Disease modifying therapy: what, why, when, and which to start

What are the currently FDA approved medications for MS?

At the time of this post, there are 18 FDA approved medications for relapsing-remitting MS and 3 FDA approved medications for progressive MS. The chart below lists most of these medications and when they were FDA approved. Of these medications, all are approved for relapsing-remitting MS. Three medications have been approved for progressive disease: ocrelizumab, siponimod, and cladribine. Ocrelizumab was shown to slow disability progression in primary progressive multiple sclerosis while the others are effective in active secondary progressive MS (which is secondary progressive MS with relapses). Mitoxantrone is no longer used because of the risk of cancer and Daclizumab was removed from the market.

From B. Greenberg MD, Emerging therapies across the disease spectrum. 2020 CMSC Virtual Annual Meeting

There are many ways to divide up the FDA approved disease modifying therapies for relapsing-remitting MS which I will discuss at greater lengths in future posts. We can look at them by: how long they’ve been on the market; their mode of administration; their mechanism of action; or, their perceived potency. For the sake of simplicity, I will list them by how they are administered.

Four disease modifying therapies for relapsing-remitting MS are self-administered by an injection under the skin. They are Interferon beta-1b (Betaseron® – self-injected every other day), Interferon beta-1a (Rebif® – self-injected three times a week), peginterferon beta-1a (Plegridy® – self-injected once every 2 weeks)  and Glatiramer acetate (Copaxone® – self-injected three times a week. The fifth interferon is Interferon beta-1a (Avonex®) self-administered by a weekly injection into muscle.

Subsequently approved disease modifying therapies are oral pills or infusions which are given through a needle placed in a vein in the arm. The oral medications are fingolimod (Gilenya®), siponimod (Mayzent®), ozanimod (Zeposia®), dimethyl fumarate (Tecfidera®), monomethyl fumarate (Bafiertam®), diroximel fumarate (Vumerity®), teriflunomide (Aubagio®), and cladribine (Mavenclad®). The medications given by infusion are natalizumab (Tysabri®), alemtuzumab (Lemtrada®), and ocrelizumab (Ocrevus®).

All these medications have been tested in short randomized clinical trials lasting a few years leading to their FDA approval. All are effective at reducing relapse rate and some reduce short-term disability over their respective study lengths. Each of these medications has its advantages and disadvantages.

For active relapsing-remitting multiple sclerosis, alemtuzumab, natalizumab and ocrelizumab appear to have the highest efficacy, followed by cladribine, fingolimod and dimethyl fumarate. Interferons, glatiramer, and teriflunomide appear to have lower efficacy (A look at disease modifying therapies for multiple sclerosis 2017). Unfortunately, the newer high efficacy medications have greater risks of side effects than the older, lower efficacy interferons and glatiramer. These side effects include serious infection, autoimmune disease and possibly cancer. Autoimmune disease is a disease in which your immune system attacks and damages one or more parts of your body.

Will disease modifying therapy prevent me from getting disabled in the future?

 All neurologists agree that disease modifying therapies for active relapsing-remitting MS are effective in the short term and most agree that a few disease modifying therapies may slow progression in progressive forms of MS but the question if disease modifying therapies will affect what happens to you in the more distant future is less easily studied and less clear. Simply asked, if you have active relapsing-remitting MS will disease modifying therapy mitigate your risk for long-term disability?[xi] Experts such as Wingerchuk & Weinshenke 2016 conclude that studies to answer this question are inconclusive but suggestive that long-term benefit may exist (Wingerchuk and Weinshenke 2016).

Should I start a disease modifying therapy?

Studies show that current disease modifying therapies may not stop active relapsing-remitting MS disease in its tracks but may extend the time it takes to enter the progressive phase of the disease and modify long term disability. Given the risk of significant disability accruing over time with active relapsing-remitting MS, there is enough evidence that disease modifying therapies improve the short term and probably long term prognosis of MS to start just about every active relapsing-remitting MS patient on a disease modifying therapy as soon as possible after their diagnosis. An exception to this may be people who wish to have children in the very near future.

The question of what constitutes inactive MS and whether people with inactive MS should be started empirically on disease modifying therapy is more complex and will be considered in a future post. For now, without a reliable means to determine who has inactive MS, it makes sense for all patients with relapsing-remitting MS to be on a disease modifying therapy. As a patient with MS recently pointed out to me, because we cannot predict when a relapse will occur, you never know when a relapse will occur which can cause permanent disability.

Current thinking is that younger progressive patients should be placed on a disease modifying therapy though longer-term follow-up of these patients may be necessary to be sure whether the benefit outweighs the risk.

When should I start a disease modifying therapy?

For active relapsing-remitting MS, therapy should start as soon as possible after diagnosis to try and suppress or stop inflammatory activity which can cause irreparable future disability.

How do I decide which disease modifying therapy to start?

