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Questions and Answers on
Natalizumab (marketed as
Tysabri)
What is Tysabri?
Tysabri is a monoclonal antibody that binds to a protein
called alpha-4-integrin. Integrins are found primarily on the
surface of white blood cells, and play a role in immune system
activity.
What is Tysabri used for?
Tysabri is approved to treat patients with relapsing forms of
multiple sclerosis (MS) to reduce the frequency of
exacerbations. It was approved based on results achieved after
approximately one year of treatment in ongoing controlled
trials.
What is Multiple Sclerosis?
Multiple sclerosis (MS) is a serious disease in which the
immune system attacks the person's brain and spinal cord. The
disease causes a wide range of symptoms including fatigue,
difficulty walking, numbness, and vision problems. MS frequently
progresses to severe disability and/or death. Relapsing MS is
the most common form of this disease.
How is Tysabri given?
Tysabri is given by intravenous infusion once every 4 weeks.
Why is marketing of Tysabri being suspended?
A patient with MS in a long-term clinical trial of Tysabri
recently died from progressive multifocal leukoencephalopathy (PML),
a rare neurologic disease; a second patient with MS in the same
trial who was receiving Tysabri has a confirmed diagnosis of PML.
Because the relationship between use of Tysabri and PML is not
clear, Biogen Idec, the manufacturer of Tysabri, has voluntarily
suspended marketing, as well as dosing of Tysabri in clinical
trials, until the relationship is better understood. The FDA
concurs with this decision.
What other steps has the manufacturer taken?
The manufacturer is notifying physicians of these cases and
informing them that use of Tysabri should be discontinued until
further notice. Similar notices are being sent to physicians who
are studying Tysabri as part of a clinical trial. Biogen Idec is
recommending that all patients who have received Tysabri and
have signs and symptoms suggestive of PML be evaluated. Any
potential case should be reported to Biogen Idec, or to the
FDA’s MedWatch reporting system by telephone (1-800-FDA-1088),
facsimile (1-800-FDA-0178), the MedWatch Web site at
www.fda.gov/medwatch,
or mailed to MedWatch (HF-2, 5600 Fishers Lane, Rockville, MD
20853-9787). The manufacturer is reviewing the records of all
patients who have received Tysabri in a clinical trial and
evaluating these patients to determine if there any other cases
of PML in this population. Biogen Idec is also convening a panel
of medical and scientific experts on this condition to give
advice on appropriate steps, including how to assess patients
who have received Tysabri and who may have developed undetected
early-stage PML. The FDA will maintain close contact with the
manufacturer during this process and issue further information
as it becomes available.
What kinds and numbers of patients have received Tysabri?
Patients have received Tysabri either in a clinical trial or,
since its approval in November, 2004, through their personal
physician. Clinical trials of Tysabri include patients with MS,
Crohn’s disease, and rheumatoid arthritis. About 3000 patients
have received Tysabri in clinical trials; over 1700 have
received it for at least a year and approximately 1100 for over
two years. Outside of a clinical trial, Tysabri is only approved
for patients with MS. According to Biogen Idec, outside of
clinical trials, approximately 5000 patients with MS have
received Tysabri through their primary physician; however,
because Tysabri was approved only recently, these patients have
only received at most a few doses of Tysabri.
Have there been any cases of PML in the 5000
patients receiving Tysabri through their primary physician?
There have been no cases of PML reported or detected in
patients receiving Tysabri outside of a clinical trial and no
cases outside of the trial in patients with MS.
How long will this suspension last?
The availability of Tysabri in the future will depend on the
analyses of the data being obtained by the drug’s manufacturer.
Why was marketing suspended because of just two confirmed
cases of PML?
Although these two confirmed cases of PML do not automatically
mean that Tysabri causes PML, and additional information needs to
be obtained to fully understand the connection, if any, between
Tysabri use and PML, the FDA and Biogen Idec are concerned about
the possibility that other patients who have received Tysabri may
have developed undetected early-stage PML. PML is a very rare and
potentially fatal condition that is not known to occur in patients
with MS. Until this situation is better understood, the
manufacturer has voluntarily suspended marketing of Tysabri and
its use in clinical trials. The FDA concurs with this decision.
The manufacturer is convening a panel of medical and scientific
experts on this condition to give advice on appropriate steps,
including how to assess patients who have received Tysabri and who
may have developed undetected early-stage PML.
In the general population, PML is extremely rare, and
virtually never occurs in individuals with normal immune
systems. 1 – 5% of AIDS patients may be diagnosed during their
lifetime; PML has also occurred in organ transplant recipients
who have received immunosuppressive medications, as well as
cancer patients.
What causes PML?
PML is thought to be caused by a virus called JC virus (JCV).
Most people are exposed to this virus in childhood and carry it
in a dormant state but never develop illness. PML occurs almost
exclusively in individuals with suppressed immune function who
carry JCV. The immune suppression allows the virus to cause
disease.
