Washington Editor

WASHINGTON - Tysabri could be coming back, at least in a limited capacity.

That’s the growing consensus among many industry observers about the once heralded multiple sclerosis drug, which was pulled from the market a year ago after it was linked to a pair of deaths. Those patients died from an often-fatal disorder called progressive multifocal leukoencephalopathy (PML), a disease also contracted by a third patient who did not die.

But recent developments indicate that the FDA might allow the developers of Tysabri (natalizumab), Biogen Idec Inc. and Elan Corp. plc, to begin selling the immune system-modifying drug again. At issue, of course, is Tysabri’s overall risk-benefit profile - one example of a broader policy debate simmering beneath the surface - and the agency’s Peripheral and Central Nervous System Drugs Advisory Committee is meeting for the next two days to consider that very question. Notably, the public hearing is expected to draw numerous patients who want to make their own choice about the therapy, with FDA critics clamoring that conservatism at the agency hinders patient access.

"I think patients are going to have a lot to say," Mike King, an analyst with Rodman & Renshaw, told BioWorld Today. "The therapeutic benefit of this drug is well beyond anything else out there."

He conceded, though, that Tysabri is likely to be "limited in its use" because of the PML risk. As a result, he is "highly confident" that the product’s label would include a black box warning, and patients on the drug would need to sign a consent form and enter a risk management program. The label also is likely to include language stating that investigators know "nothing about" the incidence of PML beyond two years.

Symptoms of PML include mental deterioration, problems with vision, speech, balance and movement, as well as coma and death in most cases. Patients with the disease stand a 50 percent chance of dying within a month, and the others face devastating neurological consequences.

The committee will discuss Tysabri’s biologic license application, resubmitted in September for treating patients with relapsing forms of the disease to reduce the frequency of clinical exacerbations. Its risks and efficacy will clearly factor in the committee’s recommendation about its possible return to the marketplace, as will a proposed risk management plan.

Officials at the two companies declined to comment ahead of the meeting, but in the wake of the FDA’s recent decision to allow Tysabri to be used as monotherapy in patients who previously received it in prior clinical trials, analysts such as King have predicted the drug stands a good chance at a restricted return to the market. That cautious outlook stems from the FDA’s stated concerns about the risk of PML and its inability to properly define that risk. No test exists to determine a patient’s predilection to the disease.

While concerns over safety risks are undeniable, high patient demand "will likely persist," said Jason Kantor of RBC Capital Markets in a research note, "because of its superior efficacy and tolerability." Like King, he noted that Tysabri’s Phase III efficacy, producing a substantial reduction in the frequency of MS relapses, and a completed safety review with no new fatal PML events, led him to believe "there may be support from physicians on the advisory committee." King added that the drug could see front-line use, or as a backup to beta interferon products.

Patient support varies, according to a survey conducted by the National MS Society and submitted to the FDA in advance of the hearing. More than 800 patients responded, and although there was significant interest in Tysabri’s return, respondents also expressed uncertainty concerning "their readiness to use the drug" and indicated a desire for more detailed safety and efficacy information. The survey also found that most would be willing to consider using Tysabri if certain conditions were met, such as the availability of a reliable test for PML, additional safety data, and whether or not their current treatment was working well.

Still, there exists a good deal of physician reticence on Tysabri. A poll released last week showed that more than half of 140 neurologists thought it was too early to bring the drug back. Most saw the product as a therapy of last resort, including Douglas Jeffrey, an associate professor of neurology at Wake Forest University and the director of the school’s MS center.

"There are a lot of unresolved issues," he told BioWorld Today, stressing his belief that the PML risk in Tysabri patients is higher than reported.

Data published in the March 2 issue of the New England Journal of Medicine suggested that PML risk associated with Tysabri was about one in 1,000 among the more than 3,000 people treated with Tysabri for MS, Crohn’s disease and rheumatoid arthritis in Phase III studies conducted by Biogen Idec, of Cambridge, Mass., and Elan, of Dublin, Ireland. That figure represents patients treated with the drug for an average of 17.9 months, and the retrospective study found no evidence of new PML cases beyond the initial three.

Still, 44 additional patients proved questionable because of clinical findings of possible PML, abnormalities on MRI, or a high blood level of JC virus, which triggers PML. In the end, though, none had detectable JC virus DNA in their cerebrospinal fluid.

But Jeffrey was skeptical, saying that the findings "just don’t reassure me at all," because about a quarter of PML patients do not have JC virus DNA in their cerebrospinal fluid, he said, and because patients’ immune systems likely fought against PML once Tysabri treatment stopped. "The risk is probably, I suspect, higher than one in 1,000," he said, noting that he suspects the chances to be closer to one in 250. Formerly a frequent Tysabri prescriber, he said he would not give it to patients again. "I have grave concerns about its safety."

Of note, researchers from the New England Journal of Medicine study warned that they cannot confirm that Tysabri patients will not develop the disease in the future, and noted that risks associated with longer-term treatment also remain unknown.

That’s one point made by sources at companies that have a competitive market stake with other MS products. Competitors also have pointed out that efficacy comparisons are difficult, especially in the absence of any head-to-head studies. The primary products used in the multi-billion-dollar MS market include four disease-modifying therapies: Avonex (beta interferon 1a, also from Biogen Idec), Betaseron (beta interferon 1b, from Berlex Laboratories Inc.), Copaxone (glatiramer acetate, from Teva Pharmaceuticals Inc.) and Rebif (beta interferon 1a, from Serono SA). An immunosuppressant, Novantrone (mitoxantrone, also from Serono), is used as well.

Jeffrey expressed concern that the FDA, which is expected to make a final decision by the end of this month following a priority review, is moving too fast. He questioned whether the agency has sought appropriate outside review, such as in the form of an ad-hoc committee of PML specialists. If Tysabri does come back, Jeffrey somberly predicted that "you’re going to see a lot of PML cases."

Tysabri received FDA approval in November 2004 to treat relapsing-remitting MS, based on one-year data, but was withdrawn from the market and pulled out of clinical trials three months later after the manufacturers identified two cases of PML in Tysabri-treated MS patients. A Crohn’s disease patient who received Tysabri was diagnosed with PML as well.

Biogen Idec has said it plans to begin an open-label safety trial in the near future.