Long-Term Treatments for Multiple Sclerosis
Treatments Given by Self-Injection
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.
In 2014, Plegridy® (peginterferon beta-1a) became the 11th DMT approved for the long-term treatment of relapsing forms of multiple sclerosis (MS) – and the fifth interferon medication approved for MS. Plegridy is a pegylated version of interferon beta-1a. Pegylation is a chemical modification of a molecule (in this case the interferon beta-1a molecule) that extends its half-life, which refers to how long a drug stays active in the body before it is metabolized or eliminated.
While Copaxone (noted earlier) was initially approved as a daily 20-mg injection, a 40-mg dose of Copaxone injected three-times weekly was approved by the FDA in 2014; physicians and their patients may choose either dose regimen. In April 2015,Glatopa® (glatiramer acetate injection) was approved as the 13th long-term treatment for individuals with relapsing forms of multiple sclerosis (MS). Glatopa is a generic version of Copaxone® (glatiramer acetate injection), given at the original 20-mg daily dose, and as of February 2018, was also approved at the newer, 40-mg three-times-weekly injected dose. This is the first generic version of a disease-modifying therapy for MS to be approved by the FDA. In October 2017, Mylan’s generic version of Copaxone was approved at both the 20-mg daily injected dose and the 40-mg three-times-weekly injected dose.
All eight of these self-injected disease-modifying therapies (DMTs) listed above 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 daily to once every two weeks, 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 May 2016, Zinbryta® (daclizumab) became the 14th disease-modifying therapy to be approved for the long-term treatment of relapsing forms of MS (RMS) in adults. However, please note that this medication was voluntarily withdrawn from the marketplace in March 2018 by its manufacturers and is no longer available to the MS community. This voluntary withdrawal was due to new safety concerns, including several cases of inflammatory encephalitis and meningoencephalitis (both forms of brain inflammation) that were reported in Europe, as well as earlier issues with liver failure. As background information, this monoclonal antibody was self-administered subcutaneously (under-the-skin) once per month and had been shown to reduce the number of relapses as well as new or newly enhancing lesions, as compared to another approved MS medication and to placebo, in two separate studies. This medication carried safety risks, which included liver injury and immune conditions. The FDA stated that Zinbryta would only be used in patients who had an inadequate response to two or more MS drugs. Zinbryta had a boxed warning, was available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy, and monthly liver-function tests were required.
Treatments Given by IV Infusion
In 2000 (prior to the approval of some of the medications 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. Anyone taking Novantrone now or given Novantrone previously needs to have annual evaluations of his or her heart function (as noted in this advisory), even if no longer receiving this medication.
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.
In November 2014, the FDA announced the approval of Lemtrada® (alemtuzumab) for the long-term treatment of relapsing forms of multiple sclerosis (MS). This is the 12th DMT to be approved for the long-term treatment of MS, and the third intravenous medication for MS. Given for a course of five days via intravenous (IV) infusion and followed one year later by a second three-day course, Lemtrada has been approved as a second-line therapy. This classification refers to a drug that may only be prescribed when other FDA-approved treatments fail or are not tolerated well by a patient. Lemtrada should generally be prescribed for patients who have had an inadequate response to two or more of the disease-modifying therapies, because of the medication’s safety profile.
Adverse events from Lemtrada can include infusion reactions to the medication, an increased risk of infection, emergent autoimmune diseases, and other serious conditions. For early detection and management of these risks, Lemtrada is only available through a restricted distribution program, the Lemtrada REMS (Risk Evaluation and Mitigation Strategy). REMS ensures that prescriptions are only given through certified prescribers and that patients are enrolled in this important safety and monitoring program.
In March 2017, Ocrevus™ (ocrelizumab) became the 15th FDA-approved treatment, notably for two types of MS: relapsing forms of MS (RMS) and primary-progressive MS (PPMS). This is the first time that a medication for MS has been approved for two types of the disease, and the first time that any medication has been approved to treat PPMS. Ocrevus is given via intravenous (IV) infusion every six months.
Ocrevus is a humanized monoclonal antibody designed to selectively target CD20-positive B cells. These are a specific type of immune cell that is an important contributor to the MS-disease process. The fact that Ocrevus targets B cells differentiates it from most of the previously approved disease-modifying therapies for MS, which target a different type of immune cell called “T cells.” Side effects can include infusion reactions and an increase in infections. Other rare adverse events, including cancer and PML (described earlier with Tysabri), could potentially occur, but these risks are still being investigated.
Treatments Given Orally
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. Until this time, all of the other approved treatments were given either 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. PML (described earlier with Tysabri), could potentially occur, but this risk is still being investigated. In May 2018, Gilenya became the first DMT also approved for the treatment of children and adolescents, ages 10 through 17, with relapsing forms of MS. At this time, Gilenya is the only DMT approved for this patient population, referred to as “pediatric MS.”
In December 2019, FDA approved the applications from three separate pharmaceutical companies for the first generic versions of Gilenya for the treatment of relapsing forms of MS in adult patients. While generic treatments carry the same benefits and risks of the initially approved medication, this approval does not include the treatment of children and adolescents. Details on when these generic versions will be available to the MS community have not yet been announced.
