
4
some of these questions, particularly when we are
5
talking about a relatively rare outcome, and we
6
need to have very large sample sizes and there are
7
places that have existing populations that are
8
relevant, not just in the United States, with very
9
good access to data. For example,
these Kaiser
10
databases do have information on treatment and it
11 is
possible to ascertain exactly who was treated
12
with what for what periods of time.
It is also
13
fairly easy to characterize the population fairly
14
well. I would pick an
observational study with a
15
large population that can be well characterized,
16
with good ascertainment of data, over a randomized
17
trial where the sort of feasibility issues are such
18
that the patient population is too small, is biased
19 in
a way which doesn't answer the question, or
20 otherwise
causes difficulties.
21
So, although I think we often think about
22
randomized trials as being the gold standard, in
240
1
this kind of situation I would encourage the
2
sponsor to think creatively about admittedly
3
observational studies but ones that perhaps we
4
might be able to answer the question.
5
The only other comment I would make is
6
that I think the availability of vital records and
7 of
good vital records is an important thing to
8
think about for these kinds of studies, and not
9
just in the United States, but where one of the
10
outcomes is something which is likely to kill
11
people sooner or later, being able to search death
12
certificate data and tumor registry data and the
13
availability of those kinds of registries and other
14
kind of vital records in whatever country you
15
happen to be working in, and in some of the high
16
prevalence countries they are available, I think
17
would be very useful in terms of really making an
18
effort to try to get at the answer to this question
19
using lots of different ways, other than simply
20
relying on a randomized trial which, as I say, is
21
good study design but if it is not doable it
22
doesn't help us.
23
DR. ENGLUND: Dr. Fish?
24
DR. FISH: I agree wholeheartedly
with Dr.
25
Bell's comments. It does look
good on paper but I
241
1 am
concerned that if I am an investigator trying to
2
convince a patient to go on the study, knowing what
3 I
know and what we have learned about entecavir and
4 its
potency and superiority to at least one major
5
hepatitis B therapy, I would be hard-pressed to
6
sell this study I think to my patient.
Moreover,
7 if
I am the patient and I know what I know, I know
8
what arm I would like to be randomized to.
9
I am not an expert in study design, but I
10
would agree with the suggestions offered, and even
11
looking at the studies that you have and having a
12
follow-up plan for the five to eight years maybe
13
even some of those patients would be willing to
14
continue to be followed in cohorts beyond five
15
years, ten years, or whatever from the studies that
16 are
currently existing and ongoing.
17
DR. ENGLUND: Dr. Gerber?
18
DR. GERBER: I am just curious to
see what
19
people think about the ethical aspects of
242
1
randomizing to an inferior regimen.
I think that
2
needs to be discussed at least here because,
3
certainly, I agree with Doug that it would be
4
difficult to convince a patient to go on lamivudine
5
when we know that there is a huge difference in
6
response.
7
DR. ENGLUND: Mr. Grodeck?
8
MR. GRODECK: To respond to your
concern,
9 I
wouldn't go on a randomized study to an inferior
10
regimen. I wouldn't do it. And you are exactly
11
correct, it is a hard sell, one that shouldn't have
12 to
be sold. Lamivudine is inferior,
period. I
13
think it is wrong to sell that kind of trial to a
14
patient. I would just not do it.
15
DR. ENGLUND: Dr. Bell?
16
DR. BELL: Just one additional
comment on
17
that point, which I think is an excellent one. You
18
know, the sponsor could be developing historical
19
controls using large databases.
Once again, this
20
idea that if it is not a randomized trial it is not
21
worth it I think is something that in this
22
situation we want to get away from.
Using some of
243
1
these available data and large patient populations
2 to
develop historical controls I think potentially
3
might be quite useful because, otherwise, we will
4 be
faced with a compared to what question if, in
5
fact, we have a large population of patients that
6 are
treated with one drug and the patients that are
7 not
are not comparable in many other ways.
So, I
8
would once again just encourage the sponsor to
9
think creatively about this and not relying on the
10
kinds of things that we do when we are evaluating
11 the
efficacy of a drug for licensure.
12
DR. ENGLUND: Dr. DeGruttola?
13
DR. DEGRUTTOLA: I just wanted to
comment
14
that I would certainly agree that we wouldn't want
15 to
develop a study in which patients were going to
16 be
randomized to an arm known to be inferior.
