Long-Term Treatments for MS

The first three long-term treatments for multiple sclerosis (MS) became available in the early to mid 1990s and were dubbed the "A-B-C" drugs because of their brand names: Avonex®, Betaseron®, and Copaxone®. These are interferon beta-1a, interferon beta-1b, and glatiramer acetate, respectively. Another interferon, Rebif® (interferon beta-1a), was added to the list of approved treatments in 2002. This is the same drug as Avonex, but is injected differently and in more frequent and higher doses. In 2009, Extavia® (interferon beta-1b) was also approved. This is the same medicinal product as Betaseron and is given in the same doses, but is marketed under a different brand name and by a different pharmaceutical company.

All five of these disease-modifying therapies (DMTs) are approved by the Food and Drug Administration (FDA) for treating either relapsing-remitting MS (RRMS) or all relapsing forms of MS. Some of these DMTs have also been approved for "clinically isolated syndrome" (CIS), which refers to the initial symptom a patient reports prior to a diagnosis of MS.

Each of these treatments is administered by self injection at one's home, with the frequency of injections ranging from once weekly to once daily, depending on the drug prescribed. These therapies have been used for several years and research shows that many people are doing well on these medications for extended periods of time (some for more than 20 years). Most side effects (such as flu-like symptoms and injection-site reactions) are manageable through various strategies and over-the-counter medications. Blood tests may be given periodically to monitor various items, such as liver enzymes, the number of red blood cells and white blood cells, and the possible development of neutralizing antibodies* (please see note below).

In 2000 (prior to the approval of Rebif and Extavia mentioned above), Novantrone® (mitoxantrone) was approved by the FDA for the long-term treatment of MS. This was the first drug indicated for RRMS, secondary-progressive MS (SPMS), and worsening RRMS. Novantrone has been used for many years to treat cancer. It is given via intravenous infusion once every three months. Side effects may include cardiac disease and leukemia, and for this reason, patients must be closely monitored and are limited to a maximum of two to three years of treatment with this drug. Because of the potential risks and with the approval of more long-term treatments for MS, Novantrone is seldom prescribed for individuals with MS.

In 2004, Tysabri® (natalizumab), was approved for relapsing forms of MS. It is administered via intravenous infusion every four weeks. After its initial approval, Tysabri was temporarily suspended after two individuals (taking Tysabri in combination with Avonex) developed progressive multifocal leukoencephalopathy (PML), which if not discovered early, is an often-fatal viral infection of the brain. Since that time, Tysabri has been re-approved and patients are closely monitored through the "TOUCH Prescribing Program."

In 2012, the United States Food and Drug Administration (FDA) announced that three factors have been identified with increasing the risk of PML for individuals with multiple sclerosis (MS) being treated with Tysabri. These include: (1) the presence of JC virus antibodies (detected through a blood test); (2) previous treatment with immunosuppressive drugs, such as Novantrone, Imuran, or Cytoxan; and (3) the length of time an individual has been taking Tysabri - specifically beyond the two-year mark. More details are included in MSAA's article, Antibody Test Identifies New Risk Factor for PML.

The eighth DMT for MS is Gilenya® (fingolimod), which was approved in September 2010. Pronounced as "Jil-EN-ee-ah," this is the first oral drug available for the long-term treatment of MS. The other approved treatments are given via self injections at home or infusions at a medical facility. The approval of an oral treatment provides a more convenient and comfortable option to some individuals, particularly if they do not respond to or are unable to tolerate the other approved medications. As with the other treatments, Gilenya also has potential side effects and adverse events, including a temporary slowing of the heart rate, edema (swelling) behind the eye, and liver changes.

In September 2012, Aubagio® (oral teriflunomide) became the ninth FDA-approved DMT for relapsing forms of MS -- and the second approved DMT that is taken orally. Aubagio has been approved in two dose levels: 7 mg and 14 mg. While the higher dose (14 mg) shows greater effectiveness, for individuals who may be more sensitive to the drug and experience greater side effects, the lower dose (7 mg) may be more appropriate. Common adverse events include headache, elevations in liver enzymes, hair thinning, diarrhea, nausea, neutropenia (a condition that reduces the number of certain white blood cells that normally fight infection), and paresthesia (tingling, burning, or numbing sensation). More severe adverse events include the risk of severe liver injury and the risk of birth defects if used during pregnancy.

