Progressive Multiple Sclerosis
Progressive multiple sclerosis (MS) is defined as a gradual accumulation of clinical disability and neurological damage, although the exact definition and underlying disease mechanisms of this form of MS are still vastly unclear, which creates challenges for accurate diagnosis.
Progressive MS includes different subtypes. Primary progressive MS (PPMS) is characterized by a gradual but continuous worsening of the disease over time, without a preceding relapsing course. Approximately 10% of people diagnosed with MS are diagnosed with PPMS. PPMS differs from the more commonly diagnosed relapsing-remitting MS (RRMS – 85% of diagnoses) in several important ways: it tends to be diagnosed after the age of 40, affects men and women equally, and is almost never diagnosed in childhood. Secondary progressive MS (SPMS) begins as RRMS, but transitions to a progressive course which may or may not be accompanied by occasional relapses. Within 10 years of being diagnosed with RRMS, approximately 50% of people with RRMS develop SPMS.
Progressive MS Research Challenges
An enormous surge in research and available treatments for MS has emerged in the last twenty years. Health Canada has approved 10 disease modifying therapies (DMTs) for treatment of RRMS to date. These therapies, which focus largely on targeting inflammation in the central nervous system, are demonstrated to be safe and effective in treating RRMS. On the other hand, inflammation has been shown to play a smaller role in progressive MS, which is characterized primarily by neurodegeneration and reduced immune cell activity. These characteristics help explain why the anti-inflammatory therapies that are the mainstay of RRMS treatment are either ineffective or less successful in altering the course of progressive MS.
Although it is clear that robust research and well-designed clinical trials are needed to develop treatments for progressive MS, researchers face a number of significant challenges. For instance, disease activity in RRMS is typically measured by relapse rate and brain lesion activity. These outcomes have been tested repeatedly and are thus reliable indicators that a drug may or may not be working in persons with RRMS. For progressive MS, such outcomes are not as useful due to differences in disease features and courses. This not only creates challenges for assessing treatments, but also for detecting disease progression in people with progressive MS versus RRMS.
Compounding this difficulty is the likelihood of small sample sizes and high dropout rates in clinical trials. Additionally, as people living with progressive MS are typically older, disease comorbidity (i.e. conditions that occur alongside the disease of interest) may be more likely to occur in this population, which may complicate the interpretation of results. Similarly, comorbidities may restrict the use of some treatments due to unpredictable interactions. Finally, since disease progression in people with progressive MS is typically quite slow, a two- or three-year clinical trial may not be long enough to capture the effects of a treatment on the course of progression.
Recent Research and Treatments in the Pipeline for Progressive MS
A recently published phase II clinical trial ( MS-STAT) by Dr. Jeremy Chataway and colleagues in March 2014 demonstrated promising results of treatment using statins – drugs that are used to lower cholesterol levels – in secondary progressive MS. A high dose of either simvastatin (80mg) or placebo (an inactive, mock drug) was administered to participants over two years. The researchers measured changes in brain volume, since the brain has been reported to shrink by approximately 0.6% per year in people with secondary progressive MS, and brain shrinkage has been correlated with disability. Findings revealed 43% lower rates of brain volume loss in participants treated with simvastatin compared to those in the placebo group. Treatment with the high dose of simvastatin was reported to be well tolerated, but larger and longer-term trials are required to determine the safety and long-term tolerability of such a high dose of simvastatin. An interesting corollary of the study was that simvastatin appears to work primarily by slowing neurodegeneration rather than influencing inflammation, suggesting that combination treatment with immunomodulatory drugs may have promising outcomes. Although the demonstrated protection against brain shrinkage is promising, there is no guarantee such results will manifest into clinical benefit. Regardless, the promising results from MS-STAT make a strong case for phase III clinical trials to proceed and offer encouraging research for those suffering from secondary progressive MS for which there are very limited treatment options.
The Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial ( MS-SMART) is an initiative aimed at examining the efficacy of three drugs in treating progressive MS.
- Amiloride: Currently used as a drug to treat high blood pressure and heart disease, Amiloride may have neuroprotective properties that are currently being explored in the context of MS. A pilot study of 14 people demonstrated that participants who received Amiloride showed a reduction in brain shrinkage compared to what was experienced prior to treatment.
