MS Speaks

Clinical Focus in MS: Novel Approaches to Progressive Disease


By John Gever, Managing Editor, MedPage Today
Reviewed by F. Perry Wilson, MD, MSCE; Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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Although the drug development pipeline still contains numerous products intended for patients with relapsing-remitting multiple sclerosis (RRMS), the consensus among clinicians is that relapses can be effectively squelched in nearly all RRMS patients with the dozen or so currently approved therapies.

Patients now have a choice between injectables and oral drugs, and within the injectable class there is a range of dosing intervals and delivery types -- expanded just this week with the approval of alemtuzumab (Lemtrada) that requires just two brief courses of therapy a year apart.

The more pressing clinical need now, researchers told MedPage Today, is for treatments that stop or reverse the progressive forms of MS. This has been a tougher nut to crack because the mechanisms underlying progressive MS are less well understood than the acute demyelinating attacks that characterize RRMS. A particularly important aspect that remains mysterious is the switch that occurs in many patients from RRMS to the secondary progressive form or SPMS.

Currently the sole FDA-approved treatment for SPMS is the chemotherapeutic agent mitoxantrone, which has only been tested in two small trials of questionable design that showed relatively modest efficacy. The drug also has significant toxicities that earned a lengthy boxed warning on its label.

But that doesn't mean MS researchers haven't made any progress -- in fact, enough knowledge about progressive MS has accumulated that rational approaches to therapy are now in clinical development. The following is a rundown, aided by Jeffrey Cohen, MD, who spoke at length recently with MedPage Today. Cohen is director of the experimental therapeutics program in the Cleveland Clinic's Mellen Center for Multiple Sclerosis.

He summarized the field's current status in progressive MS this way: "There are now a lot of candidate approaches being considered and we're finally starting to test them."

Jumpstarting Oligodendrocyte Activity

One firmly established feature of advanced MS is that the physical disability results from destruction of nerve axons following demyelination -- the process that defines MS in all its forms, stripping away the protective myelin sheaths from axons.

There is a class of cells called oligodendrocytes whose job is to maintain the myelin coatings. A problem in MS is that these cells stop functioning and/or are simply killed off. If their activity could be restarted -- thereby promoting remyelination -- it may prevent and even possibly reverse disability progression.

Several avenues are now being pursued to promote oligodendrocyte activity:

Anti-LINGO. About 10 years ago, a protein called LINGO-1 found in the central nervous system was revealed to be an inhibitor of oligodendrocyte generation from precursor cells. Subsequent animal studies confirmed that blocking this protein could promote oligodendrocyte proliferation and lead to remyelination in models of MS. A monoclonal antibody called BIIB033 targeting LINGO-1 is now in phase II clinical studies, sponsored by Biogen Idec, following favorable safety results in the first phase.

Antihistamines and other small-molecule drugs to boost oligodendrocytes. By mechanisms that are still not fully understood, it appears that certain histamine pathways also inhibit differentiation of oligodendrocyte precursor cells (OPCs) into the mature remyelination-capable types, raising the possibility that antihistamines can have the same effect as anti-LINGO-1. A histamine H3 antagonist (or inverse agonist) developed by GlaxoSmithKline called GSK239512 is now in phase II studies, although at this point the trials are testing it in RRMS patients with relatively narrow outcome measures intended to prove the concept.

Separately, researchers at the University of California San Francisco (UCSF), using a high-throughput screening approach to find drugs that promote oligodendrocyte-driven remyelination, found that their best hit was an over-the-counter antihistamine, clemastine (sold as Tavist).

The antihistamine approaches may help in MS by preventing demyelination as well as by promoting remyelination, Cohen told MedPage Today.

Groups elsewhere have programs in place to identify other small-molecule agents that promote OPC differentiation into remyelination-capable oligodendrocytes, such as this one at the Scripps Research Institute in San Diego that reported benztropine was one such candidate.

OPC-based cell therapies. A number of groups have been looking at the possibility of implanting OPCs to jumpstart remyelination -- perhaps collected autologously and expanded ex vivo, or developed in vitro from pluripotent stem cells or other sources. None of these have yet moved into clinical testing, said Cohen, who predicted it would be at least several years before human trials could begin.