But
17 as
good as the data on entecavir look, there is
18
only 48-week efficacy data and we don't know about
19
longer-term toxicity even though the drug may be
20
used in the longer term. Of
course, we don't know
21
about the longer-term carcinogenicity issues as
22
well.
23
So, I would be reluctant to characterize
24 too
quickly lamivudine as an inferior regimen over
25 the
long haul, which is what we are talking about,
244
1
since that information remains to be developed. I
2
would certainly agree that observational studies
3 can
provide a lot of useful information and it may
4
turn out that only observational studies can be
5 done in this setting. On the other hand, I think
6 we
ought to be a little careful about what we
7
conclude.
8
DR. ENGLUND: Dr. Bartlett?
9
DR. BARTLETT: I recognize
Victor's point
10
completely. I think it is a good
one. Another
11
comparator arm could be a nucleotide that you could
12
also look at. One way to
encourage people to
13
participate, recognizing that these trials are
14
likely to be done in resource limited areas of the
15
world, is through the provision of free drugs that
16
they might otherwise not have access to.
So, you
17
want to make sure it is a scientifically robust
18
study and the comparator arms represent the very
19
best standard of care, and then providing drugs to
245
1 the
participants might be a good way to motivate
2
them.
3
DR. ENGLUND: Dr. Wood?
4
DR. WOOD: I have several
comments. I
5
would have to agree that we can't make major
6
statements regarding the superiority of entecavir
7
over lamivudine for the long term.
The one issue
8
though is that patients are increasingly very
9
sophisticated and educated and they do know that
10
with any current viral infection resistance is a
11
problem. Given the fact that
resistance clearly
12
emerges to a significant level within one year of
13
treatment on lamivudine, I think that that alone,
14 in
addition to the other primary endpoint efficacy
15
data which we have heard, may make patients even
16
more reluctant to enroll in a randomized study.
17
One of the questions that I do have for
18 the
sponsor, linking on to Dr. Bell's comments
19
about observational studies, is that we have heard
20
about 049 which is the planned five-year
21
post-treatment observation study.
I am interested
22 in
knowing what the target enrollment is for that
246
1
study; what percentage of patients are receiving
2
chronic ongoing treatment or have all the patients
3
enrolled in this study stopped entecavir?
4
Then the third issue since, whatever the
5
design is of the post-marketing study, is to detect
6
excess incidence of non-hepatocellular carcinoma, I
7
think there should be careful consideration given
8 to
the types of screening tests that will be done
9 and
recommended for these cancers of excess
10
incidence, and that would need to be clearly
11
defined, and there are some issues of great debate
12 in
terms of what is the best way to do that.
13
DR. ENGLUND: We will have the sponsor
14
briefly address these issues.
15
DR. MORGAN MURRAY: I am Dr.
Morgan
16
Murray, from Bristol-Myers Squibb.
Study 049 is an
17
observational study that is ongoing and we have
18
enrolled about 440 patients to date.
We expect to
19
enroll about 1,500 patients. As
an observational
20
study, patients off of entecavir therapy might be
21 on
other HBV therapies. As a reminder, we
also
22
have the 901 study as an ongoing study which is
247
1
currently allowing up to four years of therapy on
2
entecavir, and that study is ongoing as well and we
3
have nearly 1,000 patients I believe enrolled in
4
that study.
5
Also, if I may make one
clarifying point
6
about the post-marketing study, we are not
7
specifying that patients will be randomized to
8
entecavir versus lamivudine; it is versus any
9
nucleoside or nucleotide so they can also be
10
randomized to adefovir.
11
DR. BARTLETT: Does that then mean
that if
12
they are not going to receive entecavir the other
13
drugs won't be provided by the study?
14
DR. ENGLUND: That was Dr.
Bartlett.
15
DR. MORGAN MURRAY: Most randomized study
16
drug is, indeed provided. We
haven't made any
17
formal decisions on this, and understand that
18
regulations may vary from one country to the next.
19
DR. DEGRUTTOLA: Is there any plan
for
20
crossover for patients who have failed treatment?
21
DR. MORGAN MURRAY: We don't have
any
22
planned crossover in the studies.
Patients are
248
1 eligible
to enroll if they are starting nucleoside
2
therapy or need to change their therapy.
We are
3 not
preventing switching however, and we will
4
analyze the switching information, patients who
5
switched differently.
6
DR. DEGRUTTOLA: Have you given any
7
consideration to guidelines for when to switch, or
8 are
you planning to just leave that totally to
9
physician discretion?
