Comparative Study Results

A-B-C Comparison Study

A non-randomized, open-label treatment trial was conducted using individuals with RRMS to compare the relapse rates while taking one of the three "A-B-C" drugs to those remaining untreated. Individuals elected to receive one of the three treatments or no treatment, and were put into one of four groups according to their treatment choice.

The relapse rate at the time of enrollment was fairly equal among the groups, and all participants had mild to moderate disability. Most participants had few noticeable symptoms.

At the conclusion of the 18-month study, only the Betaseron® and Copaxone® groups showed a significant reduction in annual relapse rate, compared to the untreated group. Also, the mean EDSS scores were significantly reduced in only the Betaseron® and Copaxone® groups as well.

The fact that Avonex® did not show statistically significant reductions in relapse rate or EDSS scores may be a result of study design versus the performance of the drug. Relatively small numbers of samples (participating individuals with MS – about 40 per group) and short study duration, along with the fact that the study was non-blinded and non-randomized, are all factors that may have affected study outcome. Additionally, other studies suggest that Avonex® does not become fully effective until after the first year of treatment.

Avonex® versus Rebif®

In the "EVIDENCE" trial, Avonex® and Rebif® were compared to determine if Rebif® was superior to Avonex® in the treatment of RRMS. This is the largest prospective, randomized, comparative study of two drugs for RRMS to date. It included 677 individuals with RRMS at 56 centers in the US, Canada, and Europe. In this Rebif® company-funded study, the participants and treating physicians were not blinded (they knew who was given which treatment), but the evaluating physicians and the physicians reading the MRIs were blinded (they did not know which participant was taking which drug).

Rebif® and Avonex® are the same drug, but the doses, route of administration, and frequency differ. Rebif® is given in a higher dose and more frequently, just under the skin. Avonex® is given once a week deep into the muscle. Rebif® had been approved for use outside of the US, but The Orphan Drug Act protected Avonex® in the US and prevented Rebif®’s approval until at least May 2003.

This law prevents the manufacturers of identical drugs for rare or "orphan" diseases to compete in the US marketplace until the first manufacturer has had time to recoup the costs for the initial research. In order to be approved sooner, the makers of Rebif® had to demonstrate "clinical superiority" over the existing orphan drug (Avonex®).

After only 24 weeks into the one-year study, results showed "statistically significant differences" in favor of Rebif®. A higher percentage of people in the Rebif® group were relapse-free (75 percent) during these 24 weeks, versus the 63 percent who were relapse-free in the Avonex® group. The Rebif®-treated group also had one-third fewer active brain lesions (as measured on an MRI) than those in the Avonex® group. These findings gave the FDA the evidence they needed to deem Rebif® "clinically superior," and grant the drug early approval in March 2002.

Betaseron® versus Avonex®

The results of a two-year "INCOMIN" study of Betaseron® versus Avonex® once again suggest the clinical benefits of higher dose interferon given more frequently. Both the clinical outcome measures (those remaining relapse free and those who sustained progression) as well as MRI outcomes (new T2 lesions) were more favorable in the Betaseron®-treated group.

This independent study was funded by the Italian government without pharmaceutical industry support. Neither the participants nor the physicians were blinded, although those reading the MRIs were blinded.

fDose, Administration, and Side Effects

With so many factors the same, most decisions regarding treatment choice are made according to dose, method of administration, and side effects.

Avonex® is given via intramuscular injection of 30 µg once weekly. Side effects include flu-like symptoms, typically occurring within 24 hours following the injection and then not occurring again until a week later when the next dose is given. These flu symptoms tend to diminish with each dose and often subside completely after four or five months. In studies, injection-site skin reactions did not differ from those of the control group.

Betaseron® uses subcutaneous injections of 250 µg every other day. Side effects include transient flu-like syndrome, injection-site skin reaction, along with blood count and liver test abnormalities. Some evidence suggests depression and thyroid involvement as well, although a definitive link has not been found.

Interpretation of the dosage levels of the interferons is confusing. The weekly dose of Rebif® and Betaseron® are clearly higher than Avonex®, but dose levels of Betaseron® and Rebif® are harder to compare because each uses different standards to measure dosage.

The effect of NAbs is also confusing. High-dosed interferons have a greater incidence of NAbs but are still judged more effective than lower-dosed interferons. NAbs are usually transient and therefore have little lasting effect. Patients with constantly elevated NAbs may encounter reduced effectiveness.

Effectiveness with the interferons appears to be dose-related, but side effects and the development of neutralizing antibodies are dose-related as well. Most physicians do not rely on NAbs to determine treatment. The American Academy of Neurology and MS Council state that the utility of measuring NAbs is uncertain.

Another way to view this issue is to carefully monitor patients on all treatments. If an individual is deemed to have a less than optimal response to therapy, other treatment options may be explored. Either raising the dose or switching to another therapy may be considered, even if the individual has no NAbs. On the other hand, if an individual is doing well on treatment but has NAbs, most physicians would not change treatments at that time.

Rebif® is given via subcutaneous injections of 44 µg three times per week. The most commonly reported side effects are injection-site reactions and flu-like symptoms. Because of its increased dose and frequency as compared to Avonex®, liver function disorders and reduced white blood cell counts were observed with greater frequency with Rebif®. All of these problems were usually temporary.

The EVIDENCE and INCOMIN studies helped the American Academy of Neurology and the MS Council to conclude that higher dosed interferons are more effective than lower dosed interferons.
Copaxone® is administered via subcutaneous injections of 20 mg daily. Side effects include injection-site skin reactions as well as an occasional systemic reaction. For five to 15 minutes following an injection, approximately 10 percent of those tested experience reactions such as anxiety, flushing, chest pain or tightness, dizziness, palpitations, and/or shortness of breath. These symptoms are transient and do not require specific treatment.

Novantrone® is administered differently from the interferons and Copaxone®. Novantrone® is given in 12 mg/m2 IV infusions once every three months, reaching a lifetime limit of the drug (140 mg/m2) within two to three years.

Currently, Novantrone® is most commonly used as a backup treatment for individuals with a less than optimal response to one of the other approved drugs for MS. Novantrone® was studied in combination with IV doses of steroid, but many physicians now use it in combination with one of the interferons or Copaxone®. Preliminary studies suggest that the toxicity is not increased by such combinations.

Additional doses carry the risk of cardiotoxicity. People undergoing treatment are required to have regular testing for cardiotoxicity, white blood cell counts, and liver function. While generally well tolerated, common side effects include nausea, thinning hair, loss of menstrual periods, bladder infections, and mouth sores.