Oral multiple sclerosis medications

Selecting the Right Oral MS Drug

ORLANDO—After years of waiting, patients with multiple sclerosis (MS) can now choose between three approved oral agents. Patients’ choices will be improved, however, if they first investigate which of the three drugs would be most appropriate for them.

All three oral drugs—fingolimod, teriflunomide, and dimethyl fumarate—are “definitely” suitable as first-line therapy in selected newly diagnosed patients with MS, said Mariko Kita, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, Director of the Virginia Mason MS Center in Seattle and Director of the MS Clinical Trials Unit at Virginia Mason’s Benaroya Research Institute.

Few neurologists are prescribing an oral agent as a first-line therapy, partly because of cost and reimbursement issues, but mainly because most physicians do not believe that the oral agents’ safety profiles are fully understood. Most practitioners hesitate to administer new drugs. The hesitation may be understandable in light of the cautions added to the labels for natalizumab—considered the most effective of the injectable agents—and fingolimod—the first oral agent to receive marketing approval—shortly after they were introduced.

Nevertheless, physician experience with the oral medications is expected to grow quickly. Barring revelations of new side effects, observers anticipate that the use of oral agents for MS will surge within the next few years, leading to a corresponding decline in the popularity of injectable therapies.

Oral Therapies May Appeal to All Patients With MS
Demand for oral therapy will be high among all types of patients, predicted Dr. Kita. Newly diagnosed patients and individuals with a lengthy disease history who have tried all the available disease-modifying therapies with unsatisfactory results will be interested in oral medications, she said. The same will be true for patients who cannot tolerate a given first-line injectable agent or who experience breakthrough disease while using it. Likewise, patients who are stable on their current injectable disease-modifying therapy but are tired of injections or concerned about the parenteral therapy’s long-term risks will consider the oral drugs, added Dr. Kita.

Choosing an appropriate oral medication requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and how the oral drug would fit into a long-term, staged therapy plan, she added.

Fingolimod
Fingolimod is best reserved for patients with MS who are otherwise relatively healthy, said Dr. Kita. It is a less favorable option for patients with diabetes, smokers, individuals with reduced pulmonary function, and those with an increased risk of infection, including people with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so that they cannot participate in autoimmune activity. The testing required before initiating fingolimod therapy, the need for careful observation during the first dose, and the necessary ongoing monitoring for the duration of treatment make this a labor-intensive drug, said Dr. Kita.

Bearing those factors in mind, she continued, fingolimod is “reasonable” to use as a first-line agent or as a second-line agent in the setting of intolerance to prior therapy or of breakthrough disease on therapy.

Expectations for First- and Second-Line Therapies
“I would caution those who are reserving these oral agents as second-line that we need to think about what we can reasonably expect from them,” said Dr. Kita. “If we’re moving to them as second-line because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral will be better than a failed injectable has not yet been proven,” she added.

Choosing the Right Oral Drug
Of the three oral MS agents currently available in the US, dimethyl fumarate has the most benign side effect profile, which consists mostly of short-term flushing and gastrointestinal complaints. Dimethyl fumarate could gain broad use as a first-line drug in newly diagnosed patients and as a second-line therapy in patients intolerant to other agents or in patients experiencing breakthrough disease.

It remains unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. In several studies, patients who took fingolimod after natalizumab discontinuation had a high relapse rate. No data exist yet about the effects of the two newer agents under these circumstances, Dr. Kita said.

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 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. 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.

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®).

View MSAA’s Chart of Approved Treatments (PDF)

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:
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 May 2018.

Please refer to MSAA’s listing of Prescription Assistance Programs for information on financial help with many of these medications.

Multiple sclerosis disease-modifying drugs: first line treatments

There are currently five DMDs used as first line treatments for relapsing-remitting multiple sclerosis.

  • Beta interferon 1a (available under the trade name Avonex®) – given by injection into a muscle (intramuscular) once a week using a pre-filled syringe.

  • Beta interferon 1a (Rebif®) – given by injection under the skin (subcutaneously) three times a week using a pre-filled syringe.

  • Beta interferon 1b (Betaferon® and Extavia®) – given by injection under the skin (subcutaneously) every other day. The injection needs to be prepared by mixing the ingredients before drawing it up in a syringe.

