West Coast Editor

Further bolstering the companies' hopes that the withdrawn multiple sclerosis drug Tysabri might one day become available again, Biogen Idec Inc. and Elan Corp. plc disclosed full two-year data from their Phase III monotherapy trial with the compound.

Biogen Idec's stock (NASDAQ:BIIB) closed Wednesday at $36.45, down 25 cents. Dublin, Ireland-based Elan's (NYSE:ELN) shares fared better, ending the day at $4.29, up 52 cents, or 13.8 percent.

Specifically, two-year data from the AFFIRM Phase III monotherapy study presented Wednesday at the American Academy of Neurology meeting in Miami Beach, Fla., showed Tysabri (natalizumab) led to a 42 percent (p=0.0002) reduction in the risk of disability progression compared to placebo, the primary endpoint.

The drug also reduced the rate of clinical relapses by 67 percent (p<0.0001) compared to placebo, which was sustained and consistent with the previously reported one-year results, as was the safety profile.

But those top-line data from AFFIRM were disclosed in February, and the details offered at the scientific meeting only back them up, while offering little insight into Tysabri's link with progressive multifocal leukoencephalopathy (PML) in treated patients. Incidents of PML caused the drug's removal from the market in late February. Company officials still are examining MRIs from Tysabri patients for more insight, and three PML cases have been found so far.

"That's something I discussed with investors today," analyst Winton Gibbons, with William Blair & Co. in Chicago, said Wednesday. "The third [case] was a little hard to find, but that doesn't mean there are not more. I don't think it's coming back to the market, at least not anytime soon."

Gibbons attached little significance to the Phase III data and called the way they were presented - that is, without making stronger reference to the three cases of frequently fatal PML, and without framing the Phase III results in that context - "in poor taste, at best. It was as if you had a drug currently on the market and it's great."

Analysts at Prudential Financial in New York reiterated their "neutral weight" rating on Cambridge, Mass.-based Biogen Idec with a price target of $42, and most others made no changes.

"Because [PML] was found in three confirmed patients in two different medical indications, because Tysabri has such a broad mechanism of action, and because of the current safety environment at the FDA, I think there's little chance in the short term or midterm that Tysabri will return to the market," Gibbons said. "Knowing that this [PML risk] exists, how do you restart any clinical trials? I just don't see it."

AFFIRM, testing 942 patients at 99 sites worldwide, examined the effects of Tysabri on progression of disability as measured by at least a one-point increase on the Expanded Disability Status Scale (EDSS) sustained for three months, and the rate of clinical relapses. Patients were randomized to get either a 300-mg IV infusion of Tysabri (627 patients) or placebo (315) every four weeks.

Along with the 42 percent reduction in the risk of disability, Tysabri given to patients resulted in 17 percent of the group progressing, as compared with 29 percent of placebo-treated patients, for a 41 percent reduction in the proportion of patients progressing (p<0.0001).

Tysabri also slowed progression of disability as demonstrated by the mean Multiple Sclerosis Functional Composite score, testing ambulation, upper extremity dexterity and cognitive function.

A pre-defined sensitivity analysis of the primary endpoint defined progression as at least a one-point increase on the EDSS, sustained for six months. Using that definition, the risk of disability progression was reduced by 54 percent with Tysabri.

Added to the 67 percent reduction in the rate of clinical relapses, the annualized relapse rate was 0.22 for Tysabri-treated patients compared to 0.67 for placebo-treated patients. The proportion of patients who remained relapse free was 67 percent in the Tysabri-treated group compared to 41 percent in the placebo-treated group (p<0.0001).

MRI analysis examining brain lesions found that Tysabri provided sustained and statistically significant reductions in the number and volume of gadolinium-enhancing, T2-hyperintense and T1-hypointense lesions compared to placebo. The pre-specified secondary endpoint MRI measures were the volume of T2-hyperintense lesions and the number of new T1-hypointense lesions.

Over two years, there was a significant difference in the burden of disease as measured by change in T2-hyperintense lesion volume. Placebo-treated patients showed an increase, while those on Tysabri decreased. Tysabri also showed a 76 percent reduction in the mean number of new T1-hypointense lesions compared to placebo.

Tysabri, formerly known as Antegren, won accelerated approval based on single-year results from AFFIRM plus data from the SENTINEL study, which combined the compound with Avonex, Biogen Idec's already-marketed MS drug. (See BioWorld Today, Nov. 29, 2004.)

At the Florida meeting, Biogen Idec also presented one-year data from SENTINEL, showing that Tysabri with Avonex (interferon beta-1a) reduced the annualized clinical relapse rate by 54 percent over Avonex alone.

New Tysabri data came at the same time as word from Elan, which appears in the company's annual report, that the SEC's Division of Enforcement is conducting an "informal inquiry" into securities trading. The annual report said the probe "primarily relates" to events around the late-February suspension of Tysabri marketing. (See BioWorld Today, March 1, 2005, and April 1, 2005.)

Elan has tangled with the SEC's Division of Enforcement before. Last year, the company reached a provisional settlement with the SEC related to an earlier probe, and agreed to a $15 million penalty. A class-action lawsuit also was laid to rest in a proposal involving a cash payment of $75 million by Elan, out of which the court would award attorney's fees to the plaintiffs, with $35 million of the amount paid by Elan's insurance carrier.

Under the terms of the class-action proposal, yet to be formally ratified by the court, "all claims against us and the other named defendants would be dismissed with no admission or finding of wrongdoing on the part of any defendant," Elan noted in its annual report.

The class-action lawsuit and the SEC probe focused on similar issues, namely claims that financial results were not properly reported. Elan faced questions starting in 2002 over accounting methodology in its many joint ventures, and in the course of resolving them reorganized as a biotechnology rather than a pharmaceutical firm. (See BioWorld Today, June 18, 2004.)

Ill-fated Tysabri, though, hasn't made the transformation easy. Since the drug's withdrawal from the market, Elan's stock has nosedived by about 85 percent, showing a 52-week high of $30.45 - and observers noted that the SEC typically investigates when a stock plunges to such a degree. In any case, Elan's stock was up slightly Wednesday.

"It's possible that Elan was just oversold, and this quasi-positive news may have brought people modestly to their senses," Gibbons told BioWorld Today, regarding the uptick in Elan's shares. "That's not uncommon. I wouldn't over-read the reaction and think that investors somehow believe the product is coming back to the market."