Top 8 MS Research Advances of 2014
Eight top papers showcase scientific progress in multiple sclerosis research in 2014
A new year is a fine reason to gaze back on the accomplishments of MS researchers. The task of choosing the most notable advances fell to Jiwon Oh, M.D., Ph.D., and Paul O’Connor, M.D., of St. Michael’s Hospital and the University of Toronto, Canada, who published their selections in the February 2015 Nature Review Neurology (Oh and O’Connor, 2015).
Their top-eight list samples representative articles from the highest impact neurology journals and spans topics including clinical trials, imaging, and basic science, Oh told MSDF in an email. MSDF explores each highlighted paper in a little more detail, below, in the same order Oh and O’Connor presented them in the original paper. That order is not a ranking but instead was chosen for its narrative flow.
MSDF invites readers to submit any additional picks for last year’s research highlights. Make your case in the comments section below. It’s all for the good of speeding progress toward a cure for MS.
1. Redefining MS
MS may need classifications beyond the standard relapsing-remitting, secondary progressive, progressive relapsing, and primary progressive categories. While the categories are helpful, the clinical course of MS subtypes in each is still strikingly heterogeneous, potentially complicating and even invalidating clinical trial results for new therapies.
Researchers from the International Advisory Committee on Clinical Trials of MS proposed the first major revisions for MS phenotypes since the originally published 1996 consensus description (Lublin et al., 2014; Lublin and Reingold, 1996). The update includes MRI and fluid biomarkers “to better characterize patients with MS and provide a framework for both clinical research and ongoing clinical care,” lead author Frank Lublin, M.D., of Mount Sinai Hospital said in a press release. In summary, the new guidelines would place relapsing patients in “active” or “nonactive” categories. The same categories apply to progressive patients, and the researchers suggest two more categories: “progression” or “no progression.”
In addition to adding disability and MRI data to the clinical definitions of MS, the researchers also recommended that clinically isolated syndrome—but not radiologically isolated syndrome—be added to the classification tree.
Key open questions
- What future research is needed to better understand and define MS phenotypes?
- Might the additional classifications hint at the idea that MS is a family of diseases rather than a single disease?
2. Statins Make Progress as Progressive MS Treatment
Progressive MS is still untreatable, but new hope may come from an old drug. Simvastatin is an inexpensive cholesterol-lowering drug that, when taken in high doses (80 mg daily), may slow the progression of MS, according to phase 2 clinical trial results published last March in The Lancet (Chataway et al., 2014). Due to the fact that the drug is relatively safe and well-tolerated, simvastatin is an appealing candidate to test for its effectiveness in progressive MS.
Researchers noted that after 2 years, the 70 patients with secondary progressive MS (SPMS) showed a 43% reduction in annualized brain atrophy rate compared to 70 patients on placebo. They even showed a “slight but significant” slowdown of disability progression.
“I think that underscores the need to move away from drugs we used in RRMS and hope that they work in progressive disease to novel neuroprotective drugs,” Jeremy Chataway, M.A., Ph.D., FRCP, of the University College London Hospitals told MSDF. The research has also drawn attention to the laborious process of repurposing drugs for off-patent use in the United Kingdom.
Chataway told MSDF that researchers are trying to uncover the mechanism by which simvastatin reduces brain atrophy. He also told MSDF that his group has embarked on another phase 2 trial called MS-SMART, looking at three other promising repurposed drugs (ibudilast, riluzole, or amiloride) that target one or more of the pivotal neurodegeneration-causing pathways implicated in SPMS.
Key open questions
- How does simvastatin work to reduce brain atrophy in progressive MS?
- Could people with progressive MS receive the same benefits from other cholesterol-lowering drugs?
3. Some PPMS Patients May Respond to Immune Therapy
Some primary progressive MS (PPMS) patients with a particular biomarker of highly active inflammatory disease may benefit from immunotherapy, according to research published in the Annals of Neurology in July (Villar et al., 2014). The findings suggest that the only available therapies for MS patients may have a role in treating some people with PPMS.