  • Glatiramer acetate (Copaxone®) – given by injection under the skin (subcutaneously) once a day using a pre-filled syringe.

There are two drugs used for second line treatment (fingolimod and natalizumab) covered in another information sheet.

The treatments do not cure MS, but can reduce the number of relapses. In adult trials, the relapses decreased by around a third and the effect on relapses in young people with MS appears to be significantly greater than this. By decreasing the number of relapses, it appears that the long-term development of disability can also be slowed down. Some research also suggests that the earlier treatment starts, the more effective it is likely to be. These drugs may also not work for everyone, and the pros and cons of treatment need to be constantly reviewed.

How are they given?

Currently, the five first line treatments are all given by injection. All the medications come with injection devices that make giving an injection much easier and the needle is almost always hidden. In the near future, there will be oral medication available, but it will take some time before we know exactly how these should be used and how safe they are in young people. You may be asked to consider a research trial involving these medications.

Who should not take first-line DMDs?

People with any of the following should discuss using first-line DMDs with their doctor:

  • Hypersensitivity to Beta interferon 1a or Beta interferon 1b or glatiramer acetate or any of their ingredients such as human serum albumin (Avonex®).

  • Pregnant, could be pregnant, planning to become pregnant or breastfeeding.

  • Depression or dark thoughts.

  • Severe liver disease.

What are the side effects?

Common side effects of Beta interferon 1a and Beta interferon 1b include flu-like symptoms after having the injection and irritation at the injection site. In addition to reactions at the injection site, glatiramer acetate can cause flushing and panic after having the injection. Other more common side effects are headache, injection-site bruising, tiredness, gastrointestinal upsets and mood changes.

If these side effects cause problems, please discuss them with your doctor. It may be better for your child to switch to another of the five first line treatments.

  • Flu-like symptoms can be improved by giving the injection at bedtime alongside a dose of paracetamol or ibuprofen according to the instructions on the bottle.

  • Injection site reactions can be managed by rotating the injection site. There are several areas of the body suitable for giving injections. As a general rule, suitable areas are those with a substantial amount of fat below the skin, so the thighs, buttocks and abdomen tend to be most suitable in children. As your child grows, other areas may become suitable as well, such as the upper arms but these vary from child to child.

Four of the five first line DMDs can cause liver and blood abnormalities in less than one per cent of people. Unless your child is having glatiramer acetate injections, which does not cause these abnormalities, they will initially need to be monitored regularly with blood tests. Usually, your child will need blood tests once a month for the first three months, then every three months. Once they are stable on treatment, blood monitoring will only be needed every six months.

Your child will be seen regularly and examined and may also have a MRI brain scan. If your child continues to have relapses, then the treatment will be changed to something more effective for your child after the appropriate discussions. The current second line DMD options are fingolimod and natalizumab – information about these are in another information sheet.

First line DMDs and other medicines

Some medicines can react with first line DMDs, altering how well they work. Always check with your doctor or pharmacist before giving your child any other medicines, including herbal or complementary medicines. The following are known to react with first line DMDs:

  • some medicines used to treat epilepsy or depression

  • medicines that affect blood cell production

  • other medicines that damp down the immune system, except steroids

Important information

  • Once all the approvals for treatment are in place, the drugs are delivered directly to your house. A nurse will then arrange to come to your home and train you and/or someone from your family how to give the injection. The nurse usually gives the first injection and they provide full support for the next few injections until you feel confident. They also give advice on other aspects of the injection, but do not usually give any MS specific advice.

  • Store the drugs as directed on the packaging – some need to be stored in the fridge but others need to be stored at room temperature. If you are unclear, please ask the nurse from the homecare company.

  • Store all medicines in a safe place where children cannot reach them.

  • If your doctor decides to stop or change treatment, return any unused DMDs to the pharmacist. Do not flush them down the toilet or throw them away.

  • If you forget to give your child a dose and it is within a few hours of when the dose was due, give it as soon as you remember. Otherwise, do not give this dose but take the next dose when it is due. Do not give a double dose.

Multiple sclerosis: Are we close to a cure?