10
DR. MORGAN MURRAY: The intent is
that it
11
will be a normal use study so we are relying on the
12
physicians to practice according to the guidelines.
13
DR. ENGLUND: Does anyone have a
specific
14
question for Dr. Morgan?
15
[No response]
16
Thank you. Dr. Munk?
17
DR. MUNK: I find the comments
about the
18
design of a randomized trial very important and I
19
think that we are getting more and better data from
20
prospective cohort studies in other areas, and that
21
this is a concept, a design that really needs to be
22
looked into. In the area of
cardiovascular risk I
249
1
think we are getting some incredibly good data from
2
prospective cohort studies, and we should look at
3
this here because I think there are some very
4
difficult issues about randomization.
5
The other factor that I think argues for
6
prospective cohorts is the whole definition of long
7 term. I suspect that Mr. Grodeck would like to see
8
long term be considered longer than five years out.
9
DR. ENGLUND: Dr. DeGruttola?
10
DR. DEGRUTTOLA: I just want to
have a
11
comment about limitations of observational studies.
12 I
think it is an excellent idea but we have to keep
13
certain things in mind. Here,
when we are talking
14
about doing a comparison between malignancies
15
between two groups we are talking about
16
malignancies of all different types.
It is
17
different from a setting where there is one
18
particular outcome that you are focusing on. What
19 you
would need in order to make inference from an
20
observational study and then use a historic control
21 is
to know that you had controlled for confounders,
22 not
just for one condition but for all possible
250
1
cancers, and I think that that is a tall order.
2
Now, you may be able to detect very large signals
3 in
this kind of approach but what the sponsor said
4 is
that they were powering their study to detect
5
quite modest differences in increase in cancer.
6
And, it seems to me that it would be very hard to
7
imagine that you could have sufficient confidence
8
that you had controlled for all confounders when
9
using historical controls to compare to some
10
observational studies to be able to reliably detect
11
modest size effects.
12
So, while I don't by any means argue
13
against the usefulness of doing observational
14
studies, I think we need to keep some of their
15
limitations in mind. I also
understand that there
16 can
be some difficulties in trying to mount a
17
randomized trial and there will be crossover and
18
other issues to deal with. But I
think that this
19
potential should still be explored, particularly
20
since there are other licensed drugs that are
21
available, because there are certain advantages to
22 a
randomized trial that we cannot find in other
251
1
approaches.
2
DR. ENGLUND: Dr. Paxton?
3
DR. PAXTON: Yes, I just have to
agree
4
that I think this is a very difficult decision that
5 we
are dealing with right now. As an
6
epidemiologist, I dream about randomized and
7
controlled trials and, you know, whenever possible
8 I
like to do them but I admit that we have plenty
9 of
examples in the HIV world of people voting with
10
their feet. For example, in
post-exposure
11
prophylaxis early AZT trials you couldn't enroll
12
enough people because people didn't want to be
13
randomized.
14
I think it is quite possible that we may
15
find this going on with this thing as more data
16
comes out, and if the results that we saw today
17
continue where it looks like entecavir is superior
18 to lamivudine we might have problems getting
people
19 to
agree to randomization.
20
I just want to bring up one thing.
I was
21
made a little bit uneasy by the suggestion, and I
22
don't remember where it came from, about one way to
252
1 get
people to agree to a randomized trial is
2
providing the drug free. I think
that that has
3
ethical problems with it, you know, because of the
4
prescriptions against undue inducement for these
5
things. So, I think that is
something that we
6
would have to take a really hard look at because I
7
don't know that that in itself would be considered
8 to
be following ethical norms.
9 DR. BARTLETT: Yes, Dr. Paxton, I made
10
that comment and maybe I can answer you.
I very
11
importantly prefaced it by saying that all the arms
12
need to reflect the highest standard of care. But
13
there are some populations, especially as you think
14
about the geographic distribution of hepatitis B
15
infection, who don't have access to any treatment
16 and
for whom all of this discussion is irrelevant.
17 If
they can get access to treatment in the context
18 of
a clinical trial, I think that is a positive
19
thing.
20
DR. ENGLUND: Dr. Johnson?
21
DR. JOHNSON: I have just a
logistic
22
question for the agency about the reporting of the
253
1
pharmacovigilance plan. Would a
clinician--after
2
seeing the package insert, and in this current
3
climate of scrutiny of post-marketing safety, where
4
could we find these results? Will
they be posted
5 on
a web, or do they come back to you as a package?
