U.S. FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
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CELLULAR, TISSUE, AND GENE THERAPIES ADVISORY COMMITTEE
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39th MEETING
OPEN SESSION
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FRIDAY,
MAY 20, 2005
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The
meeting came to order at 2:00 p.m. in room 1113 of 5515 Security Lane,
Rockville, MD. Dr. Mahendra Rao, Chair,
presiding.
PRESENT:
MAHENDRA RAO, M.D., Ph.D., Chair
GAIL DAPOLITO, Executive Secretary
ROSANNA L. HARVEY, Committee Management
Specialist
JONATHAN S. ALLAN, D.V.M., Member
THOMAS H. MURRAY, Ph.D., Member
DAVID M. HARLAN, M.D., Member
JAMES J. MULE, Ph.D., Member
This transcript has not been edited or corrected,
but appears as received from the commercial transcribing service. Accordingly the Food and Drug Administration
makes no representation as to its accuracy.
P-R-O-C-E-E-D-I-N-G-S
2:08
p.m.
MS.
DAPOLITO: Okay, good afternoon. This is Gail. We're going to try and get started with the members and hope the
others will sign on soon. Dr. Rao, I
know Dr. Harland said he'd be a little delayed. We're trying to reach Dr. Allan now.
DR.
RAO: You have a quorum anyway?
MS.
DAPOLITO: We can get started. We should have a quorum by the time we need
to vote. We'll go ahead and get
started, if that's okay with you.
DR.
RAO: That's absolutely fine.
MS.
DAPOLITO: Okay. All right.
I'll just go ahead and take a roll again. Dr. Rao is here, Dr. Mulé is here, and Dr. Murray. Do we have Dr. Allan or Dr. Harlan at this
time? No. Okay.
At
the site with me are Drs. Keith Webber and Dr. Kathy Carbone, Gail Dapolito,
and Rosanna Harvey. We have two members
of the public joining us, too, and a member of my staff of the advisory
committee staff, Christine Walsh.
There's
the site on the NIH campus. Would you
please say who's there?
DR.
ROSENBERG: Amy Rosenberg.
DR.
DONNELLY: Ray Donnelly.
MS.
DAPOLITO: Dr. Puri's at a third site.
DR.
PURI: Hi, I'm here.
MS.
DAPOLITO: Okay. I will read - Dr. Rao, if it's okay with
you, I'll read the conflict of interest statement.
DR.
RAO: Please do.
MS.
DAPOLITO: Okay. The following announcement addresses
conflict of interest issues associated with today's meeting of the Cellular,
Tissue and Gene Therapies Advisory Committee, formerly the Biological Response
Modifiers Advisory Committee, on May 20, related to the review and discussion
of the Intramural Research Programs of the Division of Therapeutic Protein and
the Clinical Proteomics Program.
Based
on the agenda made available, it has been determined that the committee
discussions present no potential for a conflict of interest.
Before
I turn the meeting back over to you, Dr. Rao, I'd like to ask the members of
the committee, do they have all the handouts, the agenda and the slides and
their copy of the site visit report?
DR.
RAO: I do.
MS.
DAPOLITO: Okay. Because if not, we can e-mail it to you or
fax it out right now, but you should have everything, I hope. There's another note on the agenda.
We
did switch the order of the speakers for the Division of Therapeutic
Proteins. It will be Dr. Rosenberg, Dr.
Johnson, and then Dr. Donnelly. That's
all I have. Dr. Rao?
DR.
RAO: Welcome everyone. I think we'll just get right to it. The first speaker is going to be Dr. Puri,
who is the Director of Division of Cellular and Gene Therapies and he'll give
us an update on the Clinical Proteomics Program. Dr. Puri?
DR.
PURI: Yes.
DR.
RAO: Begin any time.
DR.
PURI: Oh, okay. Thank you very much. I would like to thank the committee for your
valuable time and help in the evaluation of our research program of our
colleagues in the Division of Cellular and Gene Therapies.
Evaluations
and recommendations are extremely valuable to us and I highly appreciate
it. As -- Dr. Emmanuel Petricoin is not here today, I will basically
describe the Proteomics Program and where we are with the --
MS.
DAPOLITO: Dr. Puri, may I interrupt you
for a minute?
DR.
PURI: Sure.
MS.
DAPOLITO: Hello, this is Gail. Who just - may I ask who just came on the
line?
DR.
ALLAN: I'm afraid to say. It's John Allan.
