By Alex Pham, Globe Staff, 02/18/99
It used to take Allan Bowlby five excruciating minutes to button his shirt. Bowlby's hands and limbs were ravaged by multiple sclerosis. He had difficulty walking. Completely demoralized, he talked to his employer about retiring early or taking a disability leave.
Then in the mid-1990s, he started taking Rebif, which at the time was an experimental drug developed by Serono Laboratories Inc. in Norwell. "It was a little short of a miracle,'' Bowlby, a computer consultant in Attleboro, said of the drug. "Now I feel normal.''
Rebif, however, is not available in the United States because it has not been approved for sale here by the Food and Drug Administration. To get the drug, Bowlby makes pilgrimages into his native Canada, where Rebif is approved for sale, for his six-month supply.
That's just fine with Biogen Inc., whose executives prefer that Rebif be kept off pharmacist shelves in the United States until 2003. The reason: Biogen makes a drug called Avonex, which is chemically identical to Serono's Rebif. Biogen in 1996 won exclusive rights from the FDA to sell Avonex in the United States under the Orphan Drug Act, a designation that is supposed to prevent identical drugs from competing with Avonex for seven years.
Biogen executives call Rebif "an inferior knockoff'' of Avonex. Just 25 miles away from Biogen's Cambridge headquarters, Serono executives in Norwell strenuously disagree, saying Rebif provides "significant advantages'' over Avonex and should be approved for sale here.
The verbal fisticuffs are about more than semantics. At stake is a $500 million annual market for multiple sclerosis treatments in the United States, a market that Biogen currently shares with just one other pharmaceutical company. Wall Street analysts say the market could easily grow to $1 billion within a few years.
In the meantime, Bowlby and more than 300,000 people in America who suffer from multiple sclerosis await word from the FDA, which is expected to decide in the next several weeks whether to allow the use of Rebif. Many of them, including Bowlby, say they want the opportunity to judge the drugs for themselves.
Multiple sclerosis strikes about 200 additional people in the United States each week. At first, symptoms are subtle. There is temporary blurred vision, then a slight tingling in the hands. Other symptoms include dizziness and a loss of balance. Often, the signs are so mild, they can be dismissed as fatigue. Many people with multiple sclerosis live normally for years.
For some, however, the disease gradually becomes more pronounced. Muscle spasms, slurred speech, vision loss, and weakness in the limbs are common developments. Simple tasks - buttoning a shirt, walking, opening a medicine bottle - become maddeningly difficult.
Many patients describe multiple sclerosis as a "short circuit'' in the brain. In fact, it's a breakdown in the protective coating, the myelin sheath, that surrounds nerves.
There is no cure. Instead, a number of treatments can help delay the disease's progress, including beta interferons. In 1993, the FDA approved Betaseron, a form of beta interferon produced by Berlin-based Schering AG and its US affiliate, Berlex Laboratories in Richmond, Calif. In 1995, the FDA approved Avonex, also a beta interferon.
Betaseron and Avonex were approved under the Orphan Drug Act, which was passed by Congress in 1983 to encourage pharmaceutical companies to develop drugs for rare diseases. Because treatment for illnesses that affect relatively few people can be unprofitable, Congress tucked in several incentives in the Orphan Drug Act to entice companies to research and to develop drugs for such diseases. The most important incentive is the exclusive right to market the drug for seven years.
There are exceptions. If a new drug is safer, more effective, or provides a "major contribution to patient care,'' it is allowed on the market. Avonex was allowed on the market because Biogen was able to demonstrate to the FDA that it was safer than Betaseron. Patients who used Avonex were less likely than Betaseron users to develop skin ulcers from the injections, according to Dr. Burt Adelman, vice president of medical research at Biogen.
Now comes Rebif, developed by Serono Laboratories, a US affiliate of the Ares-Serono Group, a Geneva-based pharmaceutical company.
After spending nine years and nearly $150 million developing Rebif, Serono has launched a campaign to convince the FDA and the public that its product, Rebif, is clinically superior to Avonex, even though the two are chemically identical.