6 How
does this get reported back and presented to
7 the
general clinicians?
8
DR. LEWIS: In general there are
9
regulations for post-marketing reporting that apply
10 to
every approved drug. What Bristol-Myers
Squibb
11 has
proposed is sort of a beefed up version of what
12 is
required for every drug. We have asked
them to
13 do
analyses looking at sort of rates of
14
malignancies as they develop and rates of other
15
critical events in hepatitis B on a six-monthly
16
basis, and those would come in to the review
17
division for evaluation by our statisticians,
18
clinicians, microbiologists, etc.
19
If there is nothing of particular note,
20
probably it would not be posted any particular
21
place. If some trend was noticed,
then that might
22
trigger something that might lead to different
254
1
labeling or to a "dear healthcare provider" letter,
2 or
some other method of communicating the results
3 to
the general public.
4
DR. JOHNSON: So, basically no
news is
5
good news?
6
[Laughter]
7
DR. LEWIS: That is probably the
best way
8 to
put it. But, you know, we are also still
9
working with mechanisms of how to provide better
10
communication of ongoing safety evaluations to the
11
public and, as has come out in recent discussions
12 of
other products, we are trying to be more
13
transparent about those discussions rather than
14
less.
15
DR. ENGLUND: Dr. So, you had a
question?
16
DR. SO: I would like to raise a different
17
point. As a liver cancer
specialist, you know, one
18 of
the issues we have here is trying to also
19
monitor the incidence of HCC in this post-marketing
20
study. So, I think it is
important that the
21
sponsor really standardizes the test used for
22
screening on enrollment into the study, screening
255
1 for
HCC, because if you just use ultrasound, you
2 can
miss like 20 percent of the liver cancers.
If
3 you
use AFP you probably miss 50 percent of liver
4
cancer. So, currently the best
test is triphasic
5 CT
scan. You know, whatever method you are
going
6 to
use for screening at the time of enrollment into
7
this study, it really needs to be standardized.
8
DR. ENGLUND: Dr. Bell had a
question?
9
DR. BELL: I did have a question
actually
10 for
FDA. I agree with what Dr. DeGruttola
says
11
about the benefits of a randomized trial, and I
12
wondered is there a mechanism for FDA to determine
13 or
make some kind of assessment of whether this
14
randomized trial is actually working?
In other
15
words, is it going forward as one would hope, such
16
that if all of the various concerns that have been
17
expressed about the feasibility and difficulties
18
potentially with mounting such a trial, if that
19
sort of assessment could be built into this so that
20 if
there is a need to do something else or shift
21
gears it can be identified in some fashion?
22
DR. LEWIS: Again, there are
regulations
256
1 in
place for any approved drug. One of the
things
2 that
is required is an annual report of all ongoing
3
studies so enrollment targets, things like that,
4 are
reviewed annually. You may have kind of
5
skipped over this in the company's slides but there
6 is
also discussion of having independent data
7
safety monitoring boards to review these data when
8
they get to certain levels of patient exposure.
9 So,
you know, when the details get worked out as to
10
whether it is every 5,000 patient-years or 10,000
11
patient-years, or whatever, there will be an
12
interim analysis so, yes, that can all be built
13
into the study and to the reporting.
14
DR. ENGLUND: I would like to ask
the
15
sponsor if, in your opinion, your proposed study
16 design
for pharmacovigilance is feasible.
17
DR. MORGAN MURRAY: I will try to
address
18
that. I will also ask Dr. Pierce
if he would like
19 to
comment further. We do have a large
experience
20 in
conducting large clinical trials and have lots
21 of
tactics that we have used to enhance enrollment
22 and
to enhance follow-up so that, while we may have
257
1
attrition, the patients won't be lost to follow-up.
2 We
realize this is a very large study and we
3
realize that there could be some difficulties in
4
enrolling and we will, obviously, stay on top of it
5 and
implement strategies to facilitate enrolling as
6
quickly as possible. Dr. Pierce,
anything else you
7
would like to add?
8
DR. PIERCE: Just a few points on
this,
9
one, the direction I think our pharmacovigilance is
10
actually moving towards is large simple safety
11
studies and we have been encouraged by the agency
12 to
pursue exactly this type of design. So,
I think
13
there is confidence in the universe of
14
pharmacovigilance that this is the correct way
15
forward and that these are feasible.
16
Perhaps the agency knows more studies than
17 I
do, but Pfizer is undertaking an 18,000-patient
18
study. It is not a randomized
study but observing
19
people on a therapy for specific safety endpoints.