Tecfidera™ (dimethyl fumarate or DMF, formerly known as BG-12) was approved by the FDA as a first-line therapy for the long-term treatment of relapsing forms of MS in March 2013. This is the 10th DMT for the long-term treatment of MS. Tecfidera is administered in pill form orally and is the third oral DMT approved for MS. The approved dosage is 240 mg to be taken two times daily. The most commonly reported side effects are flushing and gastrointestinal events, occurring more often at the beginning of treatment, and decreasing in frequency after the first one to two months on this medication.

Individuals are usually prescribed only one type of DMT during any one time period. Several large clinical trials have been conducted to study each of these drugs separately for their safety and effectiveness in MS. Although differences exist in study design and specific findings, trials generally showed these common results:

• Reduced the number of relapses
• Reduced the severity of relapses
• Reduced the development of new areas of inflammation as seen on magnetic resonance imaging (MRI) scans
• Showed some evidence of delaying disease progression and/or disability

The documented effectiveness of each of these drugs varies to some extent, and differences can be attributed to the type of the drug, dose and administration, as well as variations in study design. Stronger drugs may offer greater effectiveness but may also pose greater health risks. Additionally, the effectiveness and side effects of each drug may vary from one patient to another, so individuals need to consult with their physician to determine which treatment might be the best option for them.

Each of the approved treatments has side effects that are usually manageable. At this time, Novantrone is the only drug that has a set limit of doses, which is necessary to avoid cardiotoxicity (heart damage). Tysabri increases the risk of PML (described above) and patients are closely monitored through the "TOUCH Prescribing Program." Patients beginning on Gilenya are monitored for changes in heart rate and are given baseline evaluations for any issues with the heart, lungs, liver, eyes and vision, as well as white-blood-cell count. The other drugs mentioned earlier appear safe provided the person taking the drug is not experiencing any adverse effects and blood tests continue to be normal.

While no damage to the reproductive system or the fetus has been observed, these drugs are not recommended if a woman is pregnant or considering pregnancy during her treatment period. Male patients considering certain long-term treatments may want to discuss options for family planning with their doctor.

Other treatments are sometimes used to try to slow MS disease progression when other therapies have been ineffective. Such treatments are approved by the FDA for other illnesses, but not specifically for the treatment of MS. These include intravenous immunoglobulin (IVIg) therapy, methotrexate, azathioprine (Imuran®), and cyclophosphamide (Cytoxan®).

