When Biogen Idec disclosed two new cases of progressive multifocal leukoencephalopathy associated with its multiple sclerosis/Crohn's therapy Tysabri (natalizumab) last month, Wall Street reacted with something close to panic.

Investors worried that the reports would stop the remarkable rebirth of Tysabri in its tracks, causing doctors and patients to be even more wary of the risks of taking the drug. Shares of both Biogen and its partner Elan were hammered when the news broke July 31, and haven't recovered much since. Several analysts and investors expressed particular concern about how FDA will react to the reports. (¹ Also see "More PML Cases Inevitable For Tysabri, But How Many?" - Pink Sheet, 5 August, 2008.).

It will take time to determine what the commercial impact of the disclosure will be, but it certainly doesn't sound like FDA plans any further regulatory action based on the two new cases.

Three of FDA's top review managers stressed during a recent roundtable discussion with ² The RPM Report that, from their perspective, there is nothing surprising about additional reports of PML with the drug.

[Editor's Note: Click ³ here to register for a free trial of The RPM Report, an FDC/Windhover publication offering in-depth analysis of how regulation, reimbursement and policy issues impact the biopharma business.]

"We knew when we agreed to let Tysabri back on to the market that there would be, in all likelihood, additional cases of PML once enough patients got exposed for a long enough period of time," said Office of New Drugs Director John Jenkins. "We don't have any magical way of preventing them from getting PML."

"The risk-management program for Tysabri is more about making sure that the right patients get the drug and make an informed decision and get proper follow-up," he added. As for the two recent reports: "we could have predicted that."

Tysabri was withdrawn shortly after launch because of three PML cases that emerged in ongoing trials; it was reintroduced in 2006 under a restrictive risk-management program. (⁴ Also see "Tysabri Re-Launches In U.S. Through Single Distributor" - Pink Sheet, 24 July, 2006.). Biogen Idec is required to submit an application to convert that program to a formal Risk Evaluation & Mitigation Strategy in September.

Based on the comments offered by the senior FDA managers, it doesn't sound like there is going to be an effort to make changes to the existing program beyond the legal conversion process itself. (⁵ Also see "Tysabri PML Cases Pose REMS Challenges To FDA" - Pink Sheet, 1 August, 2008.).

Office of Surveillance and Epidemiology Director Gerald Dal Pan stressed that "there is nothing in the program that actually will prevent PML." The "program is designed to ensure proper patient selection and to ensure proper monitoring that will pick up any sign or symptom early enough so that you would stop the drug."

Indeed, Office of Medical Policy Director Robert Temple suggested that the new reports may produce a silver lining if they support the hypothesis that avoiding co-administration of beta interferon reduces the PML risk.

"There was some hope that there would be less of it if people weren't simultaneously on interferon," Temple said. "In the two new cases, they were not on interferon as far as we know."

The FDA officials also pointed out that the new cases occurred outside the U.S. "In the U.S., there is something like 3,500 people who have been exposed for a year and half with no cases here yet. So maybe not using it with interferon simultaneously helps, at least some," Temple added.

Jenkins offered one other dose of perspective. "Keep in mind that other immunosuppressants also had cases of PML and other serious infections reported with them, so Tysabri is not unique. Any immunosuppressant agent has the potential to cause serious and opportunistic infections, including PML."

-Ramsey Baghdadi (r.baghdadi@elsevier.com)

Biogen Idec’s Reports Of Tysabri Side Effects Don’t Rattle FDA

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