20
That is one.
21
The second point actually regarding some
22 of
this is that the success of these trials often
258
1 is
related to their simplicity. You don't
want to
2
weigh them down with a lot of diagnostic testing.
3 BMS
would like to answer those in a more nested
4
fashion, the types of things of CT scans and things
5
like that, but the real success of these is often
6
built into not involving the patient with multiple
7 visits and multiple diagnostics.
8
The third point is that this is a common
9
disease and it is particularly common in developing
10
countries where much usage of the product will be.
11
That is where we would plan to conduct a lot of the
12
enrollment of the study really, where the disease
13
is. So, the conclusion to that
was, yes, we
14
believe it is feasible.
15
DR. ENGLUND: Thank you. I think that is
16
actually very helpful. Before you
leave, I just
17
have one other question. Would
smoking be a
18
variable? I know it is supposed
to be simple but
19 we
did hear from our advisory committee on
20
carcinogenicity about the concern potentially of
21
smoking as a co-factor.
22
DR. PIERCE: We do not plan to
stratify on
259
1
smoking but we will collect a detailed
2
questionnaire on smoking so will analyze our data
3 on
smoking history.
4
DR. ENGLUND: Thank you. Dr. DeGruttola?
5
DR. DEGRUTTOLA: I just have one
quick
6
question about design. I
understand the value, and
7
agree with the value of making it as simple as
8
possible, and I understand why you don't want to
9
have specific guidelines regarding a crossover.
10 But
one concern is that in a study where you are
11
trying to show that really there is no difference
12
between two arms, when you have crossover it tends
13 to
bias things in the direction of there being no
14
difference. So, I just wanted to
recommend for
15
consideration some kind of set of potential
16
guidelines for when to cross patients over if
17
people believe that that is likely to happen, not
18
that those guidelines would have to be followed or
19
that all the tests would be required, and so forth,
20 but
potentially consideration for some advice.
21
The purpose of that would just be to
22 understand
a little bit better what the triggers
260
1
were that led to switch because that kind of
2
information could be helpful in doing later
3
analyses where you try to tease out the effect of
4
being on one drug or another, not being randomly
5
assigned to one or another but actually having
6
taken the drug in question. So, I
would just
7
request consideration of some kind of document
8
describing current medical advice, knowing it won't
9 be
completely adhered to but might help reduce the
10
noise a little bit. I would just
ask whether
11
people think that is something that could be
12
considered.
13
DR. ENGLUND: Are you asking the
company?
14
DR. DEGRUTTOLA: Yes.
15
DR. ENGLUND: We are asking the
company.
16
DR. MORGAN MURRAY: Dr. Bozzette,
would
17 you
care to comment, please?
18
DR. BOZZETTE: Sure. Hi. I
am Sam
19
Bozzette, from the University of California San
20
Diego. I am advising the company
on this aspect.
21
Although the company is designing the trial, I can
22 say
that they have not designed it completely and
261
1
they are very flexible in terms of wanting to do
2 the
best study possible.
3
In terms of what we are talking about,
4
switching, I think there are two aspects to the
5
trial to be considered. One of
them is that one
6
wants to know whether or not the animal data
7
translates into a difference in human cancers. For
8
that, I couldn't agree more with Richard and with
9
Victor that the crossover is going to be a problem
10
because it is going to mix up the time of exposure.
11 But
in that circumstance one could look at it as an
12
observational study. They are
going to be having
13
67,500 years of patient follow-up.
If you have the
14
initial randomization and you have some reasons why
15
people switch, there might be an opportunity to not
16
only look at the on-treatment events but to try and
17
unravel some of the reasons why people switched and
18 try
and correct some of the biases that are
19
associated with those simple on-treatment analyses.
20
There is a variety of techniques that many people
21 on
the panel know better than I.
22
On the other hand, there is really no
262
1
other way to get at the pragmatic question of what
2
happens when you choose to prescribe one thing
3
versus another thing with all of the myriad of
4
factors, other than randomizing people.
That very
5
pragmatic question, what is the stream of events
6 and
outcomes in terms of not only noon-hepatic cell
7
carcinomas but hepatic cell carcinomas and
8
cirrhosis and, in fact, the ability to tolerate the
9 drugs
and cross over to another treatment. All
of
10
those things really can only be seen through
11
randomization. So, I think here a
very strong
12
attempt is being made to answer the biologic
13
question and the clinical question in a very strong
14
way.
