By Brady Huggett

Serono SA released impressive 24-week data from its 677-patient, head-to-head study of its product Rebif vs. Biogen Inc.¿s Avonex in patients with relapsing-remitting multiple sclerosis, and is building its case to break Avonex¿s orphan drug status in the United States.

Later Tuesday, data from an independent study by Luca Durelli at the University MS Center in Torino, Italy, suggested that interferon beta-1b (Chiron Corp.¿s Betaseron) reduced signs of disease activity more effectively than interferon beta-1a (Avonex) during the six-to-12-month period after initial treatment in patients with relapsing-remitting MS. The data were presented at the 2001 annual meeting of the American Academy of Neurology in Philadelphia.

Geneva, Switzerland-based Serono¿s objective was the demonstration of clinical benefit of Rebif over Avonex based on predefined FDA-approved endpoints. The primary endpoint was comparison of the proportion of relapse-free patients after 24 weeks, expressed as an adjusted odds ratio. The ratio was 1.9, meaning patients treated with Rebif had a 90 percent (p=0.0005) greater chance of remaining relapse-free during the period of observation compared to patients treated with Avonex. The finding was based on a 32 percent relative reduction in the proportion of patients experiencing relapses on Rebif, as compared to Avonex.

The secondary endpoint was the reduction in combined unique lesion activity as measured by MRI over 24 weeks. Patients treated with Avonex had 50 percent (p=0.0001) more new lesions in the brain than those treated with Rebif.

Full raw data, as well as safety figures, will be released on June 22 at the World Congress of Neurology in London, and Serono will file its results with the FDA to challenge the orphan drug status immediately afterward. But the data have both sides buzzing.

¿Let me give you an answer from someone who has been in this field for a number of years,¿ said Burt Adelman, vice president of medical research at Cambridge, Mass.-based Biogen. ¿Decisions are made not only on efficacy but also on the risk-benefit profile. We know that [Serono] has tried to get the drug approved at the FDA and has not been able to do so. They have generated six months of data, with no safety data and no raw data. It¿s hard for me to understand what significant increments will be found in a six-month study.¿

Adelman pointed to the method of delivery for Rebif as problematic. Rebif is given subcutaneously; Avonex intramuscularly. Adelman said skin ulceration or necrosis are not associated with intramuscular injections, but when drugs are given under the skin, they are. And, while the assessors in the study were blinded, the patients were not, another problem with the study, Adelman said.

Not so, said Serono.

¿No, we don¿t believe that will be a problem,¿ said Thomas Lang, president of Serono Inc., located in Norwell, Mass. ¿We did work with [the FDA] in the design. They feel the blinding was appropriate. The assessor blinding was a major factor and is a common tool in neurological studies.¿

As for the subcutaneous delivery, that¿s the upside, Lang said.

¿It allows for higher doses given more frequently ¿ that is where the benefit comes from,¿ he said. ¿It¿s easier for patients, also.¿ Lang added that how the patient gets the drug, or how often, is not a problem considering the efficacy and clinical benefit patients receive.

Adelman doesn¿t agree.

¿One of Avonex¿s commercial attributes is patients¿ convenience,¿ he said. ¿Once a week is better than once a day or [several] times a week.¿

Avonex generated $552 million in sales in the United States in 2000. Lang said Rebif has 31 percent of the market outside the United States and said Rebif is getting more than 50 percent of all new patients.

Stephen Farinelli, an analyst for Merrill Lynch & Co., said if Rebif gets into the lucrative U.S. market, it could eat into Avonex¿s sales.

¿It will depend on the strength of the data, but if it does hold up, I don¿t see why Rebif wouldn¿t get more than 20 [percent] to 30 percent of the market here by 2004,¿ he said. ¿In 10 years, I would expect Rebif to become the market leader and take the lion¿s share.¿ He added that in Europe, Rebif is the market leader and there are far more patients on three-times-weekly subcutaneous injections than there are on Avonex.

Biogen¿s coveted orphan drug status for Avonex is secure until 2003 unless Serono can crack it by showing the FDA it has a product that is clinically superior and can prove it in a head-to-head study. Whether this study will do that is still not known.

¿We have a strong commitment to get Rebif to the market as soon as possible ¿ we¿ve had that commitment with the MS patients for a while,¿ Lang said. ¿We wouldn¿t have done the trial if we didn¿t.¿

¿We aren¿t into quibbling in the back yard over existing therapies,¿ Biogen¿s Adelman said. ¿We would be amazed if there were fundamentally new data on efficacy that comes out of a six-month trial. The energy should be put on what we can do going forward to make therapy better for patients.¿

Meanwhile, Durelli, the director of the University MS Center, said of the independent Avonex-Betaseron study, ¿The common belief about these two leading MS treatments is that they are equally effective, despite their unique dosing and administration profiles. The current study suggests that interferon beta 1a and 1b differ starting six months after initial treatment.¿

MRI brain scans were used to determine the extent of neurological damage in the patients and showed that interferon beta-1b-treated patients had fewer MRI-detected active lesions, both T1 gadolinium enhanced (p<0.03) and new T2 lesions (p<0.002), than interferon beta-1a-treated patients during the year after initiating treatment. The study examined 188 patients and analyzed the data at six-month intervals.

Biogen¿s stock (NASDAQ:BGEN) moved up $2.28 on Tuesday to close at $58.10. Serono¿s stock (NYSE:SRA) climbed $1.27 to close at $24.18.

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