By Randall Osborne

Editor

Like a pair of feisty tykes taking on the block's biggest kid, competitors in treating multiple sclerosis last week challenged Biogen Inc., in a war of words and trial data.

One contender in the MS treatment space, Serono SA, hopes to steer the FDA's favor away from Biogen, and by proving its Rebif (interferon beta 1-a) product works better than Biogen's Avonex (another form of interferon beta 1-a) to block the latter's orphan drug status, effective until 2003.

Biogen's second, lighter-weight problem, an old nemesis, was Chiron Corp., throwing punches and jostling for position in MS with Betaseron (interferon beta-1b), partnered with Schering AG, of Berlin, which also boasted favorable results from trials.

Emeryville, Calif.-based Chiron said an independent study at the University MS Center in Torino, Italy, showed its product reduced signs of disease better than Avonex in the period six to 12 months after treatment.

On the high-stakes biotechnology playground, combatants often change places, and history repeats itself with new players. The irony of the face-off between Biogen and Serono could not have escaped industry watchers recalling a similar scrap in 1996, when Schering's subsidiary, Berlex Laboratories Inc., sued the FDA in U.S. District Court in Washington to stop the agency from approving Biogen's Avonex, claiming market clearance would violate Betaseron's orphan drug status and other FDA procedures.

It didn't work. A judge ruled Avonex was clinically superior to Betaseron, and therefore the Orphan Drug Act didn't apply. Can Serono do to Biogen what Biogen did to Schering that is, prove superiority, and circumvent Biogen's orphan drug status for Avonex?

Peter Ginsberg, an analyst with U.S. Bancorp Piper Jaffray in Minneapolis, watched company presentations at the annual meeting of the Academy of Neurology in Philadelphia last week.

Betaseron is likely not a threat to Avonex sales, he told BioWorld Financial Watch, since its drug was "comparable" to Avonex at six months in the unblinded, 188-patient trial, which compared the number of relapse-free patients, reductions in disability and MRI lesion scores. Differences in treatment groups didn't show up until one year, Ginsberg said, and such differences did not appear at all in separate, two-year studies of each drug.

Serono's Rebif is another subject.

The Geneva, Switzerland-based firm sought to show clinical benefit superior to Avonex, based on predefined, FDA-sanctioned endpoints the primary one of which compared the proportion of relapse-free patients after 24 weeks.

Rebif patients had a 90 percent better chance of staying relapse-free during the observation period than Avonex patients, Serono said, and the 90 percent was expressed as an odds ratio comparing the proportion of relapse-free patients after 24 weeks, and Serono said the finding was based on a 32 percent relative reduction.

"But they didn't report the actual data behind it," Ginsberg said. "I'd like to see those numbers, because we have a very difficult time reconciling the odds ratio and the 32 percent reduction."

Serono, which tested 677 patients, also seemed to wallop Cambridge, Mass.-based Biogen in the secondary endpoint: reduction of new lesions in the brain. As measured by magnetic resonance imaging, Rebif patients had 50 percent fewer new lesions than patients treated with Avonex.

Biogen was quick to point out flaws in Serono's study and, by implication, its drug. Six months of data, supplemented with no safety study or raw data, is hardly enough, Biogen said.

Rebif's subcutaneous delivery may mean skin ulcers or necrosis, problems not associated with Avonex's intramuscular delivery, which is also more convenient because it is taken less frequently (once weekly compared to thrice weekly), Biogen argued further.

On June 22, Serono will offer full raw data plus results on safety at the World Congress of Neurology in London, after which the company said it will file with the FDA in a formal attempt to topple the orphan status of Biogen's drug.

Until then, Serono is mum in presentations, news releases and conference calls.

"They won't say," Ginsberg said.

The powerhouse Avonex hauled down $552 million in sales in the U.S. last year. Serono, however, said Rebif with 31 percent of the market outside the country is grabbing more than half of all new MS patients there.

Ginsberg said Rebif probably won't reach the U.S. market before the 2003 deadline because the unblinded data is from a relatively short trial. The worst that could happen for Biogen would be a Serono filing this summer, with Rebif on the market a year later but that seems unlikely, Ginsberg said.

With Rebif's impact mainly in Europe, sales there could sustain a "moderate dent," Ginsberg said, dropping from $255 million to $246 million in 2001, and from $292 million to $246 million for 2002.

"It's unlikely that Rebif will be able to break through [the orphan drug status in the U.S.]," Ginsberg said.

Not everyone agrees. Prudential Securities, in Deerfield, Ill., said in a research note that arguments discounting Serono's trial "may be misdirected," and "ignore [the trial's] true purpose." Prudential said the study was "more confirmatory" than anything else, "to show a difference between current standard of care and Rebif."

Hence, said the note by several Prudential analysts, "the rules for acceptance by the FDA may be different." The note said data disclosed a year ago from a 560-patient study with Rebif "can be amply supplied" to help prove further what Serono needs to prove. This means "the potential for considerable downside" for Biogen, Prudential said.

Authors of the note, Peter Drake and John Sonnier, were traveling and could not be reached. Eric Schmidt, of S.G. Cowen Securities Inc., in New York, was unavailable, too, but weighed in with his own research note, saying the news from Philadelphia "shift[s] the probability in favor of Rebif breaking Avonex's orphan drug exclusivity."

Schmidt said the FDA will probably want more data from the ongoing Rebif trial, but the drug could be on the market "three to six months earlier than [Serono's] previous May 2003 time frame."

Ginsberg said the MS arena is a natural fight zone.

"All three drugs that are out there are active drugs," he said. Avonex, Betaseron and Copaxone (glatiramer acetate for injection), developed by Jerusalem-based Teva Pharmaceuticals Industries Ltd., are benefiting patients, with Biogen's drug taking 55 percent of the total market share, Copaxone growing beyond 30 percent, and Betaseron taking the remainder, Ginsberg said. "The problems facing Betaseron have been more frequent dosing and significant flu-like symptoms," he said.

Biogen, meanwhile, also is trying for FDA approval of Avonex for secondary progressive MS, and in Philadelphia offered full data from its 436-patient trial in that indication. Patients on Avonex progressed on average 40 percent less than those on placebo, as evaluated by the customary MS functional composite score. Mainly, they showed better arm movement and cognitive functions, with fewer relapses and better MRI data.

But the expanded disability status scale, used for judging the clinical status of MS patients, showed no benefit from Avonex in the trial, so using that data in an effort to win FDA approval for the new label probably wouldn't work, Ginsberg said.

Should investors, sold earlier on Biogen's strength in MS, hang on? Ginsberg's answer is a firm "yes," given what he calls the "one-two punch" of Avonex and Amevive (recombinantly engineered LFA-3/IgG1 human fusion protein), Biogen's psoriasis drug which began Phase III testing in late 1999.

Data from the Amevive trials are due this quarter.

"We expect sales of Amevive to mask the slowing growth in Avonex sales, once it is launched in late 2002," Ginsberg said.

Schmidt was optimistic about the drug, too. "Should Biogen produce positive Phase III data on Amevive for psoriasis [mid-2001], an estimated $1 billion market opportunity, its stock could rapidly return to favor," he wrote in his research note.

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