Just 20 years ago, there was little in the way of treatments for multiple sclerosis. But now, research has built momentum, and discoveries and potential treatments are always emerging. How far have we come in treating the symptoms of multiple sclerosis and how close are we to a cure? We find out.

Share on PinterestResearchers are uncovering many potential treatment routes for MS. Could they be close to a cure?

Multiple sclerosis (MS) is a potentially disabling disease that affects the brain and spinal cord. Around 400,000 people are living with MS in the United States and approximately 2.1 million individuals have the condition worldwide.

The exact mechanism that drives MS is not entirely understood. However, many researchers suggest that the condition is an autoimmune disease that attacks the myelin sheath – that is, the protective layer surrounding the nerves that help electrical signals to travel from the brain to the rest of the body – in the brain and spinal cord.

Over time, the disease can deteriorate or permanently damage the nerves. Symptoms tend to vary depending on the nerves affected and the damage caused. While some people may lose the ability to walk, others experience extended periods of remission.

Drugs recently approved by the FDA

At present, disease-modifying therapies (DMTs) are the best strategy to slow the course of MS. DMTs reduce the frequency and severity of relapses – or attacks and exacerbations – and the development of new lesions, and slow down the progression of disability.

Share on PinterestOcrelizumab is the latest MS drug approved by the FDA.

The number of available DMTs has increased rapidly in recent years, and there are now 15 of them approved by the U.S. Food and Drug Administration (FDA) for relapsing forms of MS, including relapsing-remitting MS (RRMS). One of these is also the first to be approved for use in primary progressive MS (PPMS), and the FDA has approved another for use in secondary progressive MS (SPMS).

The newest addition to the DMT repertoire is ocrelizumab (Ocrevus).

Ocrelizumab

The FDA approved a groundbreaking new drug in 2017 for the treatment of relapsing MS. The drug is also the first approved to treat PPMS. Research conducted by a team of researchers has shown that ocrelizumab significantly reduces relapses in relapsing MS and slows the progression of symptoms in PPMS.

Ocrelizumab, as with many other MS treatments, is an immunosuppressant drug. While most drugs for MS target T cells, ocrelizumab targets a subset of B cells that are thought to play a role in the destruction of myelin.

Phase III clinical trials for RRMS indicated that compared with interferon beta-1a, ocrelizumab was able to reduce relapse rates by up to 47 percent, cut back disability by up to 43 percent, and decreased inflammatory lesions in the brain by 95 percent.

A phase III clinical trial for PPMS found that after 12 weeks of receiving ocrelizumab or a placebo, progression of disability was 39.3 percent in the placebo group compared with 32.9 percent in those receiving ocrelizumab. By 120 weeks of treatment, a timed 25-foot walk worsened performance by 55.1 percent for placebo versus 38.9 percent for the ocrelizumab group.

Patients receiving ocrelizumab also had fewer brain lesions and less loss of brain volume than the placebo group.

Latest innovations in the MS drug pipeline

The development of new medicines can take 10 to 15 years from testing in a laboratory to being commercially available. For every 10,000 compounds tested, fewer than one or two become licensed treatments, with many rejected on the grounds of their safety, quality, and efficacy.

Some therapies in their final phase of clinical trials are listed below. If the drugs prove effective in this phase, data from phases I through III are presented to the FDA for approval. Only 25 to 30 percent of drugs progress to the next stage following FDA approval.

Laquinimod

Laquinimod is an experimental drug in phase III trials for relapsing MS, and phase II trials for PPMS. Laquinimod may prevent immune cells from reaching the brain. Investigations have indicated that Laquinimod has both anti-inflammatory and neuroprotective actions, and it may affect the levels of certain cytokines, which are substances secreted by immune cells, as well as diminish the immune cells that gain passage to the brain and spinal cord.

Phase III studies of Laquinimod have shown a 23 percent reduction in annual relapse rate compared with a placebo, a 33 percent decrease in disability progression, and a 44 percent reduction in brain volume loss.

AHSCT

The idea behind autologous hematopoietic stem cell transplantation (AHSCT) is to “reboot” the immune system in people with MS. Hematopoietic, or blood cell-producing, stems cells derived from the person’s own (autologous) blood or bone marrow are collected and stored.

Share on PinterestAHSCT may stop MS disease progression for at least 5 years.

