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Smart Choices: Follow this expert guide to choosing an appropriate disease-modifying therapy for multiple sclerosis

Shaw, Gina

doi: 10.1097/01.NNN.0000513029.55806.cb
Departments: Eye on Therapy

If you were diagnosed with relapsing-remitting multiple sclerosis (MS) seven years ago, you had just seven disease-modifying treatments to consider. This year, with the expected approval from the US Food and Drug Administration (FDA) of ocrelizumab (Ocrevus) in late spring or early summer, people with MS will have as many as 15 treatment options.

That's both good news and bad, says Bruce Bebo, PhD, executive vice president for research with the National Multiple Sclerosis Society. “We've seen a revolution in new drug approvals, with significant advances in both effectiveness and convenience. Knowing which treatment to choose can be challenging for patients and doctors, but it's a great problem to have. It just means you have to do your research.”

All disease-modifying MS drugs work by altering or suppressing the activity of the body's immune system, to keep it from attacking the protective myelin that shields nerve fibers. But the newer MS drugs such as alemtuzumab (Lemtrada), natalizumab (Tysabri), fingolimod (Gilenya), and ocreli-zumab are significantly more effective than older treatments such as glatiramer acetate (Copaxone) and several interferon drugs (Avonex, Plegridy, Rebif, Betaseron, Extavia). And three medications—dimethyl fumarate (Tecfidera), fingolimod, and teriflunomide (Aubagio)—can be taken orally instead of being injected or infused.

With all these options, experts say, choosing a treatment comes down to three factors: efficacy, risk, and convenience.

“Many older agents are seemingly less effective, but have a well-defined safety profile,” says David Jones, MD, a neurologist with the James Q. Miller Multiple Sclerosis Clinic at the University of Virginia in Charlottesville. “Many newer agents appear more effective but come with more safety issues. This puts individuals with MS in a bit of a quandary. Do you want more safety or more efficacy?”

We take a look at all the options to help you make the most informed decision.

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NEWER AND MORE POWERFUL

Relatively few head-to-head clinical trials have compared the various MS drugs, and most have compared new agents to older agents. For example, the trials that led to the approval of alemtuzumab compared it with interferon beta-1a (Rebif) and a phase 3 trial of fingolimod compared it to another form of interferon beta-1a (Avonex). And in December 2016, a study published in the New England Journal of Medicine compared ocrelizumab with interferon beta-1a (Rebif) in patients with relapsing-remitting MS. Patients were randomly assigned to receive either ocrelizumab or interferon beta-1a for 96 weeks. Those who took ocrelizumab showed lower rates of disease activity and progression than those assigned interferon beta-1a. The researchers say longer and larger studies are needed to determine the drug's long-term safety.

Beyond these studies, the most objective guide of effectiveness and safety comes from a meta-analysis published in 2015 by the independent group the Cochrane Collaboration, says Lauren B. Krupp, MD, FAAN, director of the Multiple Sclerosis Comprehensive Care Center at NYU Langone Medical Center in New York. The group ranked the drugs' relative efficacy for reducing relapses and decreasing the probability of worsening neurologic impairment, says Dr. Krupp. These four head the list.

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THE DRUG: Alemtuzumab (Lemtrada)

Effectiveness: At or near the top when it comes to efficacy. “The rate of tissue loss that can occur over time seems to virtually stop with this drug,” Dr. Krupp says.

How it works: Targets an antigen found on white blood cells (T cells and B cells) known as CD52, stopping the autoimmune response of MS.

Dosage: 12 mg per day on five consecutive days, followed by 12 mg per day on three consecutive days one year later, as a supervised intravenous infusion.

Side effects: A possible increased risk of several types of cancer, including thyroid, melanoma, and blood cancers. It can also cause serious and sometimes fatal autoimmune reactions, including bleeding conditions and kidney complications, and dangerous infusion reactions while the medication is being given.

Caveat: Because of the serious side effects, the drug is only available under a carefully monitored program called Risk Evaluation and Mitigation Strategy (REMS). You and your neurologist may consider alemtuzumab only after a serious review of the risks involved and after at least two other MS drugs have failed and your disease is progressing significantly.

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THE DRUG: Natalizumab (Tysabri)

Effectiveness: “Natalizumab may not be quite as effective as alemtuzumab, but it is still highly effective and does not have the same extreme risks,” Dr. Krupp says.

How it works: Prevents white blood cells of the immune system from entering the brain and spinal cord.

Dosage: An infusion once every 28 days.

Side effects: A certain percentage of people who take natalizumab will develop a rare, often fatal brain infection called progressive multifocal leukoencephalopathy (PML). Signs of PML include impaired mental functioning, vision loss, speech disturbances, and clumsiness and lack of coordination. About 20 percent of people who develop PML will die, and those who survive usually are significantly disabled. The infection is caused by the John Cunningham (JC) virus, a common virus to which about half of all people have been exposed. If you have not been exposed to the virus, your risk of PML is extremely low. Otherwise, your risk is higher. If you've also taken other immuno-suppresant drugs in the past and have taken natalizumab for two years or more, your risk could be as high as one in 70.