The biomarker is measured by oligoclonal bands (OCBs), which describe a pattern seen when a fluid sample (such as blood or cerebrospinal fluid) is separated into distinctive types of antibodies using an electrified gel. “Historically, attention has largely focused on OCBs made of immunoglobulin type G (IgG), which are present in essentially all MS patients—useful in diagnosis of MS but not so much in predicting response to treatment,” the study’s corresponding author, Amit Bar-Or, M.D., FRCP(C), of McGill University, wrote in an email to MSDF. So Bar-Or, who is a scientific advisory board member of the Accelerated Cure Project, the nonprofit publisher of MSDF, and his co-authors examined IgM OCB, which is only present in roughly 25% of PPMS patients—most of whom present with more aggressive disease. These patients may benefit from immunotherapy, Bar-Or said, potentially alleviating some of the “therapeutic nihilism” surrounding progressive MS research. However, the study was only done on a relatively small sample—103 patients—so the results are far from definitive.
Key open questions
- Might this subset of IgM OCB-positive progressive MS patients be their own disease subtype?
- If so, do they fall into a subcategory of the newly proposed guidelines?
4. Pegylated Interferon β Works Well, Costs a Lot
Researchers published phase 3 results from the ADVANCE trial in 2014 for a new type of interferon β that needs less frequent injections (Calebresi et al., 2014). The drug, called pegylated interferon β-1a (Plegridy, Biogen), is a longer-acting version of its original form, interferon β-1a (Avonex, Biogen). RRMS patients in the two treatment groups received injections every 2 or 4 weeks. Pegylated interferon reduced the annualized relapse rate by roughly one-third compared to the placebo group in both the 2-week and 4-week treatment groups. The convenience of having to inject every 2 weeks instead of three times a week may be a relief for many MS patients, but it comes at a hefty cost of $62,036 per patient per year, according to The Boston Globe. A spokesperson for Biogen told the Globe that the cost reflects “pricing for the innovation.”
Key open questions
- What differences might the pegylated interferon have from regular interferon that may go unnoticed in clinical trials?
- How can patients and clinicians best decide between pegylated interferon and other treatment options?
5. Titrating PML Risk on Natalizumab
Since it was approved in 2006, natalizumab (Tysabri, Biogen Idec) has been one of the most powerful therapies for active relapsing MS. Its usefulness is limited by the risk of a fatal demyelinating side effect known as progressive multifocal leukoencephalopathy (PML), now estimated to strike 3.72 in every 1,000 patients who have received at least one dose (Antoniol and Stankoff, 2015).
PML is caused by the JC virus (JCV), which infects glial cells, in particular the myelinmaking oligodendrocytes. About one-half of people with MS are positive for JCV antibodies, but only a small portion will develop PML. To improve the PML risk prediction, a Biogen team evaluated samples from three natalizumab clinical studies (AFFIRM, STRATIFY-1, and STRATIFY-2), totaling 71 PML patients and 2,522 non-PML, anti-JCV antibody-positive patients.
It may be possible to further stratify the PML risk based on how many antibodies to the JCV virus are circulating in the blood. Higher levels of serum or plasma anti-JCV antibodies are associated with higher PML risk in people with MS who had not previously taken an immunosuppressant, the authors reported (Plavina et al., 2014).
Neither the authors nor Biogen Idec spokespeople were available for comment. The potentially useful tool for assessing risk must “be further validated and is not yet recommended for general use, and clinical decisions are still mainly based on the positive or negative serological status,” given every 6 months, the authors of a recent review (Antoniol and Stankoff, 2015) conclude.
Key open questions
- Will the quantitative anti-JCV antibody index be validated by other studies?
- Will other markers or following people over time improve the PML risk estimate for an individual on nataluzimab?
6. From Radiologically Isolated Syndrome to MS
Early treatment is the new trend in MS care, born of a desire to ward off further relapses and cumulative damage to the central nervous system. One team of researchers wonders if treatment would work better if begun even earlier, before the first relapse, in people with MS-like brain scans but no clinical symptoms, also known as radiologically isolated syndrome (RIS).
But the cost and side effects of MS drugs means researchers first need to determine who is most at risk for that first relapse. Darin Okuda, M.D., at the University of Texas Southwestern Medical Center in Dallas and his colleagues in five countries published a study laying the groundwork for such a clinical trial in preventing MS. Okuda formally described RIS in 2009 as a probable early stage in MS (Okuda et al., 2009).