After chemotherapy drugs are used to deplete much of the immune system, the stored stem cells are then reintroduced to the body, and the new cells make their way to the bone marrow and gradually rebuild the immune system within 3 to 6 months.

Imperial College London in the United Kingdom recently published the long-term outcomes of AHSCT in people with relapsing MS. They revealed that AHSCT might halt the symptoms of the disease from progressing for 5 years in 46 percent of MS patients.

However, the treatment carries significant risk due to the involvement of aggressive chemotherapy, the researchers stress.

MD1003

MD1003 (high-dose biotin) is being tested in phase III trials for primary and secondary progressive MS. The drug is a highly concentrated form of biotin – 10,000 times the recommended daily intake – that activates enzymes involved in cell growth and myelin production. High doses of biotin may promote myelin repair.

Investigators compared MD1003 with a placebo in primary and secondary progressive MS. They found that 13 percent of individuals in the MD1003 group improved in disability after 9 months compared with no improvement in the placebo group.

Siponimod

Siponimod is being developed for use in SPMS. The drug works by trapping T cells and B cells in the body’s lymph nodes, which prevents them from entering the brain and spinal cord and causing damage to myelin.

In a phase III trial, siponimod was found to lower the risk of disability progression by 21 percent at 3 months of treatment and 26 percent at 6 months compared with a placebo. The drug was also shown to reduce the number of relapses experienced and brain shrinkage, or atrophy.

Recent MS treatment research

MS treatment research is moving at a rapid pace. Recent study findings have highlighted new areas for investigation, potential causes that have opened up new targets for treatment, and novel therapies for tackling disease progression and symptoms.

Resistance training

According to research by the Aarhus University and Aarhus University Hospital, both in Denmark, the University of Southern Denmark, and the University Medical Center Hamburg-Eppendorf in Germany, while cognitive training helps to reduce the cognitive symptoms of MS, resistance training may protect the nervous system, and, as a result, slow down the progression of MS.

Share on PinterestTraining with weights may help to protect the nervous systems and slow MS progression.

Study findings showed that physical training relieved some MS symptoms, including mobility impairments and excessive fatigue.

“Among persons with MS, the brain shrinks markedly faster than normal,” said Prof. Ulrik Dalgas, of the Department of Public Health at Aarhus University. “Drugs can counter this development, but we saw a tendency that training further minimizes brain shrinkage in patients already receiving medication. In addition, we saw that several smaller brain areas actually started to grow in response to training.”

Antioxidant

An over-the-counter antioxidant called lipoic acid may prove valuable in the treatment of SPMS, according to researchers from the Oregon Health & Science University in Portland.

Their study revealed a 68 percent improvement when using lipoic acid compared with a placebo in slowing the rate of whole brain atrophy. As a comparison, the recently approved ocrelizumab showed an 18 percent improvement over placebo in slowing the rate of whole brain atrophy in primary progressive forms of MS.

Gut microbes

Researchers from the Mayo Clinic in Rochester, MN, have reported that a human gut microbe called Prevotella histicola suppressed MS in mice. It decreased the levels of pro-inflammatory cells and increased levels of cell types that fight disease, including T cells, dendritic cells, and a form of macrophage.

“This is an early discovery but an avenue that bears further study,” says Dr. Joseph Murray, a Mayo Clinic gastroenterologist. “If we can use the microbes already in the human body to treat human disease beyond the gut itself, we may be onto a new era of medicine. We are talking about bugs as drugs.”

Is a cure for MS imminent?

As yet, there is no cure for MS. However, we are at a pivotal moment wherein researchers are making significant progress and breakthrough solutions toward a world free of MS.

Share on PinterestResults from early mouse studies have indicated paralysis reversal in MS, which may have treatment implications for humans in the future.

Today, more therapies for MS are in development than ever before, and the disease is being diagnosed at a quicker rate, enabling early treatment to slow disease activity.

There is greater awareness of all the associated symptoms of MS and how to manage them to improve life quality. Furthermore, scientists have identified risk factors that make individuals more susceptible to MS, which may potentially lead to new ways to prevent the disease.

Researchers are making headway in testing approaches that protect the nervous system from MS-related damage. These strategies include using therapies that are already approved by the FDA for use in other disorders. Clinical trials assessing novel approaches to treating all forms of MS are also under way.