Caveat: Must also be prescribed under a REMS program.

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THE DRUG: Fingolimod (Gilenya)

Effectiveness: Fingolimod comes next in the Cochrane group's ranking, and appears to both reduce exacerbations and slow the progression of the disease. In studies presented at the 2014 Annual Meeting of the American Academy of Neurology (AAN), patients taking fingolimod had a slower rate of loss of brain volume than those on either placebo or interferon over the course of as many as seven to eight years.

How it works: Traps some white blood cells in the lymph nodes, so they aren't released into the bloodstream, where they can attack the nervous system.

Dosage: A daily pill.

Side effects: Known risk of PML, although lower than with natalizumab. So far, nine of the approximately 160,000 people who have taken fingolimod have developed PML, says Dr. Krupp. It can also cause a temporary slowing of the heart rate after the first dose, which requires extra monitoring. There is also a risk of macular edema (fluid and protein deposists that cause swelling in the eye) and fungal infections.

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THE DRUG: Ocrelizumab (Ocrevus)

Effectiveness: Ocrelizumab was not included in the Cochrane analysis because it has yet to receive approval from the FDA, but Dr. Krupp says trials show it to be very similar to natalizumab in efficacy, and possibly a little stronger in both reducing exacerbations and slowing the progression of the disease.

How it works: Targets a different marker on the surface of B cells, known as CD20.

Dosage: An infusion twice a year.

Side effects: As an immunosuppressive drug, it could come with a risk of PML, but Dr. Krupp says the risk appears to be significantly lower than with natalizumab. No cases were reported in the clinical trials, although some have been reported among the four different medications in this class (rituximab, ofatu-mumab, and ublituximab are the other three). In both phase 3 trials of ocrelizumab, patients taking the drug had higher rates of cancer than the control group. Many experts are excited about this new drug, but others are concerned that the long-term risks or complications are unknown because it hasn't been studied over a long period of time.

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NEWER, BUT NOT AS EFFECTIVE

Other newer drugs are generally more effective than older medications such as the interferons, but not as effective as the four that head the Cochrane list.

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THE DRUG: Dimethyl fumarate (Tecfidera)

Effectiveness: Moderately effective in controlling MS; appears to sustain that efficacy over the long term. In a study presented at the AAN Annual Meeting in 2016, which came out too late to be included in the Cochrane analysis, more than 50 percent of patients taking dimethyl fumarate had no relapses through six years of treatment.

How it works: Reduces inflammation and the ability of white blood cells to attack the nervous system.

Dosage: A twice-daily pill.

Side effects: Some risk of PML, although substantially lower than with natalizumab. This risk may be due in part to low white blood cells seen in a minority of patients treated with dimethyl fumarate. Also a risk of severe and dangerous allergic reactions and skin reactions, some of which require hospitalization. Also, flushing and gastrointestinal distress (stomach pain, nausea, and vomiting).

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THE DRUG: Daclizumab (Zinbryta)

Effectiveness: Approved in 2016, daclizumab is generally considered moderately effective—comparable to the older drugs glatiramer acetate (Copaxone) and interferon beta-1a (Avonex). Studies presented at an international MS meeting last September showed that 44.7 percent of patients taking daclizumab had no evidence of disease activity by 24 to 96 weeks of treatment, compared to 22.4 percent of those taking interferon beta-1a. How it works: Decreases levels of T cells and other pro-inflammatory cells.

Dosage: A single monthly injection.

Side effects: Severe and potentially life-threatening liver damage.

Caveat: Recommended only for patients who have tried at least two other MS drugs with no success; requires careful monitoring under a REMS program.

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THE DRUG: Teriflunomide (Aubagio)

Effectiveness: Moderately effective; proven to reduce relapses by about 31 to 36 percent, which is about the same as the interferons.

How it works: Decreases the production of T cells and B cells.

Dosage: A daily pill.

Side effects: Liver damage, but the risk is lower than with the interferons and does not require such close monitoring. Compared with other drugs, its risk of side effects—especially severe ones—is among the lowest. But teriflunomide is the only MS drug contraindicated in pregnancy, rated category X by the FDA because it poses such a high risk of causing permanent damage to a fetus. The drug has appeared in semen, so both men and women are advised to use contraception while taking teriflunomide and for two years after stopping treatment.

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OLDER AND MORE ESTABLISHED

THE DRUGS: Glatiramer acetate (Copaxone), biosimilar to glatiramer acetate (Glatopa).

(A biosimilar is a biological medical product very similar to a previously licensed biologic drug. Unlike standard drugs, which are chemicals derived from other chemicals, biologics are complex proteins derived from living organisms. All the newer-generation MS drugs—except for the oral medications—are biologic agents.)

Effectiveness: Moderate efficacy, significantly below newer drugs, according to the Cochrane review. Glatopa, a generic version of Copaxone, is thought to have similar efficacy, but no clinical studies were done before its approval. A different generic version of the drug is approved in Europe; a phase 3 trial of the drug showed that it was as effective and safe as the brand-name drug.