15
DR. ENGLUND: Thank you. Dr. Munk?
16
DR. MUNK: Yes, I am encouraged to
hear
17
what Dr. Bozzette has said. At
the same time, I
18
want to echo what Dr. Paxton said.
Particularly
19
with the knowledge that the company will be
20
developing this product in the developing world, I
21
think we have to be extremely careful with the
22
definition of equipoise which could be very
263
1
definition in different countries, in different
2
parts of the world. The provision
of free drug
3
could be an unreasonable inducement, kind of
4
overwhelming the decision about equipoise that we
5
might have in the U.S. So, I
would just encourage
6 the
company to be extremely careful as the trial is
7
designed to address that issue.
8
DR. ENGLUND: Dr. Haubrich?
9
DR. HAUBRICH: I want to put Sam
on the
10
spot again, if I could. I know
you have probably
11
thought of this but obviously randomized is the
12
best way but if that turns to be unfeasible or have
13 the
problems that we have addressed, could you use
14 a
different observational strategy, more like you
15 did
with the HICSA [?] study and use that to try to
16
address a priori some of the potential confounders
17
that you would have with an observational study?
18
DR. BOZZETTE: Yes, I think that
you could
19 use
the full armamentarium of techniques to try and
20
sort through the biases involved.
But I would hope
21
that it will be possible to accrue this,
22
particularly since we are talking about standard of
264
1
care. It may well be that unusual
things will have
2 to
be considered. I mean, it may be
possible that
3
standard of care is even--this is a suggestion--is
4
entecavir in some circumstances.
So, one is going
5 to
have to be flexible I think in terms of the
6
design. But as long as people are
being accrued
7 and
being observed in a standardized fashion you
8
really do have a prospective observational study of
9 a
pretty hefty size.
10
So, it seems to me that that is really the
11
default, that the worst you are going to do is to
12
have a very large, worldwide prospective
13
observational cohort. Even if the
randomization
14
turns out to be randomization to advice, advising
15
someone to start one treatment rather than the
16
other, you will have a situation a lot like the one
17
that Dr. DeGruttola described for switching, which
18 is
that you will have a little bit of a lever to
19 try
and pry apart direction versus preference and
20
separate those factors and perhaps reduce bias that
21
way.
22
DR. ENGLUND: Thank you. Dr. Birnkrant,
265
1 would you like even more advice from us?
2
DR. BIRNKRANT: A really quick
question as
3
pertains the pharmacovigilance study, they had
4
proposed a study of five to eight years.
Could we
5
just get a quick discussion on the duration of the
6
trial? In other words, should it
be what was
7
proposed or should it be longer?
8
DR. ENGLUND: I would like to ask
our
9
statisticians, like Victor.
10
DR. DEGRUTTOLA: Well, I think the
issue
11
always comes down to the value of the information
12 and
the feasibility of doing the study.
Obviously,
13
long-term information is always useful but getting
14
information in a reasonable amount of time is also
15
important. If one believes that
if entecavir is
16
likely to have an impact in inducing a cancer, that
17
impact is likely to be seen within five to eight
18
years, then obviously one can increase the power to
19
detect that study by having a fairly large sample
20
size, which is the case for this particular
21
proposal which allows you to detect a reasonable
22
signal in terms of increased risk.
23
Now, if the risk of the cancer doesn't
24
increase for the first eight years but increases
25
sometime in the future, then obviously this kind of
266
1
study won't be able to detect it.
So, I think the
2
question really turns on what biologically is
3 reasonable in terms of the amount of time it
would
4
take entecavir to have an impact on the risk of
5
cancer.
6
DR. BIRNKRANT: So then we may
need to
7
reassess at various time points and as we are
8
approaching that fifth to eighth year make a
9
determination whether or not the trial should be
10
continued or not.
11
DR. ENGLUND: I would just like to
add
12
that as this drug gets used in adolescents and down
13 to
children five to eight years is not sufficient
14
and, hopefully, we would welcome this drug in
15
pediatrics but I also think that the surveillance
16
would need to be longer in that age group.
17
DR. BIRNKRANT: We understand
that.
18
DR. ENGLUND: Dr. Munk?
19
DR. MUNK: I think there clearly
are
267
1
options other than extending the proposed large
2
simple trial, and I would encourage the sponsor to
3
work with the FDA to look at alternatives because I
4
think several of us would like to see longer-term
5
monitoring, whether it is of pediatric patients or
6 of
adult patients, and that doesn't necessarily
7
have to happen within the context of the large
8
simple trial.
