Rebif [in context].
Only 10 years ago, physicians could do nothing to influence the course of MS for anyone. Nothing. They could control symptoms, and recommend therapies to improve people's lives, preserve some abilities, and help people learn to compensate for losses. But the central problem--the MS--was beyond the reach of medicine. Those days ended in 1993 with FDA approval of Betaseron.
By 1997, there were two more "disease-modifying" drugs--all with proven ability to cool down part of the MS process. All are immune-system modulators.
A committee of MS specialists who advise the National MS Society reviewed the evidence available in 1998. The group found the benefits of Copaxone, Betaseron, or Avonex to be so clear that they issued the Society's Disease Management Consensus Statement. It strongly supports early intervention with one of these drugs by people with relapsing-remitting MS, "to reduce future disability and improve quality of life." This recommendation was made despite the fact that these drugs don't cure MS, they don't stop symptoms, and they don't help everyone equally.
[Why Rebif was approved]
Two trials led to FDA approval of Rebif this past March. The first, called the PRISMS trial, was conducted at 22 centers in Europe, Canada, and Australia. It tested an inactive placebo against two different doses of Rebif taken three times a week for two years. All 560 trial participants injected themselves.
The trial was "double-blinded", meaning neither the volunteers nor the health-care professionals knew who belonged to which group, a standard technique to prevent bias. The results, made public in 1997, showed that Rebif caused a statistically significant reduction in the number and frequency of MS attacks, slowed the progression of disability, and reduced the evidence of MS damage in the brain as revealed by MRI.
Additionally, the investigators concluded that the higher dose of Rebif was preferable to a lower dose and that starting treatment early on rather than later benefited patients. Following this trial, Rebif has been prescribed to people with MS in some 60 countries around the world.
A second trial, called EVIDENCE, was sponsored by the manufacturer of Rebif, and used a study design reviewed by the FDA. It was a "head-to-head" test of Rebif vs. Avonex. This study was done to see if any clinical superiority could be detected that might persuade the FDA to permit marketing Rebif in the United States sooner than mid-2003. Since Avonex and Rebif are identical molecules--both are interferon beta-la--Rebif had been denied the U.S. market under the terms of the Orphan Drug Act which protected Avonex from competition by an identical drug for seven years.
EVIDENCE was a short-term, six-month trial, involving 677 people with relapsing-remitting MS. Half of them injected Avonex; the other half, Rebif. The clinical assessors were "blinded" to minimize bias, but the volunteers knew what they were using because of the different injection schedules.
According to the FDA's report on the study, if the outcomes for the two groups were different, it could rule that Rebif is a "different drug" and thus not subject to Orphan Drug Act restrictions, even though it is the same as Avonex at the molecular level. Similar reasoning previously permitted the marketing of Avonex in 1996, when the nearly similar Betaseron was already available. (Betaseron, approved in 1993, is interferon beta-1b. The "b" refers to a structural variation in the interferon beta molecule.)
At the end of six months, Rebif showed a statistical advantage over Avonex on all primary and secondary outcome measures, including the number of relapses and volume of new lesions as detected by MRI. There were some differences in side effect levels. Injection site reactions, including pain; liver abnormalities; and drops in white blood cell counts (not, however, associated with increases in infections), were more common in the Rebif group.
[Three experts comment]
Inside MS asked three internationally known neurologists who specialize in MS research and patient care, all members of our Medical Advisory Board, how this development affects what they now advise their own patients.
Dr. Kenneth Johnson, who heads the Maryland Center for MS, was an investigator in the pilot and definitive clinical trials of Betaseron and lead investigator in the trials that led to approval of Copaxone.
"We don't have four drugs. We have two," he said. "Three of these are different forms of the same thing, interferon beta. The other drug is glatiramer acetate. The Rebif interferon is a welcome and useful addition to my clinical practice for two reasons: first, it is the only interferon drug available in a prefilled syringe. My patients find that very helpful. Second, Rebif is available in two doses, which gives me more flexibility in prescribing.
"Does this mean I would switch someone who is doing well on Avonex? Certainly not. And we follow all our MS patients very closely. We do MRIs every 18 to 24 months as part of ongoing assessments, so we're looking at the silent lesion burden as well as the clinical symptoms.
"The evidence that higher interferon doses are more effective is good. We also know higher doses produce more side effects. It's a balancing act. If a person can tolerate a higher dose, that's all to the good. But we may hear more about side effect problems with higher-dose interferons in the coming months. We have an excellent alternative option in Copaxone. Frankly, I consider it first for someone newly diagnosed."
Dr. Fred Lublin, director of the Corinne Goldsmith Dickenson MS Center at New York's Mt. Sinai Hospital, was an investigator in the trials that led to approval of Betaseron. He agrees with Dr. Johnson about dosing issues. "The data supporting higher doses (referred to as `the dose response') are not perfect, but they aren't bad, and they are certainly suggestive," Dr. Lublin said. "I'm telling my newly diagnosed patients that there is now another interferon to consider. It is a higher dose, and is taken less often than Betaseron and more often than Avonex. I want my patients to have some choices. Convenience and `life style' are still issues--but frankly so is dosage."
Like Dr. Johnson, Dr. Lublin would not recommend a change for anyone who is currently doing well, regardless of which drug she or he is taking. He is not overly worried about the "neutralizing antibodies" that a certain percentage of people taking an interferon drug will develop. "If one of my patients on an interferon therapy is not doing well, not responding, I wouldn't necessarily consider it an antibody issue. Depending on the individual situation, I might try a higher dose or switch the patient to Copaxone," he said.