MS.
DAPOLITO: Hi, Dr. Allan. Welcome.
Okay. Dr. Puri - I'm sorry, we
interrupted Dr. Puri in his brief presentation. I'm sorry, Dr. Puri.
DR.
PURI: That's okay. I'm going to continue on that train that as
Dr. Petricoin is not here today, I'll briefly describe the Proteomics Program
and tell you a little bit about where we are with the program.
The
site visit committee heard from Dr. Petricoin the details of the research
program during his presentation. His
main focus of his work is on the establishment of proteomics technology, -- to
the development of a standard for the technology, even in the diagnosis and
implication of response to drug therapies.
Dr.
Petricoin's presentation mainly focused on tissue proteomics, looking at the
possible for proteomic profile, but not much on the serum proteomics
identifying biomarkers for early diagnosis of cancer, particularly ovarian
cancer, that he has published and it was provided to you in the briefing
document.
Dr.
Petricoin's research projects were undertaken under the umbrella of FDA/NCI
Clinical Proteomics Program, which was published over four years ago by the
Center for Biologics Evaluation and Research, FDA, and the National Cancer
Institute Center for Cancer Research for invention, government, and employment
of proteomic technologies for translation from bench to bedside.
Dr.
Petricoin was a Co-Director from the FDA side.
Lance Liotta was a Co-Director from the NCI side.
Dr.
Petricoin had recently moved on to a local university, George Mason University,
where he's now a Co-Director at Center for Applied Proteomics and Molecular
Medicine and Professor of Life Sciences at George Mason University and his appointment
there began on April 1, 2005.
After
his departure, his fellows are still with us.
They're trying to complete their ongoing activities and also they are
helping their colleagues to learn some aspects of this technology, particularly
tissue proteomics.
Some
of -- colleagues, -- division of
cellular and gene therapy colleagues are learning this technology from
his fellows and a technical person.
We
intend to maintain this resource in the Division of Cellular and Gene Therapies
and this technology is what we consider very important in the correct tradition
of our complex biological projects, such as cellular and gene therapy and
combination of products.
NCI
has expressed interest in continuing a joint collaboration on this
technology. Therefore, Dr. Carbone, who
is our Scientific Director of Research at CBER, and I recently met with the new
Director at Center for Cancer Research, Dr. Bob Wiltrout and a clinical
person - the Clinical Director is Dr.
Lee Hellman - about a couple of weeks ago to express our interest in this
collaboration.
The
Division of Cellular and Gene Therapy and CBER intends to commit significant
space, equipment, and some personnel to continue this collaboration,
particularly in the area of critical path need for biomarket development to
assess safety, toxicity, efficacy of cellular and gene therapy products for
cancer, and linking the outcome of biomarkers with the clinical outcome.
They're
also interested in the development of biomarkers for product quality and manufacturing
our cellular and gene therapy products and combination products.
At
this point this might spark some of the -- at this point and open any
discussion for any questions. We'll
appreciate any committee insights and recommendations of the Clinical
Proteomics Program at CBER. Thank you.
DR.
RAO: Thank you, Dr. Puri. We have time for a couple of questions and
maybe I can lead off with a question.
Is there a plan to replace Dr. Petricoin's position or hire, recruit
somebody into his position, or is it to absorb this into another program?
DR.
PURI: I believe so, yes. The answer to that question is yes. We have a plan that we are under negotiation
with the National Cancer Institute of their level of their commitment, but DCGT
is willing to commit at least to one person, to bring perhaps an additional -
preliminary part to bring a tenure track person that will not only be expert in
the proteomics technology, but also a protein biochemist that can also help in
correct -- similar to a vaccines product that we have, that person can also
bring the expertise on some analytical tools that the proteomics technology
uses.
DR.
EPSTEIN: Raj, can I comment?
DR.
PURI: Sure.
DR.
EPSTEIN: This is Sue Epstein and you
might want to mention that that one person would have additional support.
DR.
PURI: Right. We also have - I didn't want to go into a whole lot of details,
but we had a couple other people within the Division of Cellular and Gene
Therapies.
They're
one of the technical staff and a staff scientist. They were left behind when their principal investigator moved on
to a different position about a couple of years or so ago.
The
plan is that we could certainly support that new tenure track person with these
two people to mobilize that particular group so we can establish this program
and --
DR.
RAO: Is the take home message then that
the new group will be smaller or the same size that what was Dr. Petricoin's
current level of support?
