The history of treatments for multiple sclerosis (MS) has been marked by eras, each defined by the introduction of new groups of medications and, importantly, the modification of the disease by suppression or alteration of the immune system.

The first was that of the ABC drugs—interferon ß-1a (Avonex), interferon ß-1b (Betaseron), and glatiramer acetate (Copaxone)—an era marked by the ability to treat patients long-term with self-administered injections that allowed them easier access and produced manageable adverse events (AEs).1 Still widely utilized, these therapies were joined by additional formulations of interferon ß-1a (Rebif) and interferon ß-1b (Extavia) in 2002 and 2009, respectively, among others, which helped build the class of disease-modifying therapies (DMTs). After this period, there was a new era characterized by oral medications and intravenous (IV) monoclonal antibodies. 

“We got fingolimod [Gilenya], then dimethyl fumarate [Tecfidera], then teriflunomide [Aubagio],” Tanuja Chitnis, MD, told NeurologyLive. “Dispersed in between, we got the first intravenous monoclonal antibodies—natalizumab [Tysabri] was introduced and then taken off the market, then reintroduced. That has also been an important treatment for severe forms of MS. Most recently, we have alemtuzumab [Lemtrada] and then ocrelizumab [Ocrevus]. Many physicians have also used its precursor, rituximab [Rituxan].”

As of 2018, the list of DMT options for clinicians treating MS extends to 15 therapies. Chitnis, the director of the Partner Pediatric Multiple Sclerosis Center at Massachusetts General Hospital, explained that having the breadth of selections—something that is not available in many other neurological conditions—is wonderful for both patients and physicians. Having choices, she said, allows for clinicians to adjust treatment when efficacy issues or AEs arise.

“I think the choices that are available are very helpful and important, and I think now physicians are entering an era, at least I am, where they’re trying to very carefully consider what would be the right match of treatment for a specific patient,” Chitnis said.

Amidst a robust pipeline and strong stockpile of options, the MS field has arguably never been more exciting. As the use of DMTs expands to different approaches and subtypes of MS, fresh challenges and unanswered questions remain. 

Choosing From Efficacious Oral Options

The oral era has been dominated by fingolimod, which ushered in the era with its approval in 2010; dimethyl fumarate, and teriflumonide.2,3 Choosing between each oral agent can represent a challenge, given a lack of head-to-head comparisons for the available treatments, according to Chitnis. However, due to the difficulty of conducting those trials in MS, head-to-head comparisons will likely never come to fruition, Darin Okuda, MD, told NeurologyLive.

“The therapies, when they’re super effective, are so effective that you would need over 5000 to 10,000 patients for that study to be appropriately powered,” said Okuda, a professor of neurology and neurotherapeutics, director of the Multiple Sclerosis and Neuroimmunology Imaging Program, director of neuroinnovation, and deputy director of the Multiple Sclerosis Program and Clinical Center at UT Southwestern Medical Center. 

For Okuda, the future in MS does not include head-to-head trials. “If we ran that experiment over and over again, we may have answers that are completely different versus the first observation,” he said.

“One of the biggest challenges that we have is understanding which therapy is really more effective than the other, and I think that from a 30,000-foot view, we can somewhat arrive at conclusions in our head on which agent might be better than the other,” Okuda explained. “But know that this list is not going to be uniform in the minds of all clinicians.”

Help deciding which therapies are more efficacious could come from other analyses. Most pertinent, for Chitnis, would be advancements in predictive models and biomarkers, an ability to predict or associate patient response with a certain DMT. Given the variation from patient to patient, biomarkers could mitigate guesswork.

“That could be a combination of early biomarkers of treatment response, biomarkers of the mechanism of action for each drug,” she said. “Then [we could use biomarkers] to match the baseline characteristics of a patient to a particular drug that would match their own biology.”

There are several biomarkers that are under exploration. One of particular interest to Chitnis is serum neurofilament light chain (sNfL), a marker of axonal or neuronal damage in the central nervous system (CNS). It is now measurable in serum using a single molecular array assay with high sensitivity “with fairly good correlation to CSF [cerebral spinal fluid] values,” Chitnis said.
In a study, patients with higher levels of sNfL were more likely to relapse or experience a worsening in expanded disability status scale, particularly for those with levels in the 97.5 percentile.4 The marker was also associated with acute inflammation, correlated with gadolinium-enhancing lesions, and could predict future brain atrophy.5 

“It is a way to potentially understand response to a DMT,” she added. “We typically have used either relapses or new MRI lesions, however, this could potentially give another correlate of response to DMT or possibly an earlier response to DMT markers.”

Induction or Escalation?

Research into optimal management approaches for DMTs in MS has increased with the wealth of current options. Whether to use an induction or escalation strategy remains an area of debate, however. With the induction approach, patients are treated with the most potent therapies in a more aggressive strategy earlier compared with an escalation strategy, which is when patients are treated with less potent, but safer, therapies earlier that are later adjusted based on the disease state.