Mesenchymal stem cells. Another type of cell therapy in development involves autologous mesenchymal stem cells, which are usually extracted from patients' bone marrow (although other sources are possible) and then coaxed either ex vivo or in vivo to mature into oligodendrocytes. Several groups have conducted phase I trials and the treatment's safety has been fairly well established. Cohen has led one such trial and said the efficacy data are necessarily sparse at this point but have shown "encouraging hints" that this is a viable approach, including signs of "repair of demyelination." He added that other groups are expected to report results next year.

However, he stressed, much work remains to be done on cell therapies, including optimizing the cell types, the dosing regimens (numbers of cells, routes of delivery), and the manipulations the cells undergo before implantation.

Protecting the Demyelinated Axon

Another way to prevent nerve degradation is to interfere with the cellulo-chemical attacks on the exposed axon. In a recent paper appearing in The Neurohospitalist, Bruce Cree, MD, PhD, of UCSF, noted that microglia mediate one type of this attack. An inhibitor of microglial activity called NT-KO-oo3 has completed an early efficacy/safety study although results have not been released. However, mouse studies indicated that the agent was neuroprotective in a variety of degeneration models.

Mast cells are believed to participate in the axonal attacks as well. Now in a phase IIb/III trial in patients with SPMS and PPMS -- after favorable results in earlier studies -- is masitinib, an oral tyrosine kinase inhibitor targeting mast cell activity. Masitinib is currently a veterinary drug, which is also in human testing in a variety of other oncologic and inflammatory conditions. This is a full-scale, placebo-controlled trial structured like those normally conducted for RRMS drugs, lasting 2 years with a target enrollment of 450 and with a functional outcome measure as the primary endpoint.

In a phase II trial currently is a familiar neurology drug, phenytoin. The rationale is that it blocks sodium entry into cells; in the nervous system, this is a key mechanism of neuronal damage. The trial, which is sponsored by MS-related nonprofits in the U.S. and the U.K., is actually testing the drug in optic neuritis, which is a common manifestation of MS (but can have other causes also).

RRMS Drugs for Progressive Disease

Trials are now underway with several currently approved RRMS drugs in primary and/or secondary progressive MS, including natalizumab (Tysabri) and fingolimod (Gilenya). Cohen told MedPage Today that a trial in this area is now being planned as well for dimethyl fumarate (Tecfidera).

Earlier RRMS drugs including the interferon-beta class have also been studied for an effect on progressive MS, with mostly negative results. Because the mechanisms of those drugs and of the disease process were not well understood at the time, the trials could be regarded mainly as expressions of hope.

But for the newer agents, Cohen said, there are mechanistic reasons to think they may be effective. "The aspects of MS that those drugs have been shown to be effective for [e.g., lymphocyte trafficking for fingolimod] do carry over, to some extent, into progressive MS," he said, noting that SPMS patients often still show gadolinium-enhancing lesions on MRI, for example. "At least in a subset of patients, those drugs might be helpful."

Cohen added that fingolimod and dimethyl fumarate also have activity involving glia and neuronal function that may make them especially suited to neuroprotection in the purely progressive state.

Another drug that could be included in the "current drug" group is ocrelizumab, a follow-on drug to rituximab (Rituxan) that depletes B cells but in a more targeted way. It has not yet been approved but is well along in development for RRMS. A trial in PPMS is now underway as well, in the wake of mixed results with rituximab in an earlier PPMS trial. Its manufacturer and some independent researchers believe that the more selective action of ocrelizumab boost its chances for success for this indication.

Vitamin D Supplements?

Deficiencies or insufficiencies in vitamin D have been linked to many disorders, but perhaps none so closely as in MS. Many studies have found associations between serum levels as well as in risk factors for low vitamin D, such as latitude.