Dr. Richard Rudick heads the Mellen MS Center at The Cleveland Clinic, one of the centers where Avonex was studied prior to its FDA approval. His assessment of the antibody controversy is different.
"I was always concerned about the impact of neutralizing antibodies, which showed up mostly in patients on Betaseron," he said. In Dr. Rudick's opinion, the EVIDENCE trial shows that antibodies do affect outcome, with Rebif offering the greatest advantages to people who remain neutralizing-antibody negative.
"I think we will all continue to struggle with the obvious dilemma: higher doses can be more effective, but higher doses and more frequent injections mean more side effects. Is the difference for an individual patient going to be big enough to make us want to do this?"
All the specialists agreed that patience is an important part of dealing with the side effects. There are no oral formulations at this time, so everyone needs to learn safe injection techniques. The flu-like side effects of interferon drugs generally taper off in six months, or at about the same time that taking the medication has become routine. Side effects of glatiramer acetate mainly involve problems at the injection site (pain, itching, swelling) with a possibility of a rare episode of flushing, chest pain, and intense anxiety that passes in 30 minutes or less, leaving no known aftereffect.
The Consensus committee originally agreed that the statistical differences in outcomes among Copaxone, Betaseron, and Avonex clinical trials were not sufficient in themselves to warrant recommending one of the medications over the others. It will take several months, while the specialists review data, before a formal supplementary statement relating to Rebif is added to the recommendation. But the basics of the National MS Society's Disease Management Consensus Statement are certain to remain: The advantages of the disease-modifying drugs are real. They represent the best available chance to reduce future disability and improve quality of life for many people with MS.
[Cost, training, and support issues]
There is one area where Rebif is different from the other three. According to www.drugstore.com, the annual retail price of Avonex is $10,412; Betaseron is $12,544; Copaxone is $11,280. Rebif is $13,875 a year. Retail prices vary according to the pharmacy used, as do insurance co-pays and prescription drug caps.
Serono (Rebif), Berlex Laboratories (Betaseron), Biogen (Avonex), and Teva Neuroscience (Copaxone) all offer patient support programs, injection training, information about MS, reimbursement counseling to maximize insurance coverage or any available pharmaceutical benefit programs, plus some financial assistance for those who are without adequate resources.
[The bottom line]
The most important guide through all this is a knowledgeable physician. For information about the nearest MS clinical centers and MS specialists, call 1-800-FIGHT-MS and select Option #1. To assist physicians and allied healthcare professionals involved in MS care, the Society offers the Professional Resource Center at 1-866-MS-TREAT, on our professional Web site <www. Nationalmssociety.org/PRC.asp > and via e-mail: <MD_info@nmss.org> or <HealthProf_info@nmss.org>.
To review the data on PRISMS, see Lancet, V 352, No. 9139, pp. 1498-1504, November 1998, and Neurology, V. 56, pp. 1628-1636, June 2001. The FDA's analysis of EVIDENCE is online at <www.fda.gov/cber/products/ ifnbser030702.htm>.
A note on [Novantrone]
After the Consensus Statement was issued, another drug gained FDA for use in MS. Novantrone offers hope of modifying the course of secondary-progressive, progressive relapsing, and rapidly worsening relapsing-remitting MS. It is a powerful immune suppressant, which is given once every three months, has a lifetime dose limit to avoid risk of injury to the heart. It is the new drug approved for progressive of MS, but it is not in the same as the self-injectable immune recommended for long-term use.
Avonex Betaseron Interferon Beta-1a Interferon Beta-1b [Manufacturer/Distributor/When Approved] Biogen Berlex 1996 (May) 1993 [How Often/How/Common Side Effects] Weekly; intramuscu- Every other day; sub- lar (into the muscle) cutaneous (under the injection skin) injection Flu symptoms follow- Flu symptoms follow- ing injection, which ing injection, which lessen over time for lessen over time for many people. Rarer: many. Injection site mild anemia, ele- reactions, about 5% vated liver enzymes. of which need med- ical attention. Rarer: elevated liver enzymes, low white blood cell counts. [Approximate Retail Cost Per Year] $10,412 $12,544 (source: <www.drugstore.com> as of May 2002) [For Information and Financial Support] Avonex Alliance Pathways 800-456-2255 800-788-1467 <www.avonex <www.betaseron .com> .com> Copaxone Rebif Glatiramer Acetate Interferon Beta-1a [Manufacturer/Distributor/When Approved] Teva Pharmaceutical Serono, Inc. Industries 2002 (March) 1996 (December) [How Often/How/Common Side Effects] Daily; subcutaneous Three times a week; (under the skin) subcutaneous (under injection the skin) injection Injection site reac- Flu-like symptoms tions. Rarer: a reac- following injection tion immediately which lessen over after injection which time for many. Injec- includes anxiety, tion site reactions. chest tightness, Less common: shortness of breath Abnormalities of and flushing. This liver function and lasts 15-30 minutes decreases in red or and has no known white blood cell long-term effects. counts. [Approximate Retail Cost Per Year] $11,280 $13,875 (source: <www.drugstore.com> as of May 2002) [For Information and Financial Support] Shared Solutions MS LifeLines 800-887-8100 877-44-REBIF <www.copaxone <www.rebif.com> .com>
Martha King is the editor of Inside MS.
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|Date:||Jun 22, 2002|
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