Remyelination in Multiple Sclerosis: The Next Treatment Frontier
With more than a dozen disease-modifying therapies, some have set their sights on developing an agent designed to promote remyelination.
The past 5 years brought about monumental moments in the advancement of multiple sclerosis (MS) care. With the approval of ocrelizumab (Ocrevus; Genentech) in March 2017, the field not only welcomed the first treatment for primary progressive MS but also saw the number of available disease-modifying therapies rise to 15.
Although this growing number of options puts MS ahead of the curve compared with other neurodegenerative diseases, yet another new frontier in treatment has crossed the sight line of many investigators: remyelination.
A staple of MS is its demyelinating nature, in which the immune system attacks either the protective myelin sheath that encases axons or the oligodendrocytes that produce this myelin. Normally, when axonal damage occurs, myelin self-repair is initiated, with oligodendrocyte progenitor cells (OPCs) engaging the demyelinated axons and differentiating into oligodendrocytes.1,2 But in MS, this natural process does not occur properly and fails in at least 1 of those 2 steps. To combat this, investigators have set their eyes on developing therapies that aid the process.
“We have immunotherapeutic agents, immunomodulatory and targeted immunosuppressive agents that at least partially…and in some instances appear to almost fully, prevent new damage and new injury from happening,” Ari Green, MD, MCR, the medical director of the University of California, San Francisco (UCSF), Multiple Sclerosis Center and director of the UCSF Neurodiagnostics Center, told NeurologyLive™. “And yet a substantial portion of people, despite that fact, still go on to develop some progressive disability.”
Green, who has spent a large portion of his career studying the process of remyelination, pointed out that although neurologists treating MS are equipped with a large arsenal of options with which to prevent further damage, none of the therapies address the damage that exists at the time of initial presentation. “They might help calm the waters enough so that endogenous repair could at least partially take place, but we know endogenous repair is limited, and the goal with remyelinating therapeutics is developing agents that can actually enhance the capacity for endogenous repair,” he said.
For nearly 2 decades, investigators have known that a unique population of cells—roughly 5% of the cells in the adult human central nervous system (CNS)—develop into oligodendrocytes, and that maintaining or restoring saltatory conduction (the proliferation of action potentials along myelinated axons) depends on the presence of normal myelin architecture. Because MS targets myelin, the question has become: How can that be restored, or how can oligodendrocytes be brought back?
“The oligodendrocytes are evident; they’re found tiled throughout the brain, both in normal health and in disease,” Green said. “Those cells are there. How do we get them to do what they should otherwise be doing, which is, after demyelination happens, recovering and restoring that myelin? If we [take] an animal and we demyelinate the animal, either chemically or in a relatively targeted way [that] dissolves or damages myelin, or we induce an inflammatory response that targets myelin, you will see some remyelination occur in a period of just a few weeks.”
Why this process does not occur in MS is not well understood. Even so, the ability to screen therapies that are capable of allowing—or forcing—OPCs to differentiate into oligodendrocytes is beginning to allow therapies to be developed.
Recombinant Humanized-IgM 22
Right now, remyelination is the most exciting path for MS treatments, Darin Okuda, MD, the director of the Multiple Sclerosis and Neuroimmunology Imaging Program, director of Neuroinnovation, and deputy director of the Multiple Sclerosis Program and Clinical Center at the University of Texas Southwestern Medical Center in Dallas, told NeurologyLive™. One therapy he has had his eye on is recombinant humanized-IgM 22 (rHIgM22), also known as antibody .
“That was really founded by Moses Rodriguez, MD, a clinician-scientist at the Mayo Clinic [in] Rochester, [Minnesota]. That compound is now being championed by Acorda Therapeutics, and it’s currently under study,” Okuda said. A phase 1 multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial is aiming to determine if a single dose of the treatment is safe and tolerable during relapse (NCT02398461). It is expected that, if applied immediately after relapse, remyelination strategies could result in not only full recovery but also prevention of long-term neurodegeneration and progressive disease course.3 That trial was expected to be completed in late 2017, though Acorda informed NeurologyLive™ that it is “considering next steps for the program.”
In a previous phase 1 trial of rHIgM22,4 the therapy, which was assessed in 72 adults with stable MS, was found to be well tolerated with no significant safety signals. There were no discontinuations due to treatment-emergent adverse events (AEs). All told, 86% (47 of 55) of participants treated with the therapy experienced a total of 186 treatment-emergent AEs compared with 95% (16 of 17) of those administered placebo, who experienced 54 treatment-emergent AEs.
The authors noted that the most common AEs (frequency, >5%) in rHIgM22-treated individuals—that were not observed in placebo-treated patients—were MS relapse, fatigue, arthralgia, back pain, muscular weakness, pruritus, contusion, and flushing.
