JAMA recently published their interviews with two MS Specaists focusing on the medical progress against multiple sclerosis (MS) in 2017 with the approval by the US Food and Drug Administration (FDA) of ocrelizumab, a drug that has shown success against 2 different forms of the disease. The year also brought further signs that it may be possible to biochemically reverse damage wrought by MS.
In 2 phase 3 trials ocrelizumab significantly outperformed an existing therapy, interferon beta-1a, in the treatment of relapsing-remitting MS, a form of the disease that consists of recurrent exacerbations and most often transitions into the uninterrupted downward spiral known as secondary progressive MS. After a third phase 3 trial in which the drug showed success against a placebo with respect to various end points, it was also approved against primary progressive MS, which has a degenerative course from the start and for which there is no approved treatment.
It is a mostly settled question that MS is an autoimmune disease that attacks the myelin sheaths insulating the axons of the central nervous system, thereby impeding neural signaling. It was long believed that the damage was inflicted solely by the adaptive immune system’s T cells, but efforts to counteract these cells had little therapeutic effect. It was the realization that B cells are major contributors to the destructive process that led to the development of ocrelizumab, a humanized monoclonal antibody that selectively targets the CD20 surface antigen on B cells to neutralize them.
Meanwhile, the discovery that the oligodendrocytes that produce myelin remain functional after demyelination has raised hopes that they can be induced to remyelinate the axons after the disease process is controlled.
To discuss these and related developments, JAMA recently interviewed 2 MS specialists—Stephen Hauser, MD, of the University of California, San Francisco, who led the development of ocrelizumab, and Jeffrey A. Cohen, MD, of the Cleveland Clinic, who has been pursuing research into remyelination. The following is an edited version of the interview.
JAMA:Dr Cohen, what are we up against with multiple sclerosis?
Dr Cohen:It’s turned out to be a difficult opponent. It’s relatively common, frequently disabling, but very unpredictable. Each patient has different manifestations and a different course. Also, the disease appears to change over time. It begins primarily as an inflammatory process. That’s the target for most of our currently approved medications. But then [it] evolves into a more degenerative disorder, and so currently the main unmet need is to try to treat that degenerative phase.
JAMA:Dr Hauser, could you run us through the major categories of MS?
Dr Hauser:In 85% or 90% of people, the illness begins in early to mid-adult life with attacks of neurological dysfunction, reflecting disconnection between sensory or motor pathways of the brain, producing symptoms such as visual blurring, double vision, loss of sensory and motor coordination, or bowel or bladder disturbances. Such relapses tend to appear approximately once every 9 to 12 months, followed by stabilization and often, early in the disease, partial or complete recovery. That form of the disease is called relapsing-remitting MS.
But over time, the relapsing form transitions to a progressive march of worsening symptoms, usually motor disability, leading to cane, crutch, and wheelchair dependence. That form is called secondary progressive MS. And in the older literature, about 2% to 3% of people with relapsing MS would convert to secondary progressive MS annually. So after 15 years, nearly half of people with relapsing MS had developed progressive MS. However, in the age of therapy, there is incomplete but increasingly convincing data that the long-term course of MS has been favorably modified and that the transition from relapsing to progressive MS has been blunted, perhaps to about 1% a year.
Ten to 15% of people with MS have progressive symptoms from [the] onset. That form is called primary progressive MS. The female predominance in relapsing MS is not true in primary progressive MS and in fact males and females are approximately equally affected and [it] tends to begin about 10 years later than the relapsing phase.
JAMA:Dr Hauser, tell us more about how ocrelizumab came about.
Dr Hauser:It began with the concept that to create an animal model that looked like the type of tissue changes our patients have, one needed [involvement of] not only T lymphocytes but also B lymphocytes. That then led to the preliminary testing of the anti-CD20 B cell therapy rituximab, a chimeric monoclonal antibody widely used against lymphoma and rheumatoid arthritis and some other autoimmune diseases that showed remarkable efficacy against relapsing forms of MS. This led to the development of the current new FDA approved therapy, ocrelizumab, which in recently completed clinical trials demonstrated very robust efficacy against relapsing-remitting MS and for the first time efficacy against primary progressive MS.
These studies published as the OPERA and ORATORIO trials in the New England Journal of Medicine were very exciting because of the effect size against relapsing-remitting MS. [There was] an almost 50% decrease in the clinical relapse rate [the primary end point] compared with high-dose interferon beta-1a therapy. The therapy was 95% more effective than high-dose interferon in preventing new areas of white matter inflammation. Compared with baseline MRI [magnetic resonance imaging] data, [it] resulted in a 99% decrease in such new areas.
In the primary progressive MS trial, there was a statistically significant reduction of disability accumulation confirmed at 12 weeks with ocrelizumab compared with placebo. But the effect size was an only 24% relative reduction in disability progression. So extremely effective against new white matter plaques, extremely effective against new clinical relapses, but only partially effective against progressive disability accumulation.
However, the door against progressive MS is now ajar. This was the first trial demonstrating a significant improvement in disease progression for any drug, for any MS therapy.