- Ibudilast: Currently used as a drug for treatment of asthma, Ibudilast has shown promise as an anti-inflammatory drug, reducing levels of immune cells associated with damage in MS. A phase II clinical trial of 297 participants revealed that those who were administered Ibudilast showed a reduction in disability progression and evidence of neuroprotective effects.
- Riluzole: Currently used as a drug for treating motoneuron disease, riluzole works by blocking glutamate receptors. Excessive glutamate release can damage neurons, a phenomenon called excitotoxicity. Inhibiting glutamate activity could thus help prevent damage in MS. A clinical trial of 43 people investigated the neuroprotective effect of riluzole. Results did not show an appreciable benefit of riluzole treatment in reducing reductions in brain volume.
MS-SMART is leading the effort to determine the safety and efficacy of these three agents for the treatment of progressive MS. All three drugs are currently used in the clinic, have demonstrated neuroprotective properties, and have a good safety record; the aim of this trial is to determine whether they can be repurposed for slowing or stopping disease progression in people with progressive MS, based on the promising results of early studies.
The study is a multi-centre, multi-arm, double blind, placebo-controlled phase II randomized controlled trial. Approximately 440 participants with secondary progressive MS will be enrolled into the study. Participants will be followed for 96 weeks following administration of one of the drugs or a placebo (sham treatment). The primary aim of the trial is to determine whether the drugs of interest can slow the rate of brain volume loss, compared to placebo, in people with secondary progressive MS. The clinical trial is currently recruiting participants.
*The MS-SMART trial is independent-research awarded by the NIHR Efficacy and Mechanism Evaluation Programme (EME) and funded by the Medical Research Council (MRC) and the Multiple Sclerosis Society and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership. For more visit www.ms-smart.org
Results were recently released from the INFORMS study, a double-blind, randomized, multi-centre, phase III clinical trial investigating the efficacy of the drug Gilenya (fingolimod) in the treatment of primary progressive MS in 969 participants. Gilenya is an oral disease-modifying therapy that is approved for the treatment of RRMS, and works by targeting harmful immune cells and keeping them in the lymph nodes where they are unable to enter the central nervous system to attack myelin. The results of the 36-month long study showed that although Gilenya was safe and relatively well-tolerated, the drug failed to produce a significant improvement in multiple disability measures in participants with primary progressive MS compared to placebo. Although these results are disappointing, the hope is that other trials and treatments in the pipeline for progressive MS, such as MS-SMART and a follow-up to MS-STAT, will have more promising outcomes.
Following the results of the Research Priorities Discussion that engaged MS stakeholders from across Canada, the MS Society of Canada (MSSC) identified progressive MS as among its top research priorities. In 2014, the MSSC funded 17 operating grants with potential implications for progressive MS across four key focus areas: cause and mechanisms, myelin repair and neuroprotection, therapeutic avenues, and imaging. The graph below shows the distribution of funded grants across the four focus areas.
Below, we highlight just a small handful of the many pivotal studies demonstrating Canada’s continued leadership in facing the challenge of overcoming progressive MS.
Project title: MRI measurements of grey matter
in progressive multiple sclerosis
Researcher: Dr. Alan Wilman
Institution: University of Alberta
Focus area: Imaging
Dr. Wilman’s research uses advanced magnetic resonance imaging (MRI) methods to try to better quantify MS. MRI has been used for many years in MS, but the MRI findings are often very different than the patient symptoms, especially in progressive disease. Dr. Wilman’s team hopes to change the way MRI is used in the clinic for following disease progression and determining effects of therapy. Their new MRI methods will enable a biomarker of disease which can provide objective assessment of disease progression.
Project title: PPARdelta as a regulator of EAE
Researcher: Dr. Shannon Dunn
Institution: University of Toronto
Focus area: Therapeutic avenues
Dr. Dunn’s research focuses on how lifestyle factors such as gender and diet influence the development of progression of autoimmune disease. In particular, she is studying MS-like disease in animals to observe the activity of molecules in the body that are regulated by hormones and obesity and play a role in progressive MS. By learning about disease risk factors and mechanisms, her hope is to determine ways to prevent disease or identify progression in MS sufficiently early to effectively treat it.