Disease modifying therapies are graded by their perceived efficacy into higher and lower efficacy therapies. The higher efficacy disease modifying therapies are Natalizumab, Alemtuzumab, Ocrelizumab, Cladribine, and Fingolimod/Siponimod/Ozanimod. The lower efficacy disease modifying therapies are the interferons, GA, teriflunomide, and dimethyl fumarate.  If you have active relapsing-remitting MS, there are two approaches to starting a disease modifying therapy. Some neurologists advocate starting with a low efficacy therapy in most patients as this may be safer for the patient and then switching to a higher efficacy therapy if the person with MS worsens. Other neurologists favor starting early with a high efficacy therapy arguing that it is not possible to predict the outcome of an individual patient at the onset of MS and that a neurologist’s ability to detect on going damage to the nervous system is limited and unreliable. (Weiner 2020).

The William et al. study (William, 2019) described in an earlier post suggested that starting higher efficacy therapy earlier is beneficial. In another study, Harding et al, (Harding et al 2019) looked at 592 patients with relapsing-remitting MS in southwest Wales, United Kingdom who were either initially treated with a higher efficacy therapy and compared their outcome at 5 years with other patients who were treated with a lower efficacy therapy. They also looked at people initially treated with a lower efficacy therapy and then changed to a higher efficacy therapy. Higher efficacy therapies were defined as alemtuzumab and natalizumab while lower efficacy therapies were interferons, glatiramer acetate, dimethyl fumarate, fingolimod, and teriflunomide.

Patients were not assigned medication at random in this study. The patients started on the higher efficacy therapies presumably had more active disease as their annual relapse rate was higher before treatment had a higher annual relapse rate pretreatment.

The main outcome measure in this study was worsened disability as defined as a change in the EDSS at five years[xii]. After starting either a higher or lower efficacy disease modifying therapy, the annual relapse rate decreased in all groups but decreased more in the high efficacy group[xiii]. Over 5 years, the average worsening on the EDSS was less in the high efficacy group compared to the lower efficacy group[xiv]. For those who escalated from lower efficacy to higher efficacy therapy, the median time to sustained disability was 3.3 years and 60% of this group reached their sustained disability before starting high efficacy disease modifying therapy.

Better 5-year outcome as measured by change in EDSS was seen in the group that started with high efficacy therapy despite the fact they had more initial disease activity as measured by a higher pretreatment relapse rate. Adverse events were greater in the high efficacy group. This study suggests that starting with a high efficacy therapy is better than starting with a lower efficacy therapy and then switching to a high efficacy therapy when MS worsens.

The randomized clinical trials used to obtain FDA approval to market disease modifying therapy, open label extension studies after these initial trials , and other studies like the ones described above, indicate the high efficacy therapies are probably more effective at delaying disability than the lower efficacy therapies though they also have more potential for significant side effects. Increased risks from higher efficacy therapies need to be interpreted in the context of the long-term risk of severe disability from MS. Some of the risks of higher efficacy therapy can be mitigated by close follow-up.

Current disease modifying therapy treats the inflammatory aspect of MS. This occurs early in the course of relapsing-remitting MS, and treating this inflammation early and aggressively may give a patient with relapsing-remitting MS the best chance to prolong the interval to secondary progressive MS and decrease long term disability. Moreover, a significant portion of the CNS injury leading to chronic disability may occur slowly or “silently” so that it may not be noticed by the patient or the busy neurologist until it is too late. Clinical examination and routine MRI scans show relatively large-scale inflammation but may miss smaller scale inflammation that may be widespread. This is another reason to consider starting early with higher efficacy therapy in patients with active relapsing-remitting MS. This strategy seems more likely to decrease long term disability than starting a lower efficacy therapy and switching to a higher efficacy therapy at a later date.

In view of the increased risks of treatment with higher efficacy therapies, it makes sense that patients placed on these medications should be followed by an MS specialist or a neurologist who has extensive experience with these medications.

If you have inactive relapsing-remitting MS, the decision of whether or not to start a disease modifying therapy and if so which one to start is more difficult. This issue has not been well studied. For now, you will need to depend upon the knowledge and experience of your neurologist to help you decide on the best course of action.

When you and your neurologist decide upon a course of treatment, it is crucial that you feel comfortable with this decision. If not, you might consider a second opinion from another neurologist who specializes in MS.

When should I change my therapy?

A change in your disease modifying therapy should occur if you have intolerable side effects, side effects that affect your activities of daily living, or when your MS worsens as evidenced by relapses, worsening in your disability, or new lesions on your MRI. Depending on the disease modifying therapy you are on, a change should also be considered when you change from  relapsing-remitting to secondary progressive MS.

When can I stop my therapy?

Research is currently underway to help determine if and when a disease modifying therapy can be stopped. Natural history research in MS suggests that risk of relapses and new MRI changes diminish significantly as people age, especially in MS patients 55 or older. Thus, the need to continue MS medicines that reduce relapses and new MRI lesions may also decrease as people age, especially in those who have not had relapses or MRI scan changes for prolonged times. The Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCOMS) study begun in 2017 and ending in 2022 plans to learn more about the safety of stopping MS medication as compared to continuing on the medication in this population .

References

Leave a Reply

Your email address will not be published. Required fields are marked *