Dr Cohen:I agree that there’s been a great deal of excitement with the approval of ocrelizumab. It has also had an interesting effect in that it’s forced discussion of our overall treatment strategy. Should we continue our traditional escalation approach, where we start with a safe but not very effective medication and then change therapy when there’s suboptimal disease control? Or should we substitute with a highly effective therapy right from the beginning, a drug that’s more likely to produce successful outcome? And ocrelizumab is really one of the first medications in which there’s highly effective potency [and] a very favorable safety profile.
JAMA:Does it have any adverse effects?
Dr Hauser:Ocrelizumab is administered as an outpatient infusion every 6 months. The relapsing-remitting MS trials were 2 years in duration. Infusion reactions occurred in slightly more than a third of patients, and beyond that, the therapy was well tolerated. There was an imbalance in the number of malignancies, particularly breast cancers in women, seen with ocrelizumab, compared with interferon or placebo. We’re not certain if this was significant. It’s encouraging that the incidence of malignancy in the ocrelizumab group is similar to epidemiological expectations. And in open label extension trials the malignancy rate seems to be decreasing.
JAMA:Dr Cohen, can you describe the research being done on reversing the damage that MS has inflicted over the years?
Dr Cohen:One major unmet need in the MS field is treatment strategies that promote repair and specifically remyelination. Traditionally, we thought of using stem cells to accomplish that and there now have been a number of small studies of so-called mesenchymal stem cells that are probably naturally involved in mitigating inflammatory damage and promoting repair. However, one thing we’ve learned from those studies is that direct cell transfer has a number of practical challenges. In fact, we don’t understand particularly well how to best grow the cells in the laboratory to improve their efficacy.
Also, what we’ve learned is that these cells probably are of benefit not so much by directly replacing the cells of the central nervous system (CNS) but by producing a wide range of trophic or supportive factors that improve the intrinsic repair capabilities of the CNS. That’s led to a very interesting line of research to use stem cell–based high-throughput screening to identify candidate medications that may promote remyelination and then take those through a series of more stringent assays to look at their ability to promote remyelination in animal models.
And then finally, to test those in people. Using this approach, one could look at medications that are already approved for other indications. A number of laboratories, some in Cleveland and San Francisco, have identified potential candidates and one of those—clemastine, an antihistamine with antimuscarinic effects—has been tested in a phase 2 clinical trial and showed some promising results in improving optic nerve function. So I think we’re at the cusp of not only being able to control the inflammatory aspects of the disease but to also be able to promote repair of the damaged nervous system.
Dr Hauser:This is an extremely exciting area of work. It’s enabled by the observation that there are many oligodendrocyte premyelinating cells [that] remain within MS lesions that have been stripped of their myelin and if we could stimulate them to regrow myelin, we could improve repair of MS lesions.
JAMA:What are the latest thoughts on causation?
Dr Hauser:We believe the relapsing phase is related to an autoimmune attack mediated by the adaptive immune system, namely T cells and B cells, whereas the cause of the progressive phase of MS is less clear, but may be due to some combination of an adaptive immune response similar to relapsing MS but locked behind a closed blood-brain barrier, plus activation of innate immunity, cells like microglia and activated macrophages that may secrete product toxic to both myelin producing cells and nerve cells.
One of the key epidemiologic points about MS is that it has increased in frequency, and although there are now 203 genes that influence MS risk, all of these influences are very small effects, and the majority of susceptibility is not genetic and is almost certainly environmental. What in the environment is responsible for triggering MS is one of the great questions in MS research. It’s unanswered but is likely to be a virus or bacterium.
Dr Cohen:I would add that the microbe may not only be external to the person, but something in their own microbiome. It probably is not one single culprit, but many potential culprits. Or the distribution, the presence of some or absence of other microbial agents, may be what leads to susceptibility.
Dr Hauser:It’s likely that the microbiome has a substantial effect on MS in 2 ways. The first is the molecular mimicry, where some cell component of a bacterium or virus resembles a protein or substance in the brain. The second is that our microbiota influence the regulatory tone of our immune system, and that could lead to differences in the trajectory of disease after it begins.
We don’t yet know what the likely microbial culprit or culprits are. The strongest epidemiologic link to multiple sclerosis remains a late onset infection with the Epstein-Barr virus (EBV), [perhaps] the occurrence of infectious mononucleosis, but we really don’t know if EBV is causally linked or is a surrogate for some other infectious agent.
JAMA:Well, where do we go from here?
Dr Hauser:There are a number of critical front burner issues for us. We need to understand if early treatment with a highly effective, well-tolerated medication such as ocrelizumab will prevent the adverse consequences and especially the development of secondary progression that leads to neurologic disability. Second, now that we finally have a therapy that is partially effective against progressive multiple sclerosis, we need to understand how to enhance that effect—how to better understand the biology of progressive MS to more effectively advance our opportunities from a partially effective to more effective therapy.
So, the 2 questions that recent advances make possible are first, can we now stop MS in its tracks [by administering treatment] at the beginning of the disease and prevent later neurologic disability? And second, can we develop even more effective treatments against progressive forms of MS?