But these association studies, by virtue of their design, fall short of proving that low vitamin D is causative. The counter-hypothesis, which has yet to be disproven, is that low vitamin D merely reflects other factors that correlate with increased risk of diagnosis and/or increased risk of more severe or aggressive disease after diagnosis. It may simply be that people more likely to develop or progress with MS spend less time outdoors where they would be exposed to vitamin D-producing sunlight.

Cohen said a causal connection is supported by lab studies finding that vitamin D (increasingly called a hormone rather than a nutrient) affects a number of immune functions "that one would think would be involved in relapses and lesion formation, but also effects on cells that one would think would be involved in demyelination." He added that the substance is "a neurotrophic factor" as well.

Randomized trials of vitamin D supplementation are considered the key test of the so-called vitamin D hypothesis for MS, or any other condition, for that matter. The record in other conditions thus far has been largely negative. But those negative studies are often criticized for using inadequate vitamin D doses or the wrong type of vitamin D (D2 instead of the more bioactive D3, for example).

Several supplement trials are now underway in RRMS, some involving doses of 50,000 IU weekly or more, which should satisfy most adherents of the vitamin D hypothesis on the dosage score. Of course, the results -- whether positive or not -- may not translate directly to progressive forms of MS. But the hypothesis has been developed to apply to the entire disease course of MS, so results in the RRMS setting will probably be interpreted more generally by the MS community.

One problem, Cohen predicted, is that any benefit is likely to be relatively modest, meaning that a relatively large trial will be needed to detect it. The studies now underway are enrolling no more than a few hundred patients each, which may make a positive finding hard to come by.

Other Approaches

Cohen said that another important target for intervention is comorbid conditions that serve as risk factors shown to be associated with aggressive forms of MS, such as smoking and cholesterol. As with vitamin D, whether addressing these factors in patients with established disease will affect the risk or speed of progression is not yet known and needs to be tested. On the other hand, as is commonly stated, these comorbid conditions are worthy of intervention irrespective of their relationship to MS.

In fact, with respect to cholesterol, one study has already shown that a statin drug, simvastatin (Zocor), slowed brain atrophy in SPMS patients. It's unclear, though, whether this was related to the drug's cholesterol-lowering function or to a more general anti-inflammatory action that is also a known statin effect -- or to some other mechanism not yet known.

Cohen noted that a longer-term challenge in developing progressive MS treatments lies in trial design -- "For outcome measures, specifically which MRI measures are the best and, secondly, what is the best study design." For example, he said, some groups have chosen to test therapies in optic neuritis instead of MS per se, and other trials have used a variety of MRI outcomes, a marked contrast with trials of RRMS drugs for which there is an almost immutable formula in terms of outcome measures and trial duration.

"We're testing unknown agents with not fully worked-out study designs," Cohen said.
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Cohen disclosed relevant relationships with EMD Serono, Genentech, Innate Immunotherapeutics, Novartis, Vaccinex, Genzyme, Receptos, Synthon, and Teva.

Cree disclosed relevant relationships with AbbVie, Biogen Idec, EMD Serono, Genzyme/Sanofi, Medimmune, Novartis, Teva Neurosciences, and Hoffmann-La Roche.

Lancet. 2017 Oct 10. pii: S0140-6736(17)32346-2.

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

Green AJ1, Gelfand JM2, Cree BA2, Bevan C2, Boscardin WJ3, Mei F4, Inman J2, Arnow S2, Devereux M2, Abounasr A2, Nobuta H5, Zhu A2, Friessen M6, Gerona R6, von Büdingen HC2, Henry RG7, Hauser SL4, Chan JR4.

Author information

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: agreen@ucsf.edu.
2
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
3
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
4
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Program in Neuroscience, University of California, San Francisco, San Francisco, CA, USA.
5
Department of Pediatrics and Neurosurgery and Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA.
6
Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, CA, USA.
7
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA; Bioengineering Graduate Group, University of California, Berkeley, and San Francisco, San Francisco, CA, USA.

BACKGROUND:

Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis.

METHODS:

We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298.

FINDINGS:

Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported.

INTERPRETATION:

To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage.

FUNDING:

University of California, San Francisco and the Rachleff Family.