In learning how the nervous system and cells are damaged in MS, scientists have used their findings to investigate therapies aimed at repairing myelin. In mouse models of MS, researchers have already developed experimental treatments that have resulted in reversing paralysis and partially restoring myelination and limb function.

Researchers are pursuing leads that show how exercise and rehabilitation improve several functions and may help to rebuild and rewire certain areas of the brain.

Studies have uncovered modifiable lifestyle factors, such as smoking, vitamin D levels, and obesity, which could possibly decrease the chances of MS for the next generation. What is more, research teams have identified gene variations that influence a person’s susceptibility to MS.

All these clues and evidence combined help researchers to understand the causes of MS, how to develop improved treatments, and how to prevent the disease. While there is still no definitive answer on how to cure MS, advances in research and potential treatment avenues may one day unlock the solution to a cure.

MS Medications

Disease-Modifying Medication for MS

Disease-modifying drugs do not make you feel better in the short term, nor do they address specific MS symptoms. They are effective at slowing the progression of disability caused by multiple sclerosis and lowering the frequency and severity of acute attacks in people who have the most common type of the disease, known as relapsing-remitting MS (RRMS).

These drugs also reduce the development of new lesions (areas of damage, or scarring, in the brain and sometimes spinal cord), as seen on MRI (magnetic resonance imaging) scans.

For people with primary-progressive MS (PPMS), only one disease-modifying medication, Ocrevus (ocrelizumab), has been shown to lower the risk of disability progression. PPMS is marked by a gradual worsening of symptoms, without the acute attacks that occur in RRMS. (1)

RELATED: What People With MS Need to Know About Ocrelizumab

Secondary-progressive MS (SPMS) is a second phase of RRMS, during which a person usually has fewer relapses but disease progression still occurs, accompanied by increased disability. Until recently, only one drug, Novantrone (mitoxantrone), was approved for use in people with SPMS. But in spring 2019, two drugs, Mayzent (siponimod) and Mavenclad (cladribine), were approved for “active” SPMS, or SPMS in which relapses still occur and new lesions are seen on MRIs.

Drugs Approved for Relapsing-Remitting MS

The U.S. Food and Drug Administration (FDA) has approved the following drugs to treat relapsing-remitting MS:

  • Aubagio (teriflunomide) is a once-daily capsule that blocks the production of immune-system cells.
  • Avonex and Rebif (interferon beta-1a) and Betaseron and Extavia (interferon beta-1b) are injected into the muscle (intramuscular) or under the skin (subcutaneous). It’s believed that these drugs work by controlling inflammation in the central nervous system (CNS).
  • Copaxone (glatiramer acetate) or Glatopa (glatiramer acetate) is a subcutaneous injection that attracts immune-system cells (T cells) that would otherwise attack myelin sheaths.
  • Gilenya (fingolimod) is a once-daily pill that prevents T cells from getting out of lymph nodes and into the bloodstream.
  • Plegridy (peginterferon beta-1a) is a longer-lasting form of interferon.
  • Tecfidera (dimethyl fumarate) is a twice-daily oral capsule that lowers CNS inflammation and the ability of immune cells to get into the CNS.
  • Tysabri (natalizumab) is an intravenous (IV) infusion that works by binding to white blood cells and interfering with their movement from the bloodstream into the CNS.

Drugs Approved for RRMS and SPMS

  • Mavenclad (cladribine), is an oral pill, taken in two 10-day courses, one year apart. It works by killing T and B cells, preventing them from damaging the nerves in the brain and spinal cord.
  • Mayzent (siponimod) is an oral pill taken once daily that works similarly to Gilenya. It is also approved for clinically isolated syndrome, which is a single episode of MS-like symptoms that is sometimes the first sign of MS.
  • Novantrone (mitoxantrone) is an immunosuppressant drug administered by IV infusion. It requires regular cardiac monitoring, and there is a total maximum amount an individual can receive over his lifetime.
  • Vumerity (diroximel fumarate) is an oral capsule that’s taken twice daily and that works similarly to Tecfidera, but is believed to cause fewer gastrointestinal side effects than Tecfidera. Vumerity is also approved to treat clinically isolated syndrome.

