By Brady Huggett

Biogen Inc. and its product, Avonex, have the protective orphan drug status designation that provides market exclusivity until May 2003 in the U.S. for patients with relapsing-remitting multiple sclerosis. Serono SA and its product, Rebif, want into that locked-down U.S. market sooner than that.

Serono presented full results from its comparative EVIDENCE study between Rebif and Avonex Friday at the World Congress of Neurology in London, and will file the data in the third quarter with the FDA to splinter Avonex¿s orphan drug stature.

¿The [full data] provided more detail on primary and secondary outcome measures,¿ said Carolyn Castel, director of public relations at Norwell, Mass.-based Serono Inc., the U.S. affiliate of Geneva, Switzerland-based Serono SA. ¿The key issue is that we are committed to bringing Rebif to the market in the United States and we will work closely with the FDA to be able to do that.¿

Much like when the preliminary data were released in early May, Biogen maintained that the trial is incomplete and the data manipulated. (See BioWorld Today, May 9, 2001.)

¿The question is: What are the actual data?¿ said Nancy Simonian, senior director of medical research at Biogen. ¿We think the study has flaws, with it being unblinded and too short of duration for [multiple sclerosis].¿

Even data, normally the backbone of trials, are being questioned. Serono said the trial showed that patients treated with Rebif had a 90 percent greater chance of remaining relapse-free, relative to patients treated with Avonex. The numbers show 32 percent fewer patients experienced relapse when treated with Rebif, and patients treated with Rebif experienced 27 percent fewer relapses than those receiving Avonex. Also, patients treated with Avonex had 50 percent more new lesions as detected by magnetic resonance imaging brain scans. And patients receiving Rebif had a 47 percent reduced need for steroid treatment.

The 90 percent greater chance of remaining relapse-free, relative to Avonex ¿ a figure based on an odds ratio ¿ appears particularly striking on the surface. Biogen, however, fired shots at the data from its location in Cambridge, Mass., less than 30 miles from Serono Inc.

¿They used an odds ratio and are coming up with the largest number they could for marketing purposes,¿ Simonian said. ¿That is actually less than a 12 percentage point absolute difference. Rather than twisting the numbers and coming up with something that is difficult for people to understand, look at the actual numbers.¿

Serono¿s Castel stood by the method, stating it was constructed with the FDA as a legitimate measurement. ¿We are obligated to present it that way,¿ she said.

Both drugs are interferon beta-1a formulations.

What Serono, Biogen and investors have been waiting for is the release of safety data from the trial. One difference between the drugs lies in the delivery method: Avonex is given intramuscularly while Rebif is administered subcutaneously. With subcutaneous delivery comes the threat of injection site necrosis and skin ulcerations. But in the EVIDENCE trial, no problems were seen with either medication, Castel said.

The six-month trial wasn¿t long enough, Biogen said.

¿The injection-site reactions will lead to necrosis over time,¿ Simonian said. ¿That¿s a significant safety issue.¿ Simonian pointed out that Biogen was able to break Wayne, N.J.-based Berlex Laboratories Inc.¿s orphan drug status for Betaseron in the United States in 1996 for that very reason ¿ Betaseron caused injection site reactions and Avonex didn't.

¿Injection site necrosis was the worry of the FDA with Betaseron and that was how we broke it,¿ she said. ¿I¿m making the point that, for the FDA, safety is a very high priority when making these decisions.¿

Biogen fought lawsuits from Berlex while getting Avonex to market in the U.S. And then took to the Swiss courts to fight Serono. Thursday a court in Geneva issued an injunction forbidding Serono from making certain claims about its data.

¿[Biogen] made a request in the court, as you would in the U.S., in an attempt to make certain statements about the evidence of the study,¿ Castel said. ¿We are considering our response to our courts in Geneva. This was done without Serono¿s chance to participate in this, and the court moved ahead as they would in this case.¿ Castel said Serono would get its chance to address the injunction at a hearing scheduled for July 11.

Biogen has other issues with the data.

¿Look at what¿s the precedent out there for the FDA and MS trials,¿ Simonian said. ¿All the pivotal trials are based on at least two-year data and are double blind. This [EVIDENCE] trial has neither of those.

¿It has a primary endpoint that was subjective and was too short in duration,¿ she added. ¿The gold standard for MS tests is slowing of disability progression.¿

Analysts were split on the news as well. Steve Farinelli, a research analyst for Merrill Lynch International in New York, clearly sided with Serono.

¿I think it¿s excellent data for Serono; it¿s what we expected,¿ he said. ¿We expect it to get into the U.S. market. All the endpoints have been agreed upon by the FDA.¿ Farinelli said the timing is uncertain, but his firm expects Rebif to enter the market by the middle of next year. By the end of 2005, he said, the MS market in the U.S. should be about $2 billion. At that time, Farinelli conservatively expects Avonex to have a 35 percent market share and Rebif to have pinched a 27 percent market share.

Other analysts were less certain of what the results meant. According to research notes, some analysts cautioned against the six-month data while others stated they simply were not sure if the data would prove to be enough to give Rebif a shot at United States MS patients before Avonex¿s orphan drug status expires.

Last year, Avonex pulled in $552 million in sales in the United States. Rebif is available in 67 countries worldwide, where it has about a 31 percent market share, and generated approximately $254 million in sales in 2000. But it has been kept out of the U.S. market. Based on the EVIDENCE data, the lockout could be over, Castel said.

¿This is how we are going to file,¿ she said. ¿This went through numerous discussions with the FDA and we have the data on the key indicators.¿

Through Biogen¿s eyes, Avonex is safe at least until May 2003.

¿I think at the end of the day, [the FDA] will look at efficacy and safety and they will find that the data is not sufficient,¿ Simonian said.

Biogen¿s stock (NASDAQ:BGEN) dropped $6.93 Friday, or about 10.4 percent, to close at $59.87. Serono¿s stock (NYSE:SRA) also dropped, dipping 68 cents to close at $24.45.