“None of these AEs occurred in more than 7% of antibody-treated patients, so that an equivalent frequency for any of these events in the 17-person placebo group would have been represented by 1 individual or less,” Eisen et al wrote. “Most [treatment-emergent] AEs were mild or moderate in severity, and the occurrences of these events did not appear to be dose dependent.”
Recently, research done in vitro suggested that despite rHIgM22’s incompletely defined molecular and cellular mechanisms of action, microglia may play a role in inducing remyelination.5 “[They do so by] phagocytosing rHIgM22-bound myelin debris, thereby potentially disinhibiting OPC differentiation in demyelinated lesions of MS patients and possibly mediating further paracrine sequelae favorable for remyelination,” Zorina et al wrote.
Another antibody being studied for remyelination is opicinumab (BIIB033; Biogen), an anti-LINGO-1 antibody. In SYNERGY, a phase 2 trial of the therapy in patients with relapsing and progressive MS, it failed to meet its primary end point of improving disability, as measured by Expanded Disability Status Scale (EDSS) scores.6
Despite this apparent lack of efficacy, those developing the therapy were not disheartened. Michael Ehlers, MD, PhD, the executive vice president of Research and Development at Biogen, said at the time of the data’s presentation that they “provide intriguing evidence that opicinumab, which has demonstrated remyelination properties in a previous phase 2 study, may have a treatment effect in certain patients.”7
Gavin Giovannoni, MD, the chair of neurology at the Blizard Institute, part of Barts and The London School of Medicine and Dentistry in London, United Kingdom, said in a statement that upon analyzing the trials’ results, the investigators discovered the specific patients with relapsing MS that may be more responsive to opicinumab, which he noted “became a significant component” of the design for the phase 2 trial, AFFINITY. “We now have an exciting opportunity to apply a more precise biological approach when evaluating the potential of opicinumab as a therapy that may improve patients’ disability and lead to a better overall outcome,” Giovannoni said.
Now actively recruiting, AFFINITY (NCT03222973) will assess the effect of 750-mg opicinumab compared with placebo on disability improvement over 72 weeks, with a target enrollment of 240 participants. The primary outcome will be the overall response score, a multicomponent score based on EDSS, the timed 25-foot walk test (T25W), the 9-hole peg test in the dominant hand, and the 9-hole peg test in the nondominant hand.
Sarah Sheikh, MSc, BMBCh, MRCP, senior medical director at Biogen, said in an interview that those with “disease duration less or equal to 20 years and 2 MRI characteristics [lower baseline magnetization transfer ratios (MTRs) and diffusion tensor imaging–radial diffusivity values] in preexisting T2 lesions” were the 3 factors predictive of response opicinumab.8
An additional route for remyelination involves high-dose biotin, otherwise known as vitamin B7. At the 2017 joint meetings of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Paris, France, data were presented on biotin (MD1003; MedDay), which revealed improvements in EDSS and T25W compared with placebo.9
The most intriguing bit of data from the substudy10 of the phase 2b/3 trial suggested a pseudo-atrophy phenomenon that was likely related to remyelination for patients with progressive, nonclinically active MS. Douglas L. Arnold, MD, of the Montreal Neurological Institute and Hospital of McGill University Health Centre in Quebec, Canada, who presented the data, said, “The effects of MD1003 on volumetric with a decrease in virtual hypoxia. Results from MTR and DTI [diffusion tensor imaging] analyses suggest possible remyelination.”
Of the 74 patients who were part of the substudy, 49 had received the therapy from the start and 25 received placebo during randomization, followed by MD1003 in the extension period. At 12 months, there was a 0.3% decrease in whole brain volume (WBV) in the MD1003 group versus a 0.1% increase in the placebo arm (P = .046). For gray matter volume (GMV), there was a 0.6% decrease with MD1003 and no change in the placebo group (P = .0435). Changes in WMV were not statistically significant, at –0.3% with MD1003 and 0.2% in the placebo group (P = .107).
At month 24, there was a 0.5% decline in WBV in the MD1003 group and a decline of 0.6% in those initially treated with placebo who crossed over to the biotin group (P = .502). For GMV, there were declines of 0.5% and 0.8% in the initial MD1003 and placebo/MD1003 groups, respectively (P = .606). WMV declined by 0.4% and 0.5% in the MD1003 and placebo/MD1003 groups, respectively (P = .874).
Since then, a phase 3 trial of the therapy has begun (NCT02936037), with a primary end point of EDSS and T25W and a target enrollment goal of 600 patients. It is estimated to complete in September 2019.
“There is 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,” Okuda told NeurologyLive™. He explained that currently, doses of 300 mg—100 mg taken 3 times daily—can be acquired sans prescription online. “That dose is 30 times higher than the highest dose one could acquire from any drugstore,” he said.