Is PML contagious?
PML is not thought to be contagious, and isolation
precautions are not needed.
Is there any treatment for PML?
There is no known effective treatment for PML, although
reversing immune system suppression may slow or arrest the
progress of the disease.
Does Tysabri cause PML?
At this point, the connection, if any, between Tysabri use
and PML is not known.
Is PML more common in patients with MS?
Although the symptoms of PML may appear similar to those of
MS, there does not appear to be a direct relationship between
these two diseases, and patients with MS are not thought to be
at higher risk than the general population for development of
PML.
Did the patients who developed PML have other
possible reasons to develop this disease?
Neither patient had typical risk factors for PML. Both
patients were receiving Avonex (interferon beta-1a), another
approved treatment for MS, at the same time that they were being
treated with Tysabri. Prior to approval, the manufacturer of
Tysabri had studied its use in combination with Avonex; no cases
of PML were observed in patients receiving the combination. The
use of interferons, including Avonex, has not been associated
with PML. FDA has analyzed data in its post-marketing database
and not found any cases of PML reported in patients receiving a
beta interferon. It is not known if Tysabri in combination with
a beta interferon might cause PML.
How long has the FDA known about this
situation?
FDA was first provided with preliminary information about
these cases by Biogen Idec late on the afternoon of Friday,
February 18. Details of the cases became available over the next
week.
What is the FDA doing about this situation?
In addition to issuing this advisory, FDA has been in close
contact with the manufacturer of Tysabri, and concurs with their
decision to voluntarily suspend marketing of Tysabri and dosing
of Tysabri in clinical trials. FDA is also imposing a clinical
hold on trials of Tysabri, legally prohibiting further
investigational use of Tysabri until more information is
available. Although these events occurred in clinical trials,
FDA has also been analyzing data from its post-marketing
database to better understand any possible connection between
Tysabri, Avonex, and PML. FDA is also working with the
manufacturer to determine the best methods for assessing
patients who have received Tysabri in order to assure their
safety and understand the connection, if any, between Tysabri
and PML. FDA will issue further information as it becomes
available.
When was Tysabri approved?
Tysabri received accelerated approval in November 2004.
What does it mean that Tysabri received
accelerated approval?
Accelerated approval is a program the FDA developed to make
new drug products available for serious or life threatening
diseases when they appeared to provide a benefit over available
therapy. Tysabri was approved on the basis of a clinical study
showing that Tysabri, when added to Avonex, reduced the risk of
exacerbations by 54% compared to Avonex alone. Tysabri by itself
reduced the risk by 66% compared to placebo in another clinical
study. These results represented an important and meaningful
benefit for patients with MS. At the time of approval,
approximately 1,100 patients with MS had received Tysabri for
one year or more. As a condition of approval of Tysabri, the
manufacturer was required to continue these clinical trials
through a period of two years to show that the drug continues to
provide benefit. The two cases reported here occurred in
patients in the continuation phase of these trials.
Why didn’t the FDA wait longer before approving
Tysabri?
The results shown in the clinical trials of Tysabri showed an
important and meaningful benefit in the treatment of MS, a
serious disorder that can lead to permanent disability or death.
The efficacy results, in combination with the safety profile of
Tysabri observed in clinical trials, supported accelerated
approval. This allowed Tysabri to be made available to patients
with MS earlier than would be the case for traditional approval.
No cases of PML were observed in the clinical trials supporting
the approval of Tysabri.
Shouldn’t the FDA have known this might happen?
PML is a rare condition that does not occur even in the vast
majority of patients, even those with suppressed immune systems.
During the review of Tysabri, the FDA conducted an intensive
analysis of possible adverse events that might be connected to
effects of Tysabri on the immune system. No cases of PML were
seen in the clinical trials that were the basis for approval of
Tysabri, nor were infections characteristic of immunosuppression
observed. However, for any approved therapy, new and unexpected
adverse events may occur that were not seen in clinical trials.
In the case of Tysabri, required post-marketing studies were
ongoing and facilitated rapid reporting of and response to these
events.
Are patients with MS at more risk of developing
PML if they have been treated with Tysabri for a long time?
The relationship, if any, between length of treatment with
Tysabri and development of PML is not known at this time.
What are other adverse reactions have been
reported with Tysabri?
The most frequently reported adverse events with Tysabri in
clinical trials were infections, severe or life threatening
allergic reactions, depression (including thoughts of suicide),
and gallbladder problems. These events occurred at rates ranging
from 0.8% to 2.1%. No cases of PML were observed in the clinical
trials used to support approval of Tysabri.
I’ve received Tysabri for my MS. Am I going to
develop PML?
Although the risk, if any, of PML in patients receiving
Tysabri is not known, it is important to recognize that only two
confirmed cases of PML have been identified from among over 8000
patients who have received Tysabri. Patients should, however,
discontinue use of Tysabri until further notification.
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Date created: March 1, 2005 |
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