All About Multiple Sclerosis

More MS news articles for July 2003

Interferons

http://www.nationalmssociety.org/Sourcebook-Interferons.asp

July, 2003
The National Multiple Sclerosis Society

From The MS Information Sourcebook, produced by the National MS Society.

The interferons are a group of proteins that are normally produced by cells in response to viral infection and other stimuli. They were first described in 1957, and were named for their ability to interfere with viruses that are replicating. There are three main types of interferon:

Three interferon beta medications have been approved by the U.S. Food and Drug Administration (FDA) for treating relapsing forms of MS: IFN beta-1b (Betaseron®); IFN beta-1a (Avonex®); and IFN beta-1a (Rebif®).

Interferon beta (IFN-B)

IFN-B has multiple effects on the immune system, including increasing suppressor lymphocyte activity and inhibiting stimulation of other immune cells. It also can regulate production of interferon gamma. The actions of interferon beta have the net effect of reducing the immune response that is directed against central nervous system myelin in people with MS. Myelin is the fatty sheath that surrounds and protects nerve fibers. Its destruction, known as demyelination, causes nerve impulses to be slowed or halted and produces the symptoms of MS. Damage to the myelin sheath is also associated with destruction of the nerve fibers themselves.

Clinical Trials Show Effectiveness of Interferon Beta

Small-scale clinical trials (studies to see if a promising new therapy is safe and effective) in the 1980s provided preliminary indications that interferon beta reduced the number of exacerbations in patients with relapsing-remitting MS. An exacerbation-also known as an attack, relapse, or flare-is a sudden worsening of an MS symptom or symptoms, or the appearance of new symptoms, which lasts at least 24 hours and is separated from a previous exacerbation by at least one month.

In 1988, a large-scale clinical trial of IFN-beta-1b, involving 372 MS patients, was begun at several medical centers in the United States and Canada. The IFN-beta-1b (which is made in bacteria using recombinant DNA technology) was injected under the skin every other day. All the patients in the study had relapsing-remitting MS, were able to walk, and had had MS for an average of about four years. In this placebo-controlled trial, patients were chosen at random to receive one of two doses of interferon beta or the control (placebo) substance. This trial was double-blinded, with neither the researchers nor the patients knowing until the end of the study which subjects were receiving the medication or the placebo.

At the end of two years, the group receiving the higher dose of IFN-beta-1b had a lower exacerbation rate than the placebo group. In addition, the median time between exacerbations was significantly longer in the higher dose IFN-beta-1b group than in those receiving placebo, and there were more people in this group who were exacerbation-free than in the placebo group.

The patients in this study received a series of MRI (magnetic resonance imaging) scans. MRI is the preferred method of imaging the brain to detect the presence of plaques or scars caused by MS. The MRI scans showed that at the end of three years, the patients receiving the higher dose of IFN-beta-1b had a significant decrease in new lesions compared to those on placebo. There was no significant effect seen on overall disability or disease progression.

Betaseron® Approved for Relapsing-Remitting MS

The higher dose of IFN-beta-1b used in this trial was approved by the FDA in 1993 to reduce the frequency of clinical exacerbations in relapsing-remitting MS. Marketed by Berlex under the name Betaseron®, this medication is taken every other day by subcutaneous injection. In 2003, the FDA extended the approval of Betaseron® to "relapsing-forms of MS," to include people with secondary-progressive MS who continue to have relapses. Additional information about the clinical trials that led to this labeling change can be found in our Research section or on Betaseron's Web site at www.betaseron.com.

Side Effects of Betaseron®

IFN-beta-1b is generally well tolerated, with the most frequent side effects being a "flu-like" syndrome, consisting of fever, chills, muscle aches and malaise, that diminishes with continued treatment. Other, less common side effects include changes in blood cell counts and liver functions. To monitor for these changes, it is recommended that patients using Betaseron® have a baseline blood test prior to starting the medication, and periodic blood tests thereafter.

Injection site reactions, most of which are transient and self-healing, also occur. About 5% of those with injection site reactions have problems requiring medical attention. Depression and persistent suicidal thoughts may be a rare side effect of treatment, or may be related to the underlying MS disease process. As a result, the FDA indicates that Betaseron® should be used with caution in patients with depression, and anyone experiencing symptoms of depression should report them promptly to his or her physician.

Less frequent adverse effects do occur, and are listed and described in the package insert.