Hisham Samra, Serono's president, said three things set Rebif apart. The first is that it was tested at much higher doses than Avonex. Samra said studies suggest higher doses are more effective at combatting multiple sclerosis. Second, Rebif comes pre-mixed in syringes, ready for injection. Avonex users must mix that drug with sterile water before injecting. Finally, Avonex must be injected directly into muscle, while Rebif is injected under the skin, a method Samra says is more comfortable for patients.
To further its cause, Serono asked politicians to write to the FDA on its behalf, including Senator John F. Kerry and Representative Henry A. Waxman, a California Democrat who was principal author of the Orphan Drug Act. In addition, Serono's Canadian sister company placed ads in the January issue of a major medical journal, Annals of Neurology, to promote Rebif.
All of this has Biogen fuming.
"We've been very displeased with the way they've been approaching this,'' said Michael Astrue, vice president and general counsel of Biogen. "We didn't spend millions of dollars on legislative lobbying, getting patients to call the agency, on deceptive advertising. They've really tried to mislead patients into thinking that there's some new therapy out there when there's not. I think that's very sad."
Calling Rebif an "inferior knockoff'' of Avonex, Astrue said the two drugs are identical "from a biochemical perspective.'' He also attacked Serono's claim that higher doses of the drug are better. "They really have no science to back that up," said Astrue.
Astrue accused Serono of flouting FDA rules banning advertisements of drugs that are not yet approved by the agency.
Serono officials said the ad promoting Rebif was properly placed by its sister company in Canada, where Rebif has been approved for sale. Samra also said that patients are better served if there are more choices of drugs available.
In the medical community, opinions on the matter differ.
"I don't think any of us can say one is better than the other, because the clinical trials were designed so differently," said Dr. William McIlroy, the national medical director for the Multiple Sclerosis Society of Canada. "What everyone here is saying is that we'll never know unless there is a head-to-head trial of the two drugs."
Others said having a drug approved for a higher dose may help patients. Dr. Paul O'Connor, director of the Multiple Sclerosis Clinic at St. Michael's Hospital at the University of Toronto in Ontario, who prescribes both Rebif and Avonex, said: "The real issue is the dose. There are studies that seem to indicate higher doses are better, especially if the patient has more disability."
Rebif comes in doses of up to 132 micrograms per week in Canada, while Avonex is approved for only 30 micrograms per week in Canada and the United States.
Why not just prescribe double or triple doses of Avonex? O'Connor pointed out that the Canadian insurance system pays for only one dose. Extra prescriptions can be prohibitive. Better to go with Rebif, he said.
"There's a practical tendency to make sure that the patient is covered by receiving enough drugs," said O'Connor, who has done research for both Biogen and Serono.
Meanwhile, the FDA has declined to comment on the Rebif application. The agency is expected to issue its decree on the drug within the next few weeks, according to Serono officials.
The financial stakes are huge.
"Avonex is extremely vital to Biogen,'' said David Molowa, a
biotechnology analyst with Bear, Stearns in New York. "It is Biogen's primary source of revenue and earnings."
In 1998, 71 percent of Biogen's $558 million annual revenues came from Avonex, which Biogen spent a decade and $250 million to develop.
And the company is continuing to pour money and energy into improving the product. Yesterday, it signed a deal with Inhale Therapeutic Systems to develop an inhaled version of Avonex. Under the terms of the agreement, Biogen will pay Inhale royalties on product sales, an up-front signing fee, and an estimated $25 million for research funding. Biogen will be responsible for human testing and marketing.
For Bowlby, the FDA's decision will also have its consequences. Because he was part of a clinical trial, Bowlby gets free supplies of Rebif until the end of this year. Next year, if Rebif is not approved in the United States, Bowlby will either move back to Canada, or switch to Avonex or Betaseron.
"I've never tried Avonex,'' said Bowlby. ''The results I got with Rebif
were so positive that I quite frankly have no incentive to switch to anything
This story ran on page C01 of the Boston Globe on 02/18/99.
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