Editor

Hardly had the House passed the Prescription Drug User Fee Act - clearing the way for the next day's approval by the Senate - than all eyes turned from PDUFA to Amevive, Biogen Inc.'s fusion protein for psoriasis.

It passed.

At a time when industry failures seem abounding, the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee voted 8-2 to recommend approval of Amevive (alefacept), which works by blocking activation of T cells by interfering in the LFA3/CD2 pathway.

Wall Street opinion had been split regarding the panel meeting's outcome, with a thumbs-down vote for Amevive seen as a strong likelihood by more than a few analysts.

"I was one of them," said Joseph Dougherty, analyst with Lehman Brothers. "Since the Amevive panel, it's pretty clear that a number of these therapies are going to get approval. The regulatory bar is pretty low, although we haven't seen an actual approval on the label, and it may not be an instantaneous process for Amevive to get one."

Amevive seems well on its way, but "seems" is a word about which many have learned to be wary. The FDA isn't bound by the panel's advice, and even if it ultimately gives the nod to Biogen, the market for Amevive is not altogether clear.

"Even on the panel, various people during the day gave estimates and, interestingly, those estimates varied by a factor of three," Dougherty told BioWorld Financial Watch, adding that he "wouldn't want to give [an estimate] in print."

Nor is the competitive picture clear for Amevive, with competition moving up close behind. Among that competition would be Immunex Corp.'s rheumatoid arthritis heavyweight Enbrel (etanercept), an anti-tumor necrosis factor protein now in Phase IIb studies for psoriasis. It's on track for an approval decision next year, and is being used off-label for psoriasis now. (See BioWorld Financial Watch, July 9, 2001.)

Others are lining up for a slice of the market pie. At the meeting in February of the American Academy of Dermatology in New Orleans, Genentech Inc. and XOMA Ltd. offered more results from two Phase III studies of Xanelim (efalizumab), showing that some patients may get longer-lasting benefit when treated for 24 weeks.

Last year, the FDA said it wants a study to confirm the equivalence of materials used for testing and manufacturing the drug. That study is under way, completing enrollment at the end of the year, and a biologics license application was expected this summer.

Centocor Inc. is continuing to develop Remicade (infliximab) - a TNF inhibitor like Enbrel - for psoriasis. Also like Enbrel, it's already approved for RA.

Isis Pharmaceuticals Inc. is going ahead with its intercellular adhesion molecule-1 inhibitor, ISIS 2302. The drug missed one endpoint in the Phase II study detailed during the dermatology meeting, but showed promise in its topical formulation.

IDEC Pharmaceuticals Corp. has IDEC-114 in Phase II trials. MedImmune Inc. has MEDI-507 (siplizumab), also in Phase II.

There have been fall-downs in the psoriasis race. Abgenix Inc. dropped its development of the monoclonal antibody ABX-IL8 after the drug failed in a Phase IIb psoriasis trial to meet its primary endpoint of improvement in PASI scores. That was last month. In January, the same drug failed to meet its primary endpoints in a Phase IIa study in rheumatoid arthritis.

Protein Design Labs Inc. likewise gave up on Zenapax (dacluzimab) for psoriasis in late March after getting a gander at discouraging preliminary Phase II data. The move did nothing but good for PDL's stock, however, which rose 21.8 percent on the news.

The strong front-runner remains Amevive - and if it gains a label for psoriasis, another likely winner would be Genaissance Pharmaceuticals Inc., which in February signed up with Biogen for a pharmacogenomics alliance. Details were not disclosed, but Amevive likely is included in the deal deploying Genaissance's haplotypes, or HAP markers which the company says are like "genomic bar codes" showing the pattern and organization of DNA variability in individuals.

FDA approval for Amevive could come as early as August, and Genaissance is expected to have ready a diagnostic product by the end of next year that could be used with Amevive.

Marketing clearance for Amevive could be a major boon for Genaissance. The Biogen drug's expected price is estimated at $10,000 per two treatments, so determining through pharmacogenomics efforts who might be wasting their money on the drug and who would not is particularly important.

Dougherty noted the panel included no immunologists or infectious-disease specialists who might have challenged Biogen more vigorously, but the FDA was restrained and balanced, saying little about (though far from ignoring) T-cell depletion in Amevive-treated trial subjects, and their trend toward higher infection and malignancy rates.

"We believe that the FDA had plenty of means and opportunity to have sandbagged Biogen at this panel and clearly chose not to do so," Dougherty wrote in a research report.

But the uncharacteristically free-flowing panel talk was somewhat unnerving, and its outcome was not always certain, he added.

"The meeting had some characteristics of others in our experience that have seemed like comedies during the first and second acts, only to reveal themselves as tragedies in the third," Dougherty wrote.

"I soft-pedaled it a little in my note," he said. "It was really wild."

Some potential snags exist for Amevive. The FDA found incomplete data beyond the second treatment course, and is unsure about long-term therapy, which could mean consequences for Amevive's label. Dougherty said he regards an approval by August as unlikely, given that chemistry manufacture control issues are not resolved.

"We don't know what those are, and they weren't described in detail at the panel, but the FDA indicated they were resolvable," he said, adding that it's "fairly typical not to put discussion of that in front of the panel."

Nor are such glitches unusual, Dougherty said, pointing to Xanelim.

"The Phase III data look strong, but [XOMA] obviously has a real manufacturing issue of their own," he said. On the other hand, in "the Enbrels and Remicades of the world, you have drugs already on the market, so their CMC packages have passed."

Just as unclear as the total market is how it might come to be divided.

"A lot of the market-share question remains to be determined by what data Enbrel can show, and what kind of pricing [will be decided upon]," Dougherty said. "These agents all have significant cost of goods, so pricing is going to be important."

Various factors are coming together to make the marketing fray as lively and unpredictable as the panel meeting itself.

"There's clearly strong dissatisfaction with existing therapies, and having multiple biologics [available] will expand the market more quickly," Dougherty said. "It's going to be quite a battle."