The FDA now finds itself in an unenviable position, after receiving an application to clear Tysabri (natalizumab) again, seven months after the multiple sclerosis product was pulled from the market following its links to two fatalities, despite showing clinical efficacy.
And many industry observers expect the agency's risk-benefit analysis to come under scrutiny as the review process moves forward.
"I think they're bound to hold an advisory panel meeting, because these are the exact types of issues you'd want in a public forum," said Elise Wang, an analyst with Citigroup. "And I think there will be a tug of war, with us hearing from patients about how much they need this new therapy and that they're still willing to take the risk."
Still, with the agency's risk-averse nature these days and Tysabri's mysterious connection to progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal demyelinating disease of the central nervous system, the bar is set high for approval.
The supplemental biologics license application from Biogen Idec Inc. and Elan Corp. plc includes final two-year data from the Phase III AFFIRM monotherapy trial and the combination SENTINEL study that evaluated Tysabri with Avonex (interferon beta-1a, also from Biogen Idec), as well as an integrated safety assessment of Tysabri-treated patients completed after the market withdrawal, a revised label and a risk management plan.
Officials could not be reached at either company, but both issued public statements that highlighted the product's "therapeutic benefit" and their "extensive safety evaluation." That was a message often heard from the companies in the months after voluntarily pulling Tysabri from the market and suspending all ongoing clinical trials earlier this year on reports of PML, a side effect that Wang called "very severe." (See BioWorld Today, March 1, 2005.)
Patricia O'Looney, the National Multiple Sclerosis Society's director of biomedical research, called that event a "disappointment." While no test exists to determine one's propensity to the condition, Tysabri patients have been advised to watch for symptoms such as motor weakness on one side of the body, rapidly developing changes in mental function, language disturbance, visual disturbance or changes in behavior or personality.
To date in the partners' subsequent safety analysis, three cases were confirmed, two of which were fatal, but the partners' review uncovered no more. More than 8,000 people have taken the drug.
That positive safety evaluation, in which Cambridge, Mass.-based Biogen Idec and Dublin, Ireland-based Elan consulted with PML and multiple sclerosis experts, has prompted support for Tysabri and its resubmission. But Wang told BioWorld Today that it's still a struggle to discern the "appropriate steps that can be taken to be able to monitor for the risk of this happening." Should the FDA sign off on the resubmission, the risk-benefit equation will fall on the shoulders of patients and prescribers, O'Looney noted. The companies requested a priority review that would result in FDA action in about six months, rather than in 10 months for a standard review.
"We're pleased that no more PML cases were diagnosed," O'Looney told BioWorld Today, "and we're pleased that it's now at the point that the companies are submitting it to the FDA for a hopefully expedited review."
The alpha-4 antagonist first received FDA approval late last year following an accelerated review. The clearance was based on single-year results from AFFIRM and the SENTINEL study; in the former, Tysabri reduced relapse rates by 66 percent compared to placebo, and top-line results from the latter showed a 54 percent reduction in relapse rate for Tysabri combined with Avonex vs. Avonex alone. (See BioWorld Today, Nov. 29, 2005.)
"The efficacy data was exceptionally strong for this drug," Wang said, "so I have a tendency to believe that in the end that it has a chance to come back, but there are going to be some very strict criteria under which it's going to be used."
She noted that it won't be suitable for immunocompromised patients, and likely won't be indicated for combination use with Avonex, as that pairing resulted in two of the PML cases. Wang also pointed to uncertainty about Tysabri's duration of use, as well as a cloudy future for its use in Crohn's disease and rheumatoid arthritis, two other settings in which it was studied.
She added that the drug is not likely to ever hit blockbuster status, as was once touted. Her New York firm, which makes a market in Biogen Idec's securities, has no sales projections for Tysabri in its current forecast model.
O'Looney, who conceded that though Tysabri does not cure multiple sclerosis, called it "an additional option for a physician and patient to talk about in trying to control the progressive aspects" of the disease. She added that should it again receive FDA approval, use of the drug would be determined on a "case-by-case basis" depending on a patient's varying needs.
Biogen Idec and Elan will submit a similar data package update to European regulatory authorities as part of an ongoing review process that began last summer.
The Tysabri fallout has had a visible effect at Biogen Idec, which recently posted net income of only $34.5 million for the quarter ended June 30. Tightening its belt, the company reported plans to cut 650 of its 4,000 jobs worldwide by the end of the year. Earlier this summer, it divested for $408 million, a biologics manufacturing facility originally designated for making Tysabri. It also has plans to sell a clinical manufacturing facility. (See BioWorld Today, June 20, 2005, and Sept. 12, 2005.)
For Elan, the drug's suspension represented a setback to a company that had rebuilt its image largely on Tysabri's potential following a financial scandal and the resulting breakup of many of its drug development partnerships.
On Tuesday, shares in Biogen Idec (NASDAQ:BIIB) dropped 41 cents to $38.05, while Elan's stock (NYSE:ELN) rose 2 cents to close at $8.02.