Avonex®, Another Form of Interferon Beta, Approved

In 1996, the FDA approved a slightly different form of interferon beta-interferon beta-1a-that is produced in cells from mammals using recombinant DNA technology). Marketed by Biogen under the trade name Avonex®, this medication was approved for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Avonex® is taken once a week by intramuscular injection.

The pivotal clinical trial was conducted with 301 ambulatory relapsing- remitting MS patients at several U.S. medical centers. The patients received either a placebo, or weekly injections of Avonex® into muscle tissue. The trial was double-blind and lasted for two years. The results indicated that the rate of progression of disability in the Avonex®-treated patients was slower than in the placebo group, as was the relapse or exacerbation rate in the treated patients. The number of new or active lesions seen on MRI scans was also significantly smaller than that in the placebo group.

On the basis of additional clinical trials, the FDA extended the labeling of Avonex® in 2003 to include the following statement:

"Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis."

Additional information about clinical trials of Avonex® can be found in our Research section and on the Avonex® Web site at www.avonex.com.

Side Effects of Avonex®

Common side effects of Avonex® include flu-like chills, fever, muscle aches, and malaise, which diminish with continued treatment. Other, less common side effects include changes in blood cell counts and liver functions. To monitor for these changes, it is recommended that patients using Avonex® have a baseline blood test prior to starting the medication, and periodic blood tests thereafter.

The FDA recommends that Avonex® be used with caution in patients with depression and other mood disorders. Anyone experiencing symptoms of depression or other mood changes should report them to his or her physician.

Less frequent adverse effects do occur, and are listed and described in the package insert.

Rebif® (Interferon beta-1a) Approved in 2002

In September 1997, the pharmaceutical manufacturer Serono Inc., Geneva, Switzerland announced positive results in multicenter trials of Rebif®, an interferon beta-la product that is identical in chemical composition to that of Avonex®. Rebif® is taken by subcutaneous injection three times a week. The trial, conducted at 22 medical centers in Europe, Canada, and Australia, involved 560 people with relapsing-remitting MS, who were ambulatory at the start of the trial. At the end of two years, patients on both high- and low-dose Rebif® had a rate of relapse or exacerbation about one-third lower than that of the group who were treated with an inactive placebo. The rate of progression of disability in treated patients was slowed, and lesions (or damaged areas) in the brain as seen on MRI were significantly reduced. For virtually all outcomes, there was no significant difference between the two dosage levels, although results were slightly better in the high dose group. In this study, both dosages of Rebif® were higher on a weekly basis by weight than the weekly amount of Avonex® studied in the U.S. clinical trials.

The EVIDENCE Trial

Because Rebif® and Avonex® are chemically identical, Serono's application for marketing approval of Rebif® in the United States was not initially approved by the FDA. Under the Orphan Drug Act, which provides incentives to pharmaceuticals to produce medications for relatively rare diseases, Avonex® had been guaranteed market exclusivity for seven years, until 2003. To obtain approval prior to that date, Serono needed to demonstrate "clinical superiority." Serono conducted a head-to-head comparison trial of Rebif® and Avonex®, called the EVIDENCE trial. The trial results were in favor of Rebifâ on all primary and secondary outcomes, including fewer relapses and reduced accumulation of brain lesions as detected on MRI. Based on these outcomes, the FDA approved Rebif® in 2002 for relapsing forms of MS to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Details of the EVIDENCE trial can be found in our Research section or on the Rebif Web site at www.rebif.com.

Side effects of Rebif®

The most common side effects are flu-like reactions that lessen with continued treatment, and inflammation at the site of injections. Other, less common side effects include changes in blood cell counts and liver functions. To monitor for these changes, it is recommended that patients using Rebif® have a baseline blood test prior to starting the medication, and periodic blood tests thereafter. The FDA advises that Rebif®, like all interferon beta products, be used with caution in patients with depression. Anyone experiencing symptoms of depression should report them to his or her physician.

Less frequent adverse effects do occur, and are listed and described in the package insert.

Detailed information about each of these medications can be found our Treatments section.

Important Reminder Concerning Interferon Medications

Dr. Aaron Miller, the Society's Chief Medical Officer, emphasizes the need for periodic liver function testing for all patients taking an interferon medication. He recommends obtaining a baseline evaluation, doing a repeat test after one month on medication, and re-testing every three months thereafter.
 

Copyright © 2003, The National Multiple Sclerosis Society