Drug Approved for Relapsing MS and for PPMS

  • Ocrevus (ocrelizumab) is an intravenous (IV) infusion that works by targeting CD20-positive B lymphocytes and destroying them. It’s the only drug approved by the FDA for PPMS.

Second-Line Therapy for Relapsing MS

The FDA has also approved the IV drug Lemtrada (alemtuzumab) for people who have forms of MS that include relapses and who haven’t responded well to two or more types of disease-modifying medication. (2)

Alemtuzumab works by rapidly depleting the body’s supply of immune (T and B) cells, which temporarily stops the immune-system effects on your CNS and allows your body to create new cells, which might not attack myelin sheaths.

The FDA recommends using it only as a second-line therapy (after other drugs have failed) because it increases the risk of complications, including severe infections, development of new autoimmune diseases, and other potentially dangerous conditions.

RELATED: 10 Key Questions About Multiple Sclerosis Drugs

In the news: FDA approves the first oral drug for reducing multiple sclerosis relapses

Published: December, 2010

People with relapsing forms of multiple sclerosis (MS) have a new option for reducing periodic attacks (relapses) and for delaying the progression of MS-related disability. MS is typically treated with injected drugs or infusions, which can be painful and inconvenient and may discourage some patients from staying on therapy. The FDA has approved the first oral medication, fingolimod, brand name Gilenya (pronounced jil-EN-yah).

The drug, taken once a day in 0.5-milligram (mg) capsules, works by a different mechanism than other approved MS medications, and in a head-to-head comparison, it was more effective against relapses than one of the leading injectables. However, fingolimod has a number of side effects — some potentially quite serious — and its long-term safety and effectiveness are unknown.

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Oral vs. Injectable MS Treatments: What’s the Difference?

Self-injectable medications make up the largest category of DMTs. They’re used for the long-term treatment of relapsing-remitting MS (RRMS).

A medical professional will train you in the injection process so that you can safely administer your own dose. Most of these medications can cause redness, swelling, and pain at the injection site, in addition to other side effects.

Avonex (interferon beta-1a)

  • Benefit: works as immune system modulator, has antiviral properties
  • Dose frequency and method: weekly, intramuscular injection
  • Common side effects can include: headache, flu-like symptoms
  • Warnings include: liver enzymes and complete blood count (CBC) may need to be monitored

Betaseron (interferon beta-1b)

  • Benefit: works as immune system modulator, has antiviral properties
  • Dose frequency and method: every other day, subcutaneous injection
  • Common side effects can include: flu-like symptoms, low white blood cell (WBC) count
  • Warnings include: liver enzymes and CBC may need to be monitored

Copaxone (glatiramer acetate)

  • Benefit: works as immune system modulator, blocks attack on myelin
  • Dose frequency and method: daily or three times per week, subcutaneous injection
  • Common side effects can include: flushing, shortness of breath, rash, chest pain
  • Warnings include: injection sites can become permanently indented because fatty tissue is destroyed (as a result, careful rotation of injection sites is recommended)

Extavia (interferon beta-1b)

  • Benefit: works as immune system modulator, has antiviral properties
  • Dose frequency and method: every other day, subcutaneous injection
  • Common side effects can include: flu-like symptoms, headache
  • Warnings include: liver enzymes and CBC may need to be monitored

Glatopa (glatiramer acetate)

  • Benefit: works as immune system modulator, blocks attack on myelin
  • Dose frequency and method: daily, subcutaneous injection
  • Common side effects can include: redness, swelling, pain at the injection site
  • Warnings include: injection sites can become permanently indented because fatty tissue is destroyed (as a result, careful rotation of injection sites is recommended)

Plegridy (pegylated interferon beta-1a)

  • Benefit: works as immune system modulator, has antiviral properties
  • Dose frequency and method: every two weeks, subcutaneous injection
  • Common side effects can include: flu-like symptoms
  • Warnings include: liver enzymes may need to be monitored

Rebif (interferon beta-1a)

  • Benefit: works as immune system modulator, has antiviral properties
  • Dose frequency and method: three times per week, subcutaneous injection
  • Common side effects can include: flu-like symptoms
  • Warnings include: liver enzymes may need to be monitored

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