Multiple sclerosis - as many of those afflicted know all too well - is characterized in extreme forms by tissue-hardening paralysis, during its often-painful march through the brains and spinal cords of victims. But the competitive arena for MS treatments has been anything but frozen in place, especially lately.

The war of words and data picked up particular fervor last month. That's when Serono SA won U.S. approval of Rebif (interferon beta 1-a), thus dodging the orphan drug status that had given Biogen Inc.'s Avonex (another form of interferon beta 1-a) market exclusivity until May of next year.

Serono's claim of superior efficacy against relapsing forms of MS was bolstered by numbers from a 24-week study, including 677 patients and known as the EVIDENCE trial, which Biogen argued was too short to be decisive. Then, last week, Serono disclosed 48-week findings from the same trial, showing 62 percent of patients on Rebif did not relapse, compared to 52 percent given Avonex.

The Rebif approval "was quite surprising to a lot of folks, and the knee-jerk reaction was that Biogen was facing the worst," said Jennifer Chao, senior biotechnology analyst with Leerink Swann & Co. "Now, investors are starting to look at the real factors in terms of revenues coming in."

U.S. market leader Biogen, which had said earlier it was reluctant to tip its hand regarding the strategy against Serono, also last week released that it was launching an international multicenter study to determine the longer-term safety, tolerability and efficacy of its drug against Rebif.

One part of the study, Biogen said, will analyze patients who have been taking either Avonex or Rebif "for a period of time," and the second part will follow them (and others) for three more years adding up to five years of evaluation time.

Avonex and Rebif aren't the only MS drugs battling for shares, of course. Teva Pharmaceuticals Industries Ltd. has the strong Copaxone (glatiramer acetate), and Chiron Corp., along with Schering-Plough Corp., is in the ring with Betaseron (interferon beta-1b).

Teva seemed to up the ante two days after the Serono and Biogen disclosures last week. The company, based in Jerusalem, said it was conducting "the longest prospective [MS] drug trial ever," intended to last 12 years. Although not directly comparative with other treatments, the trial already has yielded eight-year data showing Copaxone patients either improved or stayed unchanged. Participants had suffered with relapsing-remitting MS for an average of 15 years.

The Teva trial started in 1991. Randomized in a double-blind study, 251 patients were evaluated in the placebo-controlled phase for about 30 months, and then invited to continue in the open-label phase, with all getting Copaxone. Of the 251 patients, 208 kept going. At the eighth year, 142 patients (68 percent) remained aboard.

"People are talking about Copaxone, but it's regarded as an agent used as front-line therapy those diagnosed with early to mid-MS or as a second-line therapy for people who fail Avonex," Chao told BioWorld Financial Watch. "It's not the agent you think of as having the greatest impact on long-term disability."

Chiron wasn't left out of the news flurry. In the same venue where Serono offered its extended data the annual meeting of the American Academy of Neurology in Denver attendees heard of numbers from an independent Italian study comparing Chiron's Betaseron to Avonex.

The results from the Italian study suggest higher frequency of dosing leads to better clinical outcomes. Such seemed the case for Betaseron as compared to Avonex, for at least two years, and Serono's farther-range EVIDENCE data upheld an earlier finding that Rebif given three times a week led to fewer side effects than Avonex once per week, which explains Biogen's resolve to go ahead with its longer-term study against the competing Serono drug.

Side effects most commonly noted with Avonex are flu-like symptoms: muscle ache, fever and chills. Headache, pain and weakness also show up, but not to a statistically significant degree as compared with control groups, and the problems usually go away within a day after the injection and lessen over time.

"Talk in the MS community" about comparative clinical studies does not avail much, anyway, Biogen insisted in a press release, since the studies have been conducted for "short periods of time and looked at only narrow measures of efficacy" and therefore (the company argues) speculations about better efficacy with higher doses of other drugs is only speculation.

A number of other papers on Copaxone were presented at AAN, including one suggesting a novel mechanism of action that might give it some added benefit. But many eyes were on newcomer Rebif, pitted against Avonex.

John Sonnier, analyst with Prudential Securities, said in a research note that "not much was presented in the way of new data from either presentation [at AAN]." Rebif is likely to prove a worthy challenger to Avonex, Biogen's only currently marketed product. This year and next "are going to be rough growth years" for the company, Sonnier wrote.