DR.
PURI: Actually, Dr. Petricoin's current
level of support was two FTEs, including himself. The new plan is that -- three FTEs, now.
--
anything at this point are NCI's commitment, but we are negotiating with Bob
Wiltrout and Lee Hellman and -- by looking into this whole program and their level
of support.
I
think in the next couple of weeks, we will have a follow-up meeting with them,
trying to come up with the overall plan.
DR.
RAO: The reason I asked was because the
recommendation from the committee was reviewed, and we'll hear a little bit I
guess on this, seemed to be extremely positive on the direction and the
necessity of that kind of program.
DR.
CARBONE: This is Kathy Carbone. Can I say something here, Raj?
DR.
RAO: Yes. Go ahead.
DR.
CARBONE: I want to emphasize that we
agree fully and we agree that without this kind of expertise, we simply can't
do our job as well as we need to do it.
Putting these under the rubric and coordinating better across the
program's genomics and proteomics and the regulatory mission, we think it's
imperative.
Now,
we have to do this in a setting of not only not increasing resources, but
shrinking resources. I want to
compliment Raj and Suzanne from OCTGT with coming up with possibilities that
involve shifting resources around, because this is basically it for a
proteomics resource at CBER.
We
have to do what we need to do because we do value this very highly.
DR.
MULE: This is Jim Mule. Just a couple of other questions. Now, I know Dr. Puri mentioned not getting
into too much detail, which I agree with, but as part of the report, with the
administration of the program, it would be good to know precisely who has left
with Chip and what impact that has, I mean, in the overall sort of continuation
of the efforts to not necessarily slow things down, but try to keep the pace
going.
Specifically,
it's Lowenthal and I'm not exactly sure how you pronounce the name, Wolfco
(phonetic)?
DR.
CARBONE: I think the bottom line is
everybody.
DR.
PURI: Everybody is left?
DR. RAO:
Everybody is here.
DR.
PURI: Everybody is here, or they left?
DR.
RAO: No, they are here, but some of
them will be leaving, they're here --.
DR.
PURI: Okay.
DR.
CARBONE: The bottom line, though, Raj,
is they're all going, and they're all going to be gone by August, correct?
DR.
PURI: Right. By August.
DR.
CARBONE: Yes. They're all going.
They're leaving with Chip, essentially, and we have to recreate from the
ground up and --
DR.
MULE: Okay. That's good to know. Then
on the NCI side, has an individual been identified by Wiltrout and Lee as to
how that connection can be maintained, if it can?
DR.
PURI: Yes, Jim. They're approving, I think, one other name I
have been interacting with, at least in the -- branch.
DR.
MULE: Okay.
DR.
PURI: I had met and CBER is involved in
the clinical proteomics program with Lance.
Now, Lance is gone. I think Bob
Wiltrout also mentioned that at least, perhaps, would be one other person that
replacing and putting him in this collaboration.
DR.
MULE: Okay. Thank you.
MS.
DAPOLITO: Can I interrupt for just a
second? This is Gail.
(UNIDENTIFIED
SPEAKER): Yes.
MS.
DAPOLITO: Dr. Harlan, did we hear you
come on?
DR.
HARLAN: You did.
MS.
DAPOLITO: Okay.
DR.
HARLAN: I'm sorry I was late.
MS.
DAPOLITO: That's okay. Welcome.
Okay, so Dr. Rao, all the members are in attendance that are going to
be.
DR.
RAO: Oh, great.
MS.
DAPOLITO: Thanks.
DR.
RAO: If there are no further questions,
maybe we can move on to the individual research programs and the presentation?
MS.
DAPOLITO: Okay.
DR.
ROSENBERG: Okay, so I think I am next
here on the agenda. I have provided
everyone with the materials that attest to the accomplishments of our two
investigators since their last site visit.
Of
course, my short presentation time really precludes me from going into those
details, so I am going to really address the recommendations.
As
a general remark, I just want to say that because we haven't seen the final
draft of the site visit report, we'll be addressing the site visit
recommendations as we understand them from the debriefing and from brief
descriptions we've been permitted to get of the final draft report.
First,
I will address the recommendations for Dr. Donnelly, and then those for Dr.
Johnson. Dr. Donnelly provides the
agency, as you know, with critical expertise in the area of type-1 interferons,
their chemistry and biology, as well as their activities in regulating cytokine
networks.