Currently, the Multiple Sclerosis Coalition suggests that physicians have access to the full repertoire of treatments due to the variability in patients. They recommend that treatment should begin as soon as possible and continue indefinitely, unless there is a suboptimal treatment response, inadequate adherence, or intolerable AEs or a more appropriate regimen becomes available.6

Although the recommended strategy has long been one of escalation, there seems to be a shift, according to Chitnis. “Among experienced clinicians, there is a consensus toward induction therapy, especially in those earlier inflammatory patients and especially now that we have more choices that are relatively safe,” she said.

A marked moment occurred at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016 Congress, where the leading hot topic centered around this debate and included an argument for induction therapy from Gilles Edan, MD.7 In this talk, induction therapy was ruled the superior option. 

Okuda noted that clinical trials are currently looking at whether starting with a highly effective therapy is the correct approach compared with a step-wise strategy. “We really don’t know which the more effective approach is right now,” Okuda said. 

Adding to this, the challenge of treatment selection may become even more difficult, as the pipeline continues to grow. Another emerging therapy that’s exciting is oral cladribine, Okuda said, due to its effects on the immune system. 

“It’s like [alemtuzumab], in the sense that it can actually reset the given immune system to a certain degree,” he explained. “Is that approach meaningful? Or this induction approach, where you’re allowing for the resetting of the immune system in hopes that the immune system that reconstitutes is one that’s more hospitable to that one individual.”

For Okuda, a strategy all clinicians can come to agreement on is general health. When managing MS, the need for healthy habits should be underscored more than it is currently. 
“Ensuring that, number one, their general health is optimized. A lot of these patients are overweight, blood sugars out of control, they have habits like smoking,” Okuda said. “There’s emerging science to suggest that general health outcomes are more meaningful than some of the important factors that we have identified in multiple sclerosis before. General health outcomes may be more meaningful than focusing on vitamin and mineral supplementation for patients with MS.”

DMTs in Primary Progressive MS

In March 2017, ocrelizumab became the first therapy approved for relapsing forms of MS and primary progressive MS (PPMS), marking the first indication specifically for PPMS. The IV infusion was notably successful in the ORATORIO trial, resulting in lower rates of confirmed disability progression, lower lesion volume as measured by MRI, and less brain-volume loss compared with placebo.8

The approval of ocrelizumab launched another era in MS treatment, on that focused on the PPMS space—although this is also surrounded by debate. Even with ocrelizumab, “There are a number of passionate opinions regarding the magnitude of the agent’s effectiveness within that cohort,” Okuda said. Moreover, the disease stage itself is still in its infancy, representing a fresh obstacle. 

“The opinions are split as to whether PPMS represents a continuum of disease or if it indeed represents its own distinct genotype,” Okuda explained. “We don’t have 100% agreement among specialists regarding that point. We know that early spinal cord disease can occur in individuals well before symptom onset. Well before patients become symptomatic, we know that spinal cord lesions can be present or can result from the immune system misbehaving.”

Because of this, Okuda believes manufacturers could develop treatments for those with progressive genotypes. “Should we really be focusing on primary prevention?” Okuda posited, “Because really, the most effective drug for any progressive form of MS is a myelin repair and axonal repair agent versus an anti-inflammatory agent.”

For Chitnis, the focus for progressive forms of MS should be on the biological mechanisms in the CNS that therapies can target, whether they’re inflammatory or neurodegenerative. “There are treatments [that] are focused on astrocytes in the CNS, and there is one—siponimod, which, of course, is a sphingosine 1-phosphate modulator—that seems to have sensitivity towards CNS and possibly CNS mechanisms, and seems to have some effect in progressive forms of MS,” she said.

Siponimod was evaluated in the phase 3 EXPAND trial, which included 1645 patients with secondary progressive MS.9 The trial results showed that 26% of patients receiving siponimod
(288 of 1096) and 32% receiving placebo (173 of 545) had 3-month confirmed disability progression, for a relative risk reduction of 21% (hazard ratio [HR], 0.79; 95% CI, 0.65-0.95; P = .013).
In the words of Dan Bar-Zohar, MD, BSc, the global head of Novartis, siponimod’s developer, EXPAND was essentially the “first and only study in secondary progressive MS that showed meaningful results.”10 Bruce Cree, MS, PhD, MAS, a study steering committee member for the trial, said that the beneficial effect on disability progression shown by siponimod was revealed to be independent from its reduction in relapse frequency.11 Cree called the therapy “very exciting” due to the oft-occurring transition patients face from relapsing-remitting MS to secondary progressive MS, a condition that truly lacks efficacious and new treatments. 

“[These patients] experience gradual worsening of disability despite infrequent relapses,” Cree said, highlighting the hole in treatment that siponimod, and similar agents, seem poised to fill. 
“Along [the lines of siponimod], new treatments that target CNS mechanisms, whether they’re neuro-inflammatory, astrocytes/microglia, the neurodegenerative component itself, or remyelination,” Chitnis said, “those are important targets for progressive MS.”

