The Food and Drug Administration announced April 22 two labeling changes for multiple sclerosis drug Tysabri (natalizumab) regarding its association with progressive multifocal leukoencephalopathy, a rare but serious brain infection.

The amendments are positive for the drug's developers, Biogen Idec, Inc. and Elan Corp. but may not lead to increased uptake of the drug near term since regulators stopped short of including a third risk factor Biogen had hoped to see included - a patient's anti-JC virus antibody status.

The JC-virus is thought to cause PML, and testing for JCV status could give physicians and patients greater confidence regarding the drug's benefits relative to the risks. That's true not only in patients who have relapsed on current standard of care therapies, such as Avonex or Rebif (interferon beta-1a), and are beginning Tysabri therapy for the first time. It's also true for patients who have taken the monoclonal antibody for more than 18 months, since duration of Tysabri treatment is known to be associated with an increased risk of PML.

"To date, based on an analysis of archived pre-PML samples from patients, 27 out of 27 Tysabri-treated related PML cases have tested positive with the JCV antibody assay," Douglas Williams, executive VP-R&D, said during Biogen's first quarter earnings call April 21. "We are committed to continuing to invest significant time and resources to evaluate additional risk factor for Tysabri so physicians and patients can make informed benefit/risk decisions."

In the U.S., the new labeling includes a table summarizing rates of PML with Tysabri use according to the number of infusions. The estimated incidence of PML per 1,000 patients for up to 24 infusions is 0.3. For 25 to 36 infusions, the risk of brain infection increases to 1.5, and for 37 to 48 infusions it is 0.9. Since Tysabri is typically dosed every four weeks for MS, the new labeling suggests greater monitoring of patients might be warranted once patients have been on the drug for two years.

The label also adds new information noting patients treated with immune suppressing medications prior to taking Tysabri have been shown to be at an increased risk for PML. Labeling already warns of a risk when immunosuppressants are taken concomitantly with Tysabri.

Biogen expects to hear from FDA on whether it will add JCV-antibody status as a risk factor in Tysabri labeling in the second half of the year, Biogen CEO George Scangos said.

For Biogen and Elan the risk in pushing for the label change is that regulators will look to limit use of Tysabri only to the JCV negative patient population. Such a decision could shrink Tysabri's market drastically. Nonetheless, the firms announced in December that they were submitting supplemental applications to regulators in the U.S. and Europe to add new PML risk-stratifying information (Also see "Biogen/Elan Submit Applications For Tysabri Label Change Ahead of Schedule" - Pink Sheet, 23 December, 2010..

EU Adopted JC-Virus Testing

In the EU all three risk factors were accepted. The Committee for Medicinal Products for Human Use issued a positive opinion earlier in April for inclusion of anti-JV virus antibody status in the Tysabri label, noting that "anti-JCV antibody testing may provide supportive information for risk stratification prior to or during treatment with Tysabri."

Scangos called the EU decision and its reference to testing "very positive steps that ... . may lead to many more patients being able to have access to the benefits of Tysabri with a risk that they'll be able to define and understand."

Biogen and Elan have obtained a CE mark for their JCV antibody assay in Europe, where it will be broadly available in May, and in the U.S. they plan to make it available as a laboratory developed test.

Now that the test is on European labeling, and once it is available, "we can actually ... make it clear to physicians and patients what their individual risk is likely to be," Williams said. "This is a huge positive event for Tysabri in the EU, and hopefully we'll have a similar event for the U.S. later this year."

Developing The Scientific Evidence Base

In the U.S. Biogen has two JVC antibody testing studies ongoing among MS patients who express interest in Tysabri therapy. STRATIFY-1, to define the presence of serum JCV antibody in patients and confirm the false negative rate for the assay, has hit its 1,000 patient enrollment ceiling and is expected to report out in the third-quarter of 2012.

STRATIFY-2, designed to "identify the correlation of JCV antibody positivity and development of PML," is at 19,000 patients and still enrolling, with a projected end in Dec. 2012. A secondary goal of that study is to define the sero-prevalence of JCV antibody in a representative U.S. patient sample.

Biogen execs declined to answer specific questions about the studies during the call. However, the Q&A provided insight into how JCV testing might affect discontinuation rates. The number of discontinuations is up, "mainly driven by the fact that through STATIFY-2, physicians get access to the JCV status," Francesco Granata, executive VP-commercial operations said. "This has been driven more by the JC virus-positive patients than other external factors."

"As more and more patients know their antibody status, you might expect positive patients who have been on for two years, some of them, to come off. You might expect more negative patients to actually begin Tysabri. And we think net-net over time, that will result in an increase in Tysabri utilization," said Williams.

During the April 20 earnings call, Biogen released additional and better than expected positive monotherapy data from the Phase III DEFINE study of its oral MS candidate BG-12. The twice daily therapy is contending to become the second oral MS therapy to market, behind Novartis AG's Gilenya (fingolimod), which was approved in October. Because of its efficacy and clean safety profile, some analysts predict BG-12 could become the oral of choice (Also see "Biogen Idec's BG-12 Results Up The Ante In The Oral MS Market" - Pink Sheet, 21 April, 2011.).

-Shirley Haley (s.haley@elsevier.com)

U.S. Tysabri Labeling Updated With More PML Risk Info But No Reference To JCV Testing

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