With progressive multifocal leukoencephalopathy a known side effect of Biogen Idec/Elan's Tysabri (natalizumab), the eventual reporting of new cases of the brain disease following the drug's relaunch in 2006 has been inevitable. Yet news released July 29 that two confirmed cases were reported in multiple sclerosis patients treated with Tysabri in Europe sent shares of Biogen and Elan plummeting.

That very well could be because the question has not been if there will be cases of PML, but rather, how many will there be? That's a question Biogen's management shed little light on during an Aug. 1 conference call, declining to provide any details on the number of suspected, but unconfirmed, cases of PML that have been reported.

Biogen/Elan are reporting confirmed cases of the disease based on an "international" standard that includes the presence of JC viral DNA either the cerebralspinal fluid or in a brain biopsy. The company did acknowledge, however, that other suspected incidences of PML have been reported, but left the investment community to grapple with the question of how many on its own.

Adding to the uncertainty, one of the confirmed cases initially did not show the presence of the JC virus during the first medical workup, although plasma exchange was initiated nonetheless based on symptoms, and subsequent testing did reveal JC viral DNA.

"We wonder how many other such 'false negatives' there are in the postmarketing experience," Bernstein analyst Geoffrey Porges said in an Aug. 1 research note. "The company's unwillingness to disclose the number of high suspicion cases is alarming to us and to physicians and probably regulators as well."

Porges recommended the companies disclose how many patients have had MRI scans consistent with or suggestive of PML, how many have had tests to detect the presence of the JC virus, and how many have initiated plasma exchange - a procedure recommended following a diagnosis of PML but used as a precautionary measure in some cases - to help investors gauge risks.

The rate of confirmed PML cases versus the number of treated patients remains below that outlined in labeling for Tysabri. Labeling currently puts the risk of PML at about one in 1,000 based on the number of patients treated in clinical studies and three PML cases. As of the end of June, more than 31,800 patients were receiving Tysabri worldwide, both commercially and clinically. However, it is possible the number of PML cases will grow exponentially with longer treatment durations.

Based on a review of data from FDA's Adverse Event Reporting System, Deutsche Bank analyst Mark Schoenebaum pointed to 12 suspected PML cases in the database during an Aug. 5 conference call. However, he said it is believed that Biogen investigated all 12 cases and determined none were PML.

"We believe there is something on the order of 50 suspected cases in reality," he wrote. Schoenebaum, however, supported Biogen's decision not to release more information on suspected cases because of the uncertainty around them, the false security or risk, and the cumbersome nature of such reporting.

Following the release of the new safety data, Biogen's stock fell 28.3 percent and Elan's 50.5 percent, from which neither has rebounded significantly.

In a report on Biogen, Rodman & Renshaw analyst Michael King said, "The short-term weakness in the stock price may be an overreaction if the FDA is comfortable that an appropriate level of PML vigilance can continue to be maintained through the TOUCH prescribing program."

It's unclear how FDA will react to the latest news. The risk of PML already is highlighted clearly in a "black box" warning in Tysabri's label, and the drug is distributed in the U.S. through one of the most restrictive access programs, TOUCH, because of the safety issue.

But Tysabri will pose a test for how the agency will handle the emergence of new safety data under a Risk Evaluation and Mitigation Strategy, which under a legal mandate requires periodic evaluation (¹ Also see "Tysabri PML Cases Pose REMS Challenges To FDA" - Pink Sheet, 1 August, 2008.).

-Jessica Merrill (j.merrill@elsevier.com)

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