This,
of course, is based on his highly regulatory related research. It's very clear that Dr. Donnelly has made
key strides in his research and in his regulatory area since the last site
visit and we heartily agree with the recommendation to promote Dr. Donnelly.
We
certainly wish we could give more support to him, but this is very unlikely,
given the fact that we are dealing with a substantial budget cut this year.
We
certainly concur with your recommendations on Dr. Donnelly. We'd love for you to put in some strong
language about the ability to offer such investigators additional support.
Now,
we'll go to Dr. Johnson's recommendations.
Again, Dr. Johnson's expertise in entomology (phonetic) and signal
transduction is vital to the agency's regulatory mission. I think that's easy to see from the kinds of
products that we regulate and are regulated in the larger CBER context.
Dr.
Johnson's scientific program is exemplary and it's highly regulatory
related. He's made very impressive
progress since the last site visit, both in terms of the number and quality of
publications, as well as novel findings.
I
want to point out that he has made this immense scientific progress despite a
very heavy regulatory and supervisory load.
He was the Chair of three BLAs from June 2001 to July 2002 and he's been
Chief of the Laboratory of Chemistry since May 2004.
I
think you received information about how extensive responsibility that is and
what kind of a time commitment it is. I
mean, it's extensive.
Now,
let's get to the recommendations.
Basically, there were several recommendations that focused on the
following. One, that he had not yet
published some key findings. The second
concerned attendance at national and international meetings. The third concerned review duties for journals. The fourth concerned collaborations.
I
would point out that he received no criticisms of his research, either the
quality or the direction, and that there was really a substantial endorsement
of his research programs.
We
are substantially in agreement with the findings and we do appreciate the
committee's advice.
DR.
RAO: Somebody joined in. Maybe they can introduce themselves? Hello?
DR.
ROSENBERG: Maybe somebody was just
shifting a microphone. I don't know.
DR.
RAO: Okay. Amy, are you done?
DR.
ROSENBERG: Oh, not at all.
DR.
RAO: Okay. Then please go ahead.
DR.
ROSENBERG: Yes. The first concern was that there was
unpublished data for two additional manuscripts and I would like to point out
that since the site visit, he has published these findings.
One
is published in molecular and cellular biology and the other is in press. It will be out in June, again in molecular
and cellular biology. We believe that
this concern has really been very successfully addressed.
Regarding
his service as a reviewer for journals, he does serve as a reviewer for three
very high-quality journals that are research appropriate, and so we believe
that this concern regarding this service has been addressed.
Regarding
the collaborations and the extent of collaborations, I think if you go through
his CV and you look at his bibliography, rather, and you go through the
publications, you will see that he has been extremely collaborative in the past
in numerous publications that were done collaboratively.
He
is in fact now establishing new collaborations in the continuing investigation
of the small serine theorine kinase. We
think that this actually - this concern has been successfully addressed.
Now
regarding attendance at national and international meetings, we substantially
agree. This is an important thing for
him to be able to do, especially given how beautiful the work is that he has
done, to be able to share this, to be able to project it out, to be able to
really maximize the impact of it.
I
just would like to point out that everybody has to prioritize their
responsibilities and their time and I think in the case of Dr. Johnson that his
ability to attend these kinds of meetings has been very strongly influenced by
the amount of regulatory responsibilities that we have put on him and he has
executed brilliantly.
I
also would like to point out that this concern will be addressed within a very
short time frame, we think substantially less than a year.
In
sum, I think just to conclude, that Dr. Johnson is really - he's an ideal
researcher regulator. He really
executes both programs brilliantly.
He's
got a cutting-edge, highly regulatory related research program, and he's
assumed extensive regulatory and supervisory responsibilities. Retaining him is absolutely critical to our
regulatory mission.
We
believe that he has in fact addressed the most substantive issues in the site
visit evaluation and that the issues concerning the attendance at scientific
meetings can be accomplished and addressed successfully in time frame far shorter than two years.
We
would appreciate further discussion on this in the closed session. That concludes my presentation.
DR.
RAO: Thank you, Amy. I want to ask the committee whether they'd
like to hold questions until they've heard from Dr. Johnson and Dr. Donnelly,
or would they like to ask specific questions for Dr. Rosenberg right now?
DR.
MULE: This is Jim Mule. I personally would prefer holding off until
we hear the presentations.
DR.
RAO: Great. I would second that. If
there's no burning question, we can maybe move on to the other two
presentations.