Project title: Modulation of neuroprotective
pathways in models of multiple sclerosis
Researcher: Dr. Jacqueline Quandt
Institution: University of British Columbia
Focus area: Myelin repair and neuroprotection
Dr. Quandt and her team are examining key genes and proteins that may play a role in ensuring the survival of nerve cells during MS, a property known as neuroprotection. By manipulating these proteins in an MS-like disease in animals, Dr. Quandt is able to examine their influence on disease mechanisms and disability through disease onset, remission, and progression. The goal of her study is to open the door to future improvements in emerging therapies by enhancing neuroprotection, thus fulfilling an urgent need to limit progression and disability in people living with MS.
To maintain the momentum of treatment discovery for progressive MS, the MSSC is collaborating with the Centre for Drug Research and Development (CDRD) to develop new disease-modifying therapies for progressive MS. Last year, the MSSC and CDRD launched a request for proposals that inviting leading researchers to submit proposals that could have important impacts for understanding and treating progressive MS.
The MS Scientific Research Foundation (MSSRF) is also funding two multi-site studies with a focus on progressive MS. The first, which was launched in 2011 by Dr. Peter Stys from the University of Calgary’s Hotchkiss Brain Institute, is aimed at investigating damage that occurs in MS prior to inflammation, which may be both relevant and beneficial for those with progressive forms of MS. The research, which involves collaboration among MS experts from around the world, hypothesizes that the inflammatory response in MS results from an underlying degenerative process, and is not the primary cause of injury in MS. The second study, announced in 2014, focuses on B cells and the role they play in MS. Recent research has revealed that B cells can be found in areas of the brain that are affected in progressive MS, thus paving the road for this research team led by Drs. Amit Bar-Or, Jen Gommerman, and Alexandre Prat from McGill University, University of Toronto, and University of Montreal, respectively, to determine which types of B cells influence MS and how they can be therapeutically targeted.
Progressive MS Alliance – An International Effort
More than 2.3 million people worldwide currently live with MS. More than half of those, over 1 million people, live with a progressive form of MS. The Progressive MS Alliance (PMSA) is a growing global initiative to end progressive MS. The Alliance began by bringing together the world’s leading experts in multiple sclerosis to identify the critical knowledge and treatment gaps where progress must be made to achieve breakthroughs necessary to change the world for people with progressive MS. As one of the founding members, the MSSC has contributed $1million to this effort and joins 10 other members that comprise the organization.
The Alliance is driving progress in three important ways
1) Global Leadership; ensuring that research is:
- Focused on barriers to treatment development
- Integrated across the MS community
- Systematically measured and refined
2) Innovation: Leveraging research already underway and stimulating new research and breakthroughs through a significant grants program.
3) Funding: Drive worldwide resources to fund the best research, wherever it may be, and unleash the research community to accelerate results with the most impact and potential.
The PMSA recently announced the first round of 22 research grants to researchers across nine countries, including Dr. David Haegert of McGill University for his work on identifying potential biomarkers that can help predict disease progression. These grants are the first step in an ambitious program that will cumulatively invest €22 million over the next six years to stimulate ground breaking international research, identify and test treatments, build repositories for progressive MS tissue samples, and improve imaging techniques to observe neurodegeneration in greater detail. This plan also includes a comprehensive rehabilitation component, in recognition of the immediate need and critical importance of developing approaches that will manage symptoms and improve quality of life for people living with progressive MS. To maintain the momentum of this international research effort, the Alliance is soliciting proposals for the next round of funding, termed the Collaborative Network Award, which is designed to support global collaborative networks of excellence engaged in transformative research. The deadline for submissions to the first stage, a 12-month Planning Award, has now passed, and applications from Planning Award recipients for the second stage competition will be accepted from 1 March 2016 through 1 May 2016.
What is the PMSA up to today?
On March 2-4, 2015, the Progressive MS Alliance hosted its first Scientific Meeting in Boston, MA. The meeting gathered approximately 80 of the top minds in progressive MS research from across the globe – including basic scientists, clinicians, and industry partners – under one roof to find solutions to progressive MS based on what we know and in spite of what we don’t know about this devastating and elusive illness. The effort culminated in the publication of a paper in Multiple Sclerosis journal that summarizes some of the key findings that were presented at the meeting, with an emphasis on determining the next steps toward translating current knowledge into effective therapies for progressive MS.
To maintain the momentum of the international research effort sparked by the Infrastructure and Challenge Awards, the Alliance solicited proposals for the next round of funding, termed the Collaborative Network Award. The awards are designed to support global interdisciplinary, collaborative networks and enable them to engage in transformative research focused on accelerating the development of new therapies for progressive MS