Approved Long-Term Treatments for MS All Additional Notes: Show - Hide Print PDF of this Chart
	Avonex	Type Interferon beta-1a* (immune system modulator with antiviral properties)	Side Effects Flu-like symptoms and headache	How Administered 30 micrograms taken via weekly intermuscular injections
	Additional Notes [show] Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies.
	Betaseron	Type Interferon beta-1b* (immune system modulator with antiviral properties)	Side Effects Flu-like symptoms, injection-site skin reaction, blood count and liver test abnormalities	How Administered 250 micrograms taken via subcutaneous injections every other day
	Additional Notes [show] Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies.
	Copaxone	Type Synthetic chain of four amino acids found in myelin (immune system modulator that blocks attacks on myelin)	Side Effects Injection-site skin reaction as well as an occasional systemic reaction - occurring at least once in approximately 10 percent of those tested	How Administered 20 milligrams taken via daily subcutaneous injections
	Additional Notes [show] Systemic reactions occur about five to 15 minutes following an injection and may include anxiety, flushing, chest tightness, dizziness, palpitations, and/or shortness of breath. Usually lasting for only a few minutes, these symptoms do not require specific treatment and have no long-term negative effects.
	Extavia	Type Interferon beta-1b* (immune system modulator with antiviral properties)	Side Effects Flu-like symptoms, injection-site skin reaction, blood count and liver test abnormalities	How Administered 250 micrograms taken via subcutaneous injections every other day
	Additional Notes [show] Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies.
	Rebif	Type Interferon beta-1a* (immune system modulator with antiviral properties)	Side Effects Flu-like symptoms, injection-site skin reaction, blood count and liver test abnormalities	How Administered 44 micrograms taken via subcutaneous injections three times weekly
	Additional Notes [show] Side effects may be prevented and/or managed effectively through various treatment strategies; side effect problems are usually temporary. Blood tests may be given periodically to monitor liver enzymes, blood-cell counts, and neutralizing antibodies.
	Novantrone	Type Antineoplastic agent (immune system modulator and suppressor)	Side Effects Usually well tolerated; side effects include nausea, thinning hair, loss of menstrual periods, bladder infections, and mouth sores; additionally, urine and whites of the eyes may turn a bluish color temporarily.	How Administered IV infusion once every 3 months (for two to three years maximum)
	Additional Notes [show] Novantrone carries the risk of cardiotoxicity (heart damage) and leukemia; it may not be given beyond two or three years. People undergoing treatment must have regular testing for cardiotoxicity, white blood cell counts, and liver function. Because of the potential risks, Novantrone is seldom prescribed for individuals with MS.
	Tysabri	Type Humanized monoclonal antibody (inhibits adhesion molecules; thought to prevent damaging immune cells from crossing the blood-brain barrier)	Side Effects Headache, fatigue, depression, joint pain, abdominal discomfort, and infection	How Administered IV infusion every four weeks
	Additional Notes [show] Risk of infection (including pneumonia) was the most common serious adverse event during the studies (occurring in a small percentage of patients). The TOUCH Prescribing Program monitors patients forsigns of PML, an often-fatal viral infection of the brain. Risk factors for PML include: the presence of JC virus antibodies, previous treatment with immunosuppressive drugs, and taking Tysabri for more than two years.
	Aubagio	Type Immunomodulator (affecting the production of T and B cells; may also inhibit nerve degeneration)	Side Effects Headache, elevations in liver enzymes, hair thinning, diarrhea, nausea, neutropenia (a condition that reduces the number of certain white blood cells), and paresthesia (tingling, burning, or numbing sensation)	How Administered 7- or 14-milligram tablet taken orally, once per day
	Additional Notes [show] More severe adverse events include the risk of severe liver injury and the risk of birth defects if used during pregnancy. A TB test and blood tests for liver function must be performed within six months prior to starting Aubagio, and liver function must be checked regularly. If liver damage is detected, or if someone becomes pregnant while taking this drug, accelerated elimination of the drug is prescribed.
	Gilenya	Type S1P-receptor modulator (blocks potentially damaging T cells from leaving lymph nodes)	Side Effects Headache, flu, diarrhea, back pain, abnormal liver tests and cough	How Administered 0.5-milligram capsule taken orally once per day
	Additional Notes [show] Adverse events include: a reduction in heart rate (dose-related and transient); infrequent transient AV conduction block of the heart; a mild increase in blood pressure; macular edema (a condition that can affect vision, caused by swelling behind the eye); reversible elevation of liver enzymes; and a slight increase in lung infections (primarily bronchitis). Infections, including herpes infection, are also of concern. A six-hour observation period is required immediately after the first dose, to monitor for cardiovascular changes.
	Tecfidera	Type Immunomodulator with anti-inflammatory properties; may have neuroprotective effects, potentially protecting the nerves and myelin covering from damage	Side Effects Flushing and gastrointestinal events; reduced white-blood cell (lymphocyte) counts; elevated liver enzymes in small percentage of patients	How Administered 240 mg tablet taken twice daily
	Additional Notes [show] Other adverse events include mild or moderate upper respiratory infection, pruritus (chronic itching), and erythema (skin redness or rash). In studies, the only serious adverse events to occur in two or more patients taking Tecfidera was gastroenteritis (an inflammation of the lining of the intestines) and gastritis (an inflammation of the stomach lining). Reduced white-blood cell (lymphocyte) counts were seen during the first year of treatment. Liver enzymes were elevated in 6 percent of individuals taking Tecfidera, compared to 3 percent on placebo.

*Additional information about interferons: Some individuals develop neutralizing antibodies (NABs) to the interferons (Avonex, Betaseron, Rebif, and Extavia), but their impact on the effectiveness of these medications has not been established. Many continue to do well on these drugs despite the presence of NABs. Others may have sub-optimal results even without NABs present.

The MS Council and the American Academy of Neurology have concluded that the higher-dosed interferons are likely to be more effective than lower-dosed interferons. Several factors, however, must be considered when selecting one of these drugs, and this decision must be made on an individual basis under the guidance of a qualified physician.

Please note that MSAA does not endorse or recommend any specific drug or treatment. Individuals are advised to consult with a physician about the potential benefits and risks of the different treatment therapies.

For more information about approved and experimental treatments for MS, please refer to MSAA's MS Research Update, published in March 2013.