MS.
DAPOLITO: Dr. Rao, this is Gail.
DR.
RAO: Yes.
MS.
DAPOLITO: Just to keep in mind if there
are some questions that would best be saved for the closed session. I'll leave that up to you and Dr. Mule.
DR.
RAO: That's right.
MS.
DAPOLITO: Okay. Thank you.
DR.
JOHNSON: This is Gibbes Johnson. I will just give a brief description of the
regulatory work, efforts, and scientific work and efforts since the January 19,
2005 site visit.
I'll
just review the regulatory work we've been doing in the Laboratory of Chemistry
since that site visit. We're very near
completion of a BLA review for an enzyme replacement therapy. We've also done a pre-BLA review for another
enzyme replacement therapy, which we'll be receiving soon.
Both
of these are priority six-month reviews, so we've been very busy with
that. We've also had 20 BLA
supplements, four pre-I&D reviews, and three I&Ds and just since I
prepared these slides yesterday and today, we've had four more I&Ds come
in, so we're very, very busy right now.
Let
me just move on to the research program.
My laboratory studies the characterization of signal transfusion protein
kinases. It has a strong relevance to
the FDA mission since disregulation of protein kinases, result in many
diseases, and numerous FDA-regulated drugs target these kinases.
CDER
currently regulates 12 drugs with target to ErbB family of receptor tyracine
(phonetic) kinases, including Herceptin (phonetic) against ErbB2 and another
example is a synthetic EGF receptor kinase active site inhibitor arresa
(phonetic).
Studies,
or discovery and studies on the protein kinase such as TK provide insight into
the molecular mechanisms underlying human infertility disorders associated with
impairment of postmyotic male germ chromatin condensation, germ cell chromatin
condensation, and this is the common defect in infertile male patients.
I
would just like to move and describe the two main projects that are ongoing in
the lab and where we're trying to -- project deals with mechanisms of
activation and signaling of the ErbB receptors, which includes the EGF
receptor, ErbB2, ErbB3, and ErbB4.
One
of our future goals is to identify the EGF receptor active site -- critical to
the ligand induced regulation of kinase specificity and signaling.
Last
year, we published, in JVC, that ligand actually not only activates the kinase,
but it regulates specificity, which is critical to downstream signaling.
We're
also interested in investigating the potential role of a protein called PELP1,
which is a coactivator of the estrogen receptor in EGF receptor signaling. Preliminary evidence suggests or indicates
that it's a substrain for the EGF receptor.
We
also have a knock-in mouse, which expresses only kinase inactive EGF receptor
and we're using that to investigate the role of the intrinsic EGF receptor
kinase activity and EGF receptor function in vivo and this will also help us
predict potential clinical toxicities that may be observed with EGF receptor
inhibitors in clinical trials.
A
last part of this project is we're also studying - trying to elucidate the
ErbB2 auto inhibition and activation mechanisms. ErbB2, unlike the other members of this family, does not have a
ligand.
Now
I'll turn to another research project involving the characterization of the
novel protein kinase SSTK, which we discovered in about 2000. We're interested in elucidations and
mechanism of SSTK action in spermiogenesis because this kinase is essential to
male fertility.
We're
interested in determination of the molecular mechanisms of the kinase's
enzymatic regulation, determination of the effect of SSTK gene deletion on
hormones whose production is controlled by the pituitary.
We're
also further characterizing the female SSTK knock-out mouse phenotype and we're
characterizing a novel protein, which we cloned and discovered, called SSTK
interactive protein and are studying its function as a substrait (phonetic) and
regulator of SSTK's action.
We've
also had two papers published in Molecular
and Cellular Biology, one published just this month, and another one in
press the June 15th issue.
The
first one is on the initial characterization and discovery of SSTK and its
demonstration that it's essential for male fertility.
The
second one is an ongoing publication studying Calorin (phonetic), which is a
row -- for rack and several of the other row guanine exchange nucleotype
factors, and NGF receptor signaling and NGF-induced neuronal
differentiation. That will be in MCB in the next issue.
That
concludes my presentation.
DR.
RAO: Thank you, Dr. Johnson.
DR.
DONNELLY: Good afternoon. This is Ray Donnelly speaking. I thought I'd just give a brief update on
the research activities in my laboratory since the site visit. As Amy mentioned during her presentation, a
lot of the work in my laboratory overlaps with the regulatory review work that
I do here at the FDA for products, specifically for the interferons, interferon
alpha and some of the more recent variants of interferon alpha that are being
developed for clinical study.