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. In October 2014, Phase III data was added to Aubagio’s label, noting that it may (1) reduce the relative risk of sustained disability progression (along with reducing the annual relapse rate) and (2) prevent or delay a second clinical attack (relapse) in individuals with clinically isolated syndrome (CIS). 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. Clinical trials with Tecfidera showed a reduction in relapse rate, a delay in progression of physical disability, and a slowing in the development of brain lesions, as compared to placebo. 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. PML (described earlier with Tysabri), could potentially occur, but this risk is still being investigated.
In March 2019, Mayzent® (siponimod) oral tablets became the 16th approved DMT to treat adults with relapsing forms of multiple sclerosis (MS). The approval includes individuals with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary-progressive MS (SPMS) – a form of MS where someone with RRMS advances to experiencing a more steady increase in disability, but relapses are still occurring. Taken by mouth once daily, Mayzent has been shown to reduce the risk of three-month and six-month confirmed disability progression (CDP), slow the rate of brain volume loss, and reduce the annual relapse rate. Headache, high blood pressure, and changes in liver function tests were the most common adverse reactions reported. Patients taking Mayzent need to be monitored for changes in vision caused by macular edema, transient decreases in heart rate, decline in lung function, and changes in liver enzymes; women who could become pregnant should use contraception during and for 10 days after stopping treatment.
Also in March 2019, Mavenclad® (cladribine) oral tablets became the 17th approved DMT to treat adults with relapsing forms of multiple sclerosis (MS). The approval is for individuals with relapsing-remitting MS (RRMS) and for individuals with active secondary-progressive MS (SPMS). Mavenclad is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS. This oral medication is given in two annual courses for a maximum of 20 days over two years; no treatment is needed for Years 3 and 4. Mavenclad has been shown to reduce disease activity in patients with relapsing MS, including disability progression, annualized relapse rate, and MRI activity. Potential adverse events include lymphopenia, a condition that causes abnormally low counts of white blood cells that play a role in fighting infection, and herpes zoster infection. Mavenclad has a Boxed Warning for an increased risk of malignancy (cancer) and fetal harm. The most common adverse reactions include upper respiratory tract infections, headache, and decreased lymphocyte counts.
In December 2019, the FDA approved Vumerity™ (diroximel fumarate) oral capsules to treat adults with relapsing forms of multiple sclerosis (MS). This approval includes the treatment of clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary-progressive MS (SPMS). This medication is taken by mouth twice daily. Vumerity is in the same class of MS therapy as Tecfidera® (dimethyl fumarate), but is believed to cause fewer gastrointestinal (GI) side effects – such as diarrhea, nausea, vomiting, and abdominal pain.
Zeposia® (ozanimod) was approved in March 2020 for the treatment of adults with relapsing forms of multiple sclerosis (RMS). This once-daily oral medication is a sphingosine-1-phosphate (S1P) receptor modulator and joins two other previously approved S1P receptor modulators: Gilenya® (fingolimod) and Mayzent® (siponimod). However, unlike the first two medications, Zeposia does not require a genetic test or label-based first-dose observation.
In clinical trials, Zeposia was shown to have a significant effect on reducing the annual relapse rate (ARR) as well as the number of brain lesions, when compared to Avonex® (interferon beta-1a). The most common adverse reactions include: upper respiratory infection; elevated liver enzymes; orthostatic hypotension, which is a sudden drop in blood pressure when changing position; urinary tract infection; back pain; and high blood pressure. Warnings and precautions include an increased risk of infections, heart-rhythm issues, liver injury, fetal risk if pregnant while taking Zeposia, a decline in pulmonary (respiratory) function, and macular edema (swelling behind the eye). The launch date for Zeposia has not yet been announced.
In April 2020, the FDA approved Bafiertam™ (monomethyl fumarate) delayed-release oral capsules to treat relapsing forms of multiple sclerosis (MS). Bafiertam is a “bioequivalent alternative” to Biogen’s Tecfidera® (dimethyl fumarate), which means that the active ingredient and site of action do not differ significantly between the two medications. The therapeutic effect is assumed to be equivalent. Since a lower dose of Bafiertam is equivalent to Tecfidera, this may potentially lead to a reduction in gastrointestinal (GI) side effects, such as diarrhea, nausea, vomiting, and abdominal pain. However, these side effects have not been evaluated in clinical trials in people with relapsing forms of MS. The launch date for Bafiertam has not yet been announced.
Additional Information on All MS Treatments
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
- Some may prevent or delay a second clinical attack (relapse) for individuals with clinically isolated syndrome (CIS). CIS refers to individuals who do not meet the criteria to be diagnosed with MS, but have experienced symptoms.
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.” For early detection and management of potentially severe adverse events, Lemtrada is only available through the Lemtrada REMS (Risk Evaluation and Mitigation Strategy). 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®).
In 2014, the Multiple Sclerosis Coalition (MSC) published two papers detailing the current evidence that supports the FDA-approved disease-modifying therapies (DMTs) for the long-term treatment of multiple sclerosis (MS). The first paper was written for medical professionals. The second paper summarizes the information and has been written for members of the MS community. To view either of these papers, please go to the following links:
For medical professionals (updated June 2019):
The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence
For members of the MS community (updated March 2017):
The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence; SUMMARY
*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 July 2020.
Please refer to MSAA’s listing of Prescription Assistance Programs for information on financial help with many of these medications.