How they work: Block the action of T cells; mechanism not entirely understood.

Dosage: 20 mg daily or 40 mg three times a week for glatiramer acetate; 20 mg daily for Glatopa. Both are injected.

Side effects: Short-term post-injection reactions such as flushing, heart palpitations, and shortness of breath, which go away on their own. Many patients develop significant injection site problems with long-term use. Overall, though, the risks are low.

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THE DRUGS: Interferon beta-1a (Avonex, Plegridy, Rebif), interferon beta-1b (Betaseron, Extavia)

Effectiveness: Ranked low effectiveness.

How they work: Thought to reduce inflammation and modulate the body's auto-immune response.

Dosage: Every other day subcutaneously (injected into the skin) for Betaseron and Extavia; three times a week subcutaneously for Rebif; once every two weeks subcutaneously for Plegridy; once a week intramuscularly (injected into the muscle) for Avonex.

Side effects: Possible liver damage, skin infections, clots in small blood vessels, and lowered white blood cell count. Each drug has its own set of side effects, which you should discuss with your physician, but overall, these drugs are considered to be very safe.

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Aggressive Treatment, with Caution

As research reveals more information about multiple sclerosis, it's changing the way neurologists prescribe treatment.

One of the challenges for people with multiple sclerosis (MS) and their doctors, especially for those recently diagnosed, is predicting whose disease will be aggressive and whose will be mild. In the past, neurologists often used an escalation approach, says David Jones, MD, a neurologist with the James Q. Miller Multiple Sclerosis Clinic at the University of Virginia in Charlottesville. “You'd start with a safer drug that perhaps has lower efficacy. If there were disease exacerbations, you'd get more aggressive and switch to a drug with greater efficacy but potentially greater risk for adverse effects.”

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A DIFFERENT APPROACH

But more recently, as studies show that the time of highest risk for disease activity and resulting long-term disability is when a person is young and newly diagnosed, some doctors have shifted their approach. “My goal is no disability in any patient at any time,” says John Corboy, MD, FAAN, co-director of the Rocky Mountain Multiple Sclerosis Center at the University of Colorado in Aurora. “That means we start with the most highly efficacious medication available within a reasonable risk profile. Disease exacerbations that happen early have an impact later on, so suppressing disease activity is important.”

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AWARE OF RISKS

Taking an aggressive approach can be a gamble, with risks such as progressive multifocal leukoencephalopathy, a rare and often fatal brain infection, or subsequent cancers. “And there is one thing we often forget: Clinical trials in MS are usually for two years, although alemtuzumab was a three-year trial,” Dr. Jones notes. “This is a disease of young people, who may be living with MS for 40 years or more. We don't know the risks of being on one of the newer agents for a decade or more.”

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FUTURE IS BRIGHT

Additional treatments are on the horizon. In another five years, this list of approved treatments may have doubled. “There's never been a time when we've known as much as we know about multiple sclerosis,” says Dr. Corboy, “or when we can do as much as we can.”

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Off-Label Options

In addition to approved treatments, doctors sometimes prescribe drugs they believe may benefit their patients that have not been formally approved by the US Food and Drug Administration to treat MS but that are approved for other indications. For example, some chemotherapy agents such as azathioprine and cyclophosphamide are still used off-label. Another example is rituximab (Rituxan), which was approved to treat certain cancers, as well as some other autoimmune diseases such as rheumatoid arthritis. Like ocrelizumab (Ocrevus), rituximab targets the CD20 marker on the surface of B cells. Unlike ocrelizumab, which is made using fully human antibodies, rituximab is synthesized using a combination of human and animal antibodies.

Several studies have found rituximab to be effective and relatively safe in treating MS. In a 2016 study published in the Annals of Neurology, patients who had to stop taking natalizumab (Tysabri) because they tested positive for John Cunningham virus activity and were at risk for progressive multifocal leukoencephalopathy (PML), a rare brain infection, were switched to either rituximab or fingolimod (Gilenya). Those on rituximab experienced significantly fewer relapses and serious side effects than those on fingolimod. Rituximab has a black box warning for PML, but the risk appears to be lower than with natalizumab.

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11 Questions to Ask Your Doctor

Before you choose any treatment for multiple sclerosis, sit down with your neurologist and discuss these important questions.

1. How aggressive do you think we should be about treating my disease? Why?

2. What are your goals, both long-term and short-term, for my treatment? What should my goals be?

3. Which drug do you think will be most likely to help me reach those goals?

4. How effective is the drug you recommend?

5. What is the dosage for this drug?

6. How often would I take it, and in what form? Is that convenient for me?

7. What are the most significant risks with this drug? What are the other possible side effects?

8. How will we know if and when the drug is working?

9. At what point would you recommend switching to another drug if we don't think this one is working?

10. How will I be monitored while I'm taking this drug? How often will I need to come in for checkups?

11. What else should I be doing to combat this disease?

© 2017 American Academy of Neurology