Not all people with RIS develop MS, he and his colleagues reported in the largest multicenter study of RIS so far. Okuda and his coauthors took a retrospective look at 451 people with RIS, based on MRIs taken for other reasons, such as migraine headaches, fertility workups, traumatic brain injuries, and family history of MS (only 10% of the overall group). About one-third converted to relapsing-remitting or primary progressive MS within 5 years of the first MRI. In the retrospective analysis, younger age, male sex, and the presence of spinal cord lesions elevated the risk of developing clinically definite MS (Okuda et al., 2014). In an upcoming paper, the researchers will report in more detail about a distinctive presymptomatic phase for people who developed primary progressive MS.
Key open questions
- Will disease-modifying drugs prevent MS in at-risk people with RIS?
- What protective mechanism in older people with RIS is preventing them from developing MS?
7. Disability Tied to Spinal Cord Gray Matter
MS has been considered a disease of the white matter, which is mostly myelin-covered axons. Recently, postmortem tissue studies and new imaging techniques have suggested that MS also attacks less-myelinated gray matter, first in the brain and now the spinal cord.
In an unexpected finding using a new imaging technique in a cross-sectional study of 113 people with relapsing-remitting and progressive MS, gray matter tissue loss in the cervical spinal cord was the strongest correlate of disability (Schlaeger et al., 2014). “Before, we would have assumed white matter atrophy was most important,” senior author Roland Henry, Ph.D., at University of California, San Francisco, told MSDF. Also surprising was the relatively minor impact of white matter damage on disability, including lesions.
In line with their findings, another study published last year also reported that gray matter abnormalities in the spinal cord explained 70% of the disabilities differences among people with clinically isolated syndrome, RRMS, and SPMS (Malkki, 2014; Kearney et al., 2014). Led by Regina Schlaeger, M.D., the Henry lab team has followed up to correlate the neck images with more functionally relevant damage lower in the cord, suggesting that the imaging could be a marker of motor disability.
Key open questions
- Does the damage to the spinal cord in MS start with the gray matter or the white matter, and are the mechanisms different?
- Is white matter inflammation and neurodegeneration confounding the imaging measures?
8. Imaging and Targeting Early Neurodegeneration
To explore the link between inflammation and early neurodegeneration in MS, researchers turned to an imaging technique that measures glutamate, a neurotransmitter that helps us speak, among many other things, but can be toxic in large amounts.
The problem in MS may be too much glutamate released by inflamed innate immune cells, compounded by oligodendrocytes and other glial cells bungling the job of sopping up the excess neurotransmitter, senior author Daniel Pelletier, M.D., of Yale University School of Medicine explained to MSDF.
In a 5-year prospective study of 343 people with MS and 42 healthy controls, the sustained elevation of glutamate in normal-appearing white matter preceded a cascade of detrimental effects. First, sustained higher glutamate predicted a higher rate of neuron and axon damage, as measured by the decline of N-acetylaspartate (NAA). In turn, the investigators found that high ratios of glutamate to NAA forecast more brain volume loss over 3 years and worse clinical decline over 4 years (Azevedo et al., 2014).
With a potential target to treat patients and additional supportive mouse data, Pelletier and others set up a phase 2 placebo-controlled trial of riluzole as an add-on therapy to interferon β-1a in early MS. The drug, given to extend the lives of people with amyotrophic lateral sclerosis, inhibits the release of glutamate and has other neuroprotective effects. Unfortunately, the clinical study showed that riluzole does not prevent progression of brain atrophy in early RRMS (Waubant et al., 2014).
Key open questions
- Are there other aspects of the glutamate excitotoxicity pathway that could be targeted to protect neurons and axons?
- What other drugs might work to limit the damaging cascade of excess glutamate?
Disclosures and sources of funding
Dr. Oh reported research funding, consulting and speaking fees, and grant support from Biogen Idec, EMD Serono, Genzyme, and Novartis. Dr. O’Connor reported consulting fees and/or grant support from Actelion, Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Receptos, Roche, Sanofi–Genzyme, and Teva. For disclosures from the authors of the eight top papers, please consult the references below.