As
you heard a lot about during the site visit back in January, one of the two
primary projects in my laboratory is a characterization of several novel
interleukin-10 (phonetic) related cytokines.
These
include IL-19, 20, 22, 24, 26, and a small group of cytokines that we refer to
as interferon lambda, that are also known as IL-28 and IL-29.
I
believe that several of these cytokines probably represent novel biologic
products that we will ultimately be charged with regulating in the
not-too-distant future.
I
think it's important to understand as much as we can about the biology of these
cytokines and the genes that are induced by these cytokines so that we're
well-positioned to be able to understand and provide good guidance with regards
to clinical development of these cytokines as biologic products.
In
terms of this first project, in the future, we are planning to determine which
cell types and tissues express receptors for these cytokines, how broadly are
the receptors distributed on different cell types and tissues.
Also,
we'd like to identify specific genes that are activated by signaling through
the receptor complexes for these cytokines.
Finally,
in collaboration with Howard Young at the NCI Frederick (phonetic), we have
embarked on a series of studies to develop transgenic mice that express the
IL-22 receptor, or the interferon lambda receptor, on lymphoid cells
specifically, and then ultimately, to test whether or not that provides an
advantage in terms of an anti-tumor effect in various tumor models that they
have in place there.
As
I've already mentioned, on some of the what we believe to be the clinical
relevance of this, I think some of the benefits or potential benefits of these
types of studies is that we may be able to identify novel markers of interferon
activity, because as I talked to you about during the site visit, interferon
lambda shares largely the same signaling pathway as interferon alpha and beta
and seems to induce essentially the same gene expression profile.
Along
similar lines, we're interested to know whether IL-22 and/or interferon lambda
are associated with certain diseases.
For
example, IL-22 seems to be elevated in patients with psoriasis. There may be a good rationale for developing
antagonists of IL-22 in certain disease states, such as psoriasis or psoriatic
arthritis.
With
regards to interferon lambda, I think one of the obvious clinical applications
that we hope to see in the not-too-distant future is whether it will provide an
alternative to classical type-1
interferons, specifically, interferon alpha, as a treatment for chronic
viral infections and in particular, chronic hepatitis C and hepatitis B virus
infections.
We
actually have, since the site visit, developed some in vitro data to
demonstrate that the interferon lambda will and does inhibit the expression of
an HCV relicon in a liver cell culture system.
That's
all I wanted to say with regards to project number one. Regarding project number two, which I really
didn't talk about in any detail during the site visit, but it was presented to
you in the briefing package, we have actually for several years been
characterizing the IL-4 IL-13 signaling pathway in macrophages and
monocytes.
I
believe that that's important because, as I'm sure many of you are aware, IL-4
and IL-13 have been implicated in the pathogenesis of many diseases, so-called
TH2 type predominant diseases, such as asthma or pulmonary fibrosis.
By
understanding how IL-4 and IL-13 signal and their role in regulating gene
expression in macrophages and monocytes, we believe that it may have
application or implications for understanding and developing better therapeutic
strategies for controlling those diseases that I mentioned, asthma --.
In
that context, we are now trying to identify genes that are specifically
inducible by signaling through the IL-4 IL-13 pathway and to see if we can
identify again potential pharmacodynamic markers of IL-4 and IL-13 signaling
that could be exploited perhaps in the future -- IL-4 and IL-13 antagonists is
doing what it should do; that is, blocking IL-4 or IL-13 signaling.
I
think I'll close with that. I just
wanted to comment that we have published quite a bit over the last few years
with regards to the first project that I talked about, the IL-10 related
cytokines.
We
have two papers now submitted for publication, one in JVC and one in the Journal of
Immunology, on this second project, and so I believe we're making progress
in both areas. That's all that I have
to say.
DR.
RAO: Thank you, Dr. Donnelly. I have a question for the committee, if
there are any specific questions that you feel you need in open session, or
would you like to just do this all in closed session?
DR.
MULE: I just have two general
questions, one for Dr. Johnson and one for Dr. Donnelly, if I could.
DR.
RAO: Go ahead.
DR.
MULE: Dr. Johnson, can you maybe tell
us where you are with the phenotype of the knock-out mouse?
DR.
JOHNSON: Well, we characterized the
defect in the --
DR.
MULE: This is the SSTK knock-out?
DR.
