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Natalizumab (marketed as Tysabri) Questions and Answers

[3/1/2005]

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.
How common is 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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