9 Question No. 6
10
DR. ENGLUND: We are going to move
ahead
11 to
Question number 6 which, in fact, gives everyone
12 a
last chance to address your pet issues.
Question
13
number 6 is are there other issues that you would
14
like to see addressed through post-marketing
15
commitments?
16
I would just like to ask one question of
17 the
agency, and that is how are these enforced?
In
18
other words, it is a post-marketing licensure but
19
this particular product is absolutely important, we
20 all
are agreeing, for advising or recommending
21
licensure based on these proposed studies. How can
22 you
enforce this?
23
DR. BIRNKRANT: Well, the
post-marketing
24
commitment requests are public so the public will
25 be
made aware of them. This is an extremely
268
1
important situation given the discussion we have
2
just had on question number 5 related to the
3
pharmacovigilance study, so we will also be
4
extremely vigilant in attempting to get the data
5
from that clinical trial.
6
With regard to enforcement, under
7
accelerated approval regulations post-marketing
8
commitments are mandatory. Under
a traditional
9
approval type of approach, less so.
But,
10
nonetheless, they are public.
11
DR. ENGLUND: Thank you. Dr. Wood?
12
DR. WOOD: I would like to request
that
13 the
company and the sponsor seek to collect data
14
about sustained viral suppression so that the
15
duration of exposure could be minimized to the
16
drug. I think the sooner that we
get those kinds
17 of
answers, whether a certain specified duration of
18
treatment results in significant sustained
19
suppression, would be very advantageous to
269
1
clinicians as well as to patients.
2
DR. ENGLUND: Mr. Grodeck?
3
MR. GRODECK: This is less of a
question
4 and
more of a statement or reminder that while
5
viral suppression is nice, the true goal is
6
seroconversion. When you look at
all the available
7
treatments it all boils down to a certain low
8
number of people seroconverting, and I just don't
9
want us all to lose sight of the bigger picture
10
because we are selling a lot of drugs to suppress a
11
virus and we are adding in a lot of problems.
12
Interferon actually shows some role in
13
seroconversion, and I just want to remind the
14
group, both the agency and the applicant, that
15
where we are really headed is seroconversion.
16
DR. SEEFF: I have a
question. Where did
17 the
name Baraclude come from?
18
DR. MORGAN MURRAY: Dr. Wilber,
would you
19
answer that for us, please?
20
DR. WILBER: Dr. Richard
Wilber. In a
21
drug's development as it is approaching
22
commercialization a name has to be selected. The
270
1
name has to be reasonable in terms of the capacity
2 to
use it around the world. Our marketers
would
3
like it to have some link to something about the
4
drug or the process. A variety of
these processes
5
generate long lists of names which then, in the
6
end, have to clear a number of regulatory hurdles
7
both here and around the world.
They cannot be too
8
close to other drug names so that there would be a
9
medication error potentially--a whole lot of other
10
processes. The names are
submitted to regulatory
11
agencies for vetting, as well as our own legal
12
processes. It is a generally
standard process and
13
sometimes interesting names arise from that
14
process.
15
[Laughter]
16
DR. ENGLUND: Dr. Schwarz?
17
DR. SCHWARZ: I just wanted to ask
if
18
there are any studies planned in adults with normal
19
liver enzymes. I raise the
question because, of
20
course, the approved agents to date--interferon and
21
lamivudine and adefovir--all are at least most
22
effective in patients with elevated ALT.
Yet, you
271
1
look at the antiviral efficacy and many of us, or
2 at
least the pediatric hepatologists, follow large
3
numbers of children with very high viral loads and
4
normal ALT values. So, I just
wonder if there is
5 any
consideration to a small number adult trial in
6
normal ALT patients.
7
DR. ENGLUND: Dr. Morgan will
answer.
8
DR. MORGAN MURRAY: We currently
don't
9
have any studies planned in HBV-infected patients
10
with normal ALT. However, as we,
hopefully, enter
11 the
post-marketing phase with the drug we will be
12 talking
with investigators and health authorities
13
worldwide to define what additional studies we
14
should be conducting with entecavir.
15
DR. ENGLUND: Are there any other
16
questions for Dr. Morgan? Dr.
Sherman?
17
DR. SHERMAN: Can you comment on any plans
18 to
do specific studies in patients with renal
19
disease, renal dialysis patients, who have chronic
20
hepatitis B? I know you have
guidelines for dose
21
adjustment but are there any plans to do specific
22
studies in that population?