JOHNSON: Exactly.
DR.
MULE: Yes.
DR.
JOHNSON: How far have I come since the
site visit, or do you just want a general overall of --
DR.
MULE: No, how far have you come since
the site visit? Because you may recall
the high level of interest the committee had with respect to that knock-out
from the standpoint it could open up numerous possibilities for collaboration
once the publication went forward with that particular mouse.
DR.
JOHNSON: Well, I've been contacted by
several individuals since then, but the paper has only been out about a week.
DR.
MULE: Okay.
DR.
JOHNSON: You're asking - do you want me
to tell you more about the phenotype or what else we know?
DR.
MULE: No, not necessarily. Just essentially, what level of effort now
will be put on that knock-out from the standpoint of additional collaborations?
DR.
JOHNSON: Well, as much as I can. Now, I only have one person working on that
and he does regulatory work also.
DR.
MULE: Right.
DR.
JOHNSON: We will - I've made some
efforts to contact an expert actually in nuclear architecture and chromatin
remodeling to try to help us understand the defect in the DNA condensation.
I
was also contacted the other day about ‑ somebody, an expert in
actual spermatozoa capacitation as to whether the knock-out might be also
influencing that process.
There
are several other interesting aspects of the phenotype. You may not remember, but we've now got
statistical data to indicate that we get approximately somewhere about two and
a half to three males for every female in the offspring of the knock-outs, and
that has now got a statistical significance of about .01.
DR.
MULE: I see.
DR.
JOHNSON: The male knock-outs are
smaller. I've also contacted a couple
individuals at NIH who are interested in behavioral studies and are going to -
I'm trying to convince them to maybe put them in some of their behavioral
studies.
DR.
MULE: Fair enough. I'm very pleased actually to hear about
these additional interactions, because the reality is, once that paper becomes
older than a week old, you're going to have a number of requests, is my guess,
and it's going to be a very valuable tool for your further progress and
interaction. It's very good, at least
for me, to hear the status of that knock-out.
I thank you for that.
Dr.
Donnelly, do you have more information about the interferon lambda toxicity
profile as it might compare to some of the other type-1 interferons?
DR.
DONNELLY: In terms of in vivo studies
in animals?
DR.
MULE: Yes. In vivo.
DR.
DONNELLY: No, although I've actually
been contacted by a fellow via e-mail.
I haven't even had the - this is just very recently - a fellow in I
believe it's the NCI; it may actually be NHLB - who is a veterinarian who
studies an HCV chimp model and he heard a presentation I gave here at the NIH a
few weeks ago and became very excited about interferon lambda.
He
is interested in actually testing it in a chimp model, because I think that's
the next best thing to an actual -- study in human beings. There is a chimp model that replicates the
HCV virus. Whether that will be - we
just haven't explored it yet.
DR.
MULE: Exactly, because clearly, it
would be very exciting if lambda offered a different perhaps, or better,
therapeutic profile than what we currently have, whether it be in virus
infections or tumors, but also critical to that is going to be how it compares
on a toxicity profile with the other interferons.
It's
very exciting and I think we all look forward to seeing some of that
information down the road.
DR.
DONNELLY: I agree. I thank you for your comments. I think - as I mentioned, there was a - we
had a, here at the NIH, a conference on type-1 interferons that I participated
in about a month ago.
One
of the speakers there was a person you may know, Jay Hooknagel --
DR.
MULE: Oh, yes.
DR.
DONNELLY: Who is an international
expert on HCV, so his presentation was quite interesting, but he also - he and
I spoke afterwards and he also was enthusiastic about the prospect of an
alternative interferon that obviously has a different receptor distribution
than the interferon alpha beta receptor distribution that could be used for
this purpose.
DR.
MULE: Exactly.
DR.
DONNELLY: -- addition, he is interested
in it as well.
DR.
MULE: Great. Well, Dr. Rao, that's all I had.
DR.
RAO: Does anybody else have any other
questions? If not, Gail, do we need to
ask for an open public hearing and comments right now?
MS.
DAPOLITO: I have had no prior
requests. There are two guests at my
site and I will ask if anyone had any interest in addressing the
committee. No? I get a no, so we have no open public
hearing speakers. We can continue.
DR.
RAO: Okay, then I would like to enter
into closed session and give Gail a couple of minutes to reorganize things.
MS.
DAPOLITO: Thank you.
(Whereupon
the open session went off the record at 2:48.)