AVONEX® and Rebif®: Your Questions Answered

The U.S. Food and Drug Administration (FDA) has approved for marketing Rebif® (Serono Inc., Geneva Switzerland), a form of interferon beta-1a, for treatment of relapsing forms of MS.  Here are common questions and answers about this new MS drug.

Q: What is Rebif®?

A: On March 8th, 2002 Serono’s Rebif® (Interferon beta-1a) was approved by the US Food and Drug Administration (FDA).  Rebif® is a treatment for relapsing forms of MS. It is a form of Interferon beta-1a, produced by living cells. It is delivered in a liquid formulation, and must be administered by subcutaneous injection three times a week. Rebif® is said to reduce the frequency of relapses and delay the progression of disability.  

Q: AVONEX® and Rebif® are similar Interferon beta-1a.  How are they different?

A: The difference is in the delivery. AVONEX® is injected directly into the muscle. It is believed that IM injection allows the medication to be released slowly into the bloodstream. Because effective amounts of AVONEX® stay in the body longer, you don’t have to inject as frequently.  Rebif® is injected under the skin, not into the muscle. Thus it is thought to remain in the body for a shorter period, and must be given three times a week.

The two drugs also show markedly different side effects. In a six-month clinical trial, 92% of patients using Rebif® developed injection site reactions (redness, pain or swelling), vs only 4% of patients using AVONEX®. In the 2-year studies of Rebif and AVONEX, elevated liver function tests, which can indicate inflammation or damage to the liver, were seen in 27% of patients using Rebif, vs 8% using AVONEX®. Lowered white blood cell counts (leukopenia) were seen in 36% of patients using Rebif, vs 1% of patients using AVONEX®. The most common side effects associated with AVONEX® treatment are mild, flu-like symptoms—muscle aches, fever and chills.

Q: Why did the FDA approve Rebif® to be marketed in the USA?  Does it work better than AVONEX® (Interferon beta-1a)?

A: The FDA allowed Rebif to break AVONEX’s market exclusivity, afforded by the Orphan Drug Act, based on the 24-week results of an open-label study.  The results of any short term study must be viewed in the context of the fact that MS is a chronic lifelong disease.  The 24-week Serono study demonstrated a short term advantage for people treated with Rebif in relapses only (a 12% difference in the proportion of patients who were free of relapses in 24 weeks).  Importantly, the Serono study does not indicate that Rebif works better than AVONEX in the long term.  In fact, the second 24 weeks of the same study showed that the risk of relapse was equivalent or, if anything, slightly less in the people treated with AVONEX compared to people treated with Rebif.  The FDA noted that Betaseron (approved in 1993) and AVONEX (approved in 1996) for the treatment of relapsing forms of MS were shown to decrease the frequency of clinical exacerbations by approximately one-third.

Q: Was Rebif® proven to have a better effect on long-term accumulation of disability than AVONEX®?

A: No. The 24 weeks study did not support any conclusion regarding the effects on the accumulation of disability and so offers only a snapshot of what is happening very early on in the course of the treatment. The two year phase III study data for AVONEX® and Rebif® – while not a head to head comparison, reflect a much more representative period within the lengthy time course of MS.

In Serono’s Phase III study for Rebif (PRISMS) a 30% effect on accumulation of disability for the 44 mcg dose was seen over two years. However, in March 1999, the FDA rejected Serono’s attempt to enter the US market because its long-term phase III study of Rebif® did not demonstrate clinical superiority over AVONEX®.

Q: Why are some drugs administered just once-a-week and others more frequently?

A: A drug like AVONEX® is injected once-weekly directly into muscle tissue (IM), from where it is released slowly into the bloodstream.  Since the drug stays in the body longer, you don’t have to inject it as frequently.  On the other hand, drugs like Rebif®, Betaseron®, and Copaxone® are injected subcutaneously, require a frequent dosing, and are thought to remain in the body for a shorter period of time.  Therefore, these injections must be given more frequently. Most patients on Rebif® and Betaseron® have to take the injection every other day, and those on Copaxone® need to take the injection every day.

Ultimately, you must weigh the benefits and the costs jointly with your physician to choose a therapy that meets your treatment goals and lifestyle. Once-a-week IM injections are less disruptive to a patient’s daily schedule than subcutaneous injections given several times a week. IM injections can also reduce the chance of having painful and unsightly injection-site reactions—such as redness, swelling, and tissue death (necrosis)—that can commonly appear at subcutaneous injection sites.

Q: What long-term factors should I consider before choosing a treatment?

A: When choosing an MS drug, the most important measure is whether the drug has a proven ability to slow the accumulation of disability. MS is a chronic disease: the question is whether the treatment will maintain its effectiveness and tolerability over time, or will its benefit eventually wear off?

Staying on therapy is the best way you can positively impact your MS.  Therefore, choose a therapy with side effects you can manage over the long run. Convenience is another key factor.  Treatments that can be administered easily, quickly and less frequently may be easiest to live with.