23
DR. MORGAN MURRAY: Dr. Wilber, do
you
24
have any additional comments on our proposed
25
studies?
272
1 DR. WILBER: I believe, as was pointed
2
out, we have an ongoing, currently enrolling study
3
with decompensated patients, many of whom have
4
renal compromise. We will get a
lot of information
5
there. If this is an area of further
interest we
6
will be glad to talk to the agency and other
7
investigators in terms of refining that information
8 and
making it more robust.
9
DR. ENGLUND: Dr. Munk?
10
DR. MUNK: I imagine it is fairly
high on
11 the
company's list but I would certainly want to
12 see
a resistance analysis of virologic
13
breakthroughs on entecavir.
14
DR. MORGAN MURRAY: In all of our
ongoing
15
studies we continue to monitor resistance and
16
rebound.
17
DR. ENGLUND: Dr. Fish?
18
DR. FISH: Can you comment, other
than in
19 the
HIV-infected population, are other combination
273
1
studies planned of oral therapies?
2
DR. MORGAN MURRAY: We don't have
any
3
combination studies currently planned but, as I
4
said, we will be discussing studies with health
5
authorities and investigators and that is a logical
6 avenue for us to pursue.
7
DR. ENGLUND: Thank you. With that, I
8
would like to give a real brief summary unless
9
there are any other final comments from the
10
committee. Dr. Wood?
11
DR. WOOD: The only comment I have
would
12 be
to commend both the sponsor and the agency.
I
13
think when we had discussions two or three years
14 ago
regarding the approval of adefovir--we clearly
15
have seen a new standard established regarding an
16 NDA proposed for hepatitis B that I think
really
17
should become the standard regarding the global
18
population, the experience of antigen positive,
19
antigen negative patients, treatment experience
20
patients and patients with co-morbid conditions.
21
DR. ENGLUND: Any final comments
from the
22
agency?
23
DR. BIRNKRANT: After you sum up I
will
24
make a brief comment.
25
DR. ENGLUND: Well, Dr. Wood took
the
274
1
words from me. I was involved,
and many of us here
2
were involved in the meeting several years ago and
3 I
would just like to, for the whole committee,
4
compliment and congratulate both the company and
5 the
agency for presenting us with a very complete,
6
well-balanced and very well-documented and
7
referenced study. I think it made
our jobs much
8
easier and we appreciate that.
9
I think we have been able as a committee
10 to
determine that entecavir is a new drug with a
11
very favorable benefit, with potential risks that
12
will be looked for and ascertained as studies go
13 on,
and we feel confident that that will be done
14
with the overseeing of the FDA.
We are happy with
15 the
trials, as Dr. Wood pointed out. It is
16
wonderful to see big enough trials in the risk
17
groups that we have been interested in, both the
18
antigen positive and antigen negative and now, of
19
course, the lamivudine resistant.
So, that has
275
1
been very good to see and the data appears to us
2
robust and when reanalyzed very well put together.
3 I think we still have some questions,
as
4 we
do with any new drug, and these questions are
5
important and we would expect some answers from the
6
company. We hope to see
these. We want to know
7 the
optimal duration of therapy. We aren't
pinning
8 you
down on that yet because we understand trials
9 are
in progress but for clinicians this is
10
critically important. We need to
be able to tell
11 our
patients when they walk in the office that you
12 are
going to be on this drug for years or not.
13
We need to be able to get this into
14
pediatrics. We have discussed
this. We need to
15
know what kind of follow-up we are going to need to
16 do
in our patients; who respond or don't respond to
17
this therapy. And, we need to be
able to give them
18
advice about malignancy and the potential risk
19
thereof.
20
I look forward, and we look forward as a
21
committee, to hearing more about this in the
22
future. So, thank you from the
committee and I
276
1
will turn it over to Dr. Birnkrant.
2
DR. BIRNKRANT: Thank you. I would also
3
like to thank the committee and the consultants for
4 the
lively and important discussions that were held
5
today. They were quite helpful to
us and we will
6
take what was discussed today back to the agency so
7
that we can continue our work on this application
8 and
work with Bristol-Myers Squibb in developing a
9
strong and robust post-marketing plan as well.
10
Thank you very much for all of your help.
11
DR. ENGLUND: Thank you. The meeting is
12
adjourned.
13
[Whereupon, at 3:17 p.m., the proceedings
14
were adjourned.]
15 - - -