Mesenchymal Stem Cells
Due to their success in other facets of medicine, as well as the interest in using them for other neurodegenerative diseases, stem cells have become a topic of conversation in MS treatment. One population of cells of particular interest is mesenchymal stem cells (MSCs), which were originally noted in part because of their ability to generate major mesenchymal lineages. More recently, investigators realized that MSCs have pronounced immunomodulatory capacities. This led to the cells’ development as a therapeutic for a number of conditions, including demyelinating diseases of the nervous system.11
This hypothesis—that MSCs could generate CNS cells—has been considered controversial and contested by some mouse-model research.12 However, several other groups have shown in animal models of MS that treatment with MSCs promoted, at least partially, oligodendrogenesis through the release of trophic factors, leading to enhanced functional remyelination.13,14
Despite these concerns, in a number of phase 1 and 2 observations of infusing in vitro expanded autologous MSCs into humans with relapsing or progressive MS, the infusion was safe, though little or no clinical benefit was realized. This has been suggested as a failure of the use of autologous MSCs, although other works in experimental allergic encephalitis revealed that the cataloged molecular changes in these cells occur in more than 2000 genes linked to immune response and neural development, which will likely limit the use of MSCs for MS in the future.15
In November, BrainStorm Cell Therapeutics announced plans for a phase 2 assessment of its cell therapy, NurOwn, in progressive MS. NurOwn utilizes a patient’s own modified MSCs to promote nerve cell-supporting mechanisms. The therapy previously showed promising results in a phase 2 trial in amyotrophic lateral sclerosis.
Muscarinic Type 3 Receptor
Investigators also aim to better understand the remyelination process, which has and will continue to allow for a parallel improvement in therapeutic targets.
In June 2018, a group of researchers from the University at Buffalo in New York identified the muscarinic type 3 receptor (M3R) as a target for therapeutic development. M3R, a key regulator in the process of remyelination, is found on OPCs, and the assessment showed that that activation of M3R blocked the differentiation of OPCs into myelin-making cells.16
“Our data provide evidence that a drug targeting M3R specifically would be a useful strategy,” Fraser J. Sim, PhD, an associate professor of pharmacology and toxicology in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo and senior author, said in a statement.17
Although this research was done in mice and has not been replicated in humans, the process allowed for remyelination to occur and is certainly promising. The work from Sim and colleagues built on previous data that identified solifenacin succinate (VESIcare; Astellas), already FDA approved for the treatment of overactive bladder, as able to inhibit M3R—though nonspecifically, which could relay AEs.
“That work identified solifenacin succinate as a possible drug useful for remyelination, but we really weren’t sure which specific receptor the drug worked on,” Sim said. He and colleagues noted that a genetic approach was taken in their work to attempt to locate the specific receptor at work. Ultimately, Sim said, M3R has a functional role in remyelination and, if blocked, could improve repair of myelin. “It better positions the field for clinical trials that will be aimed at blocking these receptors in MS patients,” he said.
Approaches to Remyelination
Excitingly, the past few years have been marked by the introduction of proof-of-concept trials for remyelination in MS. Although this has moved the field a step closer toward the next frontier in treatment, questions remain.
For one, optimal outcome measurements for assessing remyelination have yet to be fully explicated. In this realm, MRI, myelin-targeted positron emission tomography radiotracers, and optical coherence tomography have all been explored as possible options. Potential biomarkers that reveal axonal damage, such as neurofilament light, exist, though their clinical validation is awaited. On another note, the timing of remyelination therapy is an essential piece of the puzzle that still needs to be figured out.
For Green, another debate also exists: the approach of therapies. From small molecule therapies to antibodies, there are options to explore, but which approach is favorable is not yet completely understood. Green, with all of his work alongside Jonah Chan, PhD, has his ideas, though. He and Chan conducted the first successful human clinical trial in patients with a chronic lesion.
“My strong opinion is that a small molecule approach is much more likely to be successful than an antibody-mediated approach,” Green said. Although, as he has done consulting work with this approach, Green also noted his bias.
“Some people have postulated the use of antibodies because of their specificity, which is an advantage of antibody approaches over small molecules,” he continued. “But their negative is that the target is in the CNS, and antibodies are huge and don’t get into the CNS via the blood brain barrier very easily.”
He clarified that, in clinical trials, these antibodies have been given in extraordinarily high doses to produce a biological effect. In Green’s mind, that’s not an optimal setting. “Antibodies work well as immunomodulatory agents because the target is largely in the periphery [and] is largely in circulation,” he said. “Trying to get those drugs into the CNS is a challenge. Small molecules, I think, are really the way to go.”
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