In addition, recent phase 2 study results have bolstered the support for another agent in progressive MS, ibudilast.12 For those taking the therapy over the study course of 2 years, the rate of change in brain parenchymal function was –0.0010 per year (95% CI, −0.0016 to −0.0004) compared with –0.0019 per year (95% CI, −0.0025 to −0.0013) for those given placebo, for a difference of 0.009 (95% CI, 0.00004-0.0017; P = .04). Ultimately, it was equivalent to approximately 2.5 mL less brain tissue loss over 96 weeks, a relative difference of 48%.

“We found a drug that slows [the] progression of brain atrophy by about half, and although we don’t exactly know the clinical relevance of that because we haven’t validated brain atrophy in progressive MS—because we don’t have much in the way of therapies for progressive MS—it was still encouraging in pointing toward a potential therapy for progressive MS. The safety was quite strong and the tolerability was quite good,” Robert J. Fox, MD, lead author and neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, told NeurologyLive.
For comparison, although in separate trials with different patient populations, ocrelizumab, the only therapy with a progressive MS indication, slowed brain atrophy by 17.5%. Likewise, siponimod has shown a slowing of 15% in brain atrophy. While Fox noted the phase 3 data need to be included before he’s completely certain of the therapy’s ability to slow disease progression, the magnitude of the comparison with other successful agents is heartening.

“This was not just driven by a couple outliers. This wasn’t driven by a hydration shift in the first few months [and] then everything was the same. It was really an ongoing, continued, consistent effect over the course of the entire 96-week study. That’s as encouraging as it can be,” Fox said.

Upcoming Pipeline Options

As is always the case in medicine, regardless of the amount of available treatments, there is always an effort to improve or add to existing options, to further improve outcomes. Certainly, though, there is more satisfaction with the therapies that are available for relapsing or remitting MS now than there was 10 to 15 years ago.

“We’re in a good place,” Chitnis explained. “There’s always room for improved or safer drugs that fit a different profile, but we do have many options now. I think the area has really progressed. Next, we’re looking toward the potentially remyelinating therapies. The anti-LINGO-1 antibody, [opicinumab], that one is in a clinical trial, and I’m interested in seeing the next set of results that come out for that.”

The pipeline is full of novel developments, but the most exciting examples for Okuda and Chitnis are myelin-repair therapies. With demyelination existing as a main characteristic of MS, these therapies have been a long-sought target in the field.

“Recombinant humanized-IGM 22 [rHIgM22], that was really founded by Moses Rodriguez, MD, a clinician-scientist at the Mayo Clinic in Rochester, Minnesota,” Okuda said. “That compound is now being championed by Acorda Therapeutics, and it’s currently under study. Biogen has their own version of it called opicinumab, also known as anti-LINGO 1, and that drug is also being studied actively as well.”

“This is a new treatment path for us because these are therapies aimed at not modulating the immune system but allowing for actual repair of myelin and the ultimate protection of axons,” he added.

Another option of interest to both Okuda and Chitnis is cladribine, an oral therapy approved in Europe under the trade name Mavenclad, which is being investigated for relapsing MS in the United States. Thus far, it has shown promise in patients who experience relapses despite interferon-ß therapy.13 In a 96-week trial, the therapy added to interferon-ß reduced the chances of patients experiencing a relapse by 63% compared with placebo. Moreover, cladribine reduced most MRI-measures of disease activity.
In addition to pharmaceuticals, nutritional studies are underway, to explore the potential of improving outcomes. 

“Adding to the myelin repair list is the recent introduction, within clinics, of the use of biotin, vitamin B7,” Okuda said. “There’s a lot of science that has gone on in Europe and a lot of talk about how biotin may actually help to facilitate mitochondrial behavior but may also play a role in self-myelin repair.”

MedDay Pharmaceuticals in Paris, France, has a high-concentration version of the biotin therapy available, Okuda said. “It’s a dose that is 30 times higher than what you can buy at Target, Walgreens, or Costco. Thirty times the highest over-the-counter preparation,” he said.

A real investment of the future of treatment for Okuda is looking toward better measures for disease surveillance. An inability to observe the disease progression as effectively as necessary outside of large institutions has led to an inability to use some of the more potent therapies.

“Maybe comfort levels differ as well,” Okuda said. “If you’re a general neurologist, it may be tough for one to fully advocate for a therapy that’s not well understood and a therapy in which they’re not necessarily keeping track of all the safety outcomes that are occurring from a week-to-week basis.”

 A welcomed benefit of the DMTs and other therapies is that patients are beginning to live longer. With that finding, however, a fresh batch of questions are now coming into play, as patients grow older with the disease. 

“What’s really happening in our field is that we have patients with MS who are advancing in age, and for every 5 or 10 years they’re putting under their belt, the chance of them having acute inflammation is much lower than if they were younger,” Okuda said. “What do we do with that population of patients? They’re growing, and we know that inflammatory treatments are not so robust and inflammation is not really a robust finding in patients who are more advanced in age with MS.”
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