Then, late in the week at AAN, Biogen served up still more news: four-year data showing the same clinical benefit in patients given 30 micrograms of Avonex weekly and those given 60 micrograms.

The study found no difference in the cumulative rate of sustained disability progression on the expanded Disability Status Scale, decrease in mean relapse rate from baseline, or percentage of relapse-free patients in the 30-microgram and 60-microgram groups. Those results are consistent with findings in Biogen's pivotal Phase III study with 30 micrograms of the drug.

But, analysts point out, much of the debate among neurologists has to do less with Avonex compared with itself than with the advantages (or lack of them) of Rebif at higher doses over Avonex at more conservative doses. A troubling factor sometimes noted is the presence of higher neutralizing antibodies in Rebif patients taking part in the EVIDENCE trial as compared with those on Avonex. Other physicians argue it's not well known how harmful such antibodies might be, given the overall benefit of the drug although Rebif three times per week is hardly as convenient as Avonex's once-weekly dose.

Whatever the effects down the road of the hail of news from companies with MS drugs, Biogen hangs onto its front position for now. Avonex maintained a U.S. market share of more than 50 percent (although total and new prescriptions dipped slightly) in March, with analysts predicting sales totaling in the range of $800 million for the year. Avonex sales for fiscal 2001 added up to $711 million, up 29 percent over the previous year. The next Biogen earnings report is slated for April 24.

Second place since about one year ago is Teva's Copaxone, with Betaseron, also subcutaneous, taking much of the rest, weighing in with about 22 percent of the U.S. market in March. Serono, with Rebif, is shooting for 25 percent of the U.S. market over the next three or four years, the company said, when 15,000 and 20,000 new patients are expected to surface. Serono already has 38 percent outside the U.S.

All of the other MS drugs are subcutaneous except for Avonex, delivered by way of an intramuscular route which, the company says, also gives it an edge.

And each of the competitors is scrambling for an edge. In fact, "edgy" may be the best way to describe the MS-treatment space, which in the past has grown rancorous especially between Serono and Biogen and, given the high market stakes, seems likely to grow more so. Among the papers at AAN was one by researchers at the University of Washington in Seattle, who reported modest success with blood stem cells against MS in 26 patients, but the big fights, it seems, will be among interferons, Chao said.

Leerink Swann recently polled 60 physicians who have treated some 23,000 patients, or about 12 percent of the MS population.

"Once the Rebif approval went through, I was drafting this right away," Chao said. "What we found is that, in the front-line setting, Avonex and Copaxone are utilized about 38 percent to 40 percent."

Most of the doctors polled were "extremely familiar" with Rebif and had formed opinions, she added.

"The lion's share of early stage goes to Avonex, and mid-stage, it's still Avonex [in the No. 1 position], but you can see Betaseron and Rebif coming in at 20 percent apiece," Chao said. "In late stage, Copaxone is No. 4 and Rebif is No. 2, right behind Avonex." She forecast Rebif's impact will be greater on Betaseron than Avonex.

"If you think about that, it would make sense," she said. "If docs are thinking about high-dose interferons as a subclass of agents [that includes] Rebif and Betaseron, it would make sense that Rebif's better side-effect profile would take away market share. And that's what helps offset what would otherwise be a more dramatic erosion" of the market for Avonex, she added.

"Our findings are actually more conservative than [Wall Street's] interpretation of Rebif's impact," Chao said. "What you're seeing is that early to mid-stage, relapsing-remitting MS is the lion's share of the market, and Avonex will continue to be the strong player. They certainly will lose some part of the market share, but remember the overall market is growing."

Although physicians tend to deny they are influenced by sales pitches, Chao said "a lot of the destiny of these products will fall upon the marketing. On a subconscious level, I think it will play a very large role [with physicians], and certainly in the direct-to-consumer marketing."

But, she cautioned, it's too early to tell much at all. The survey is solid for the moment, and her firm will keep updating it as time goes on, more data come in and opinions change.

"It's accurate at least here, today, this year," she said. "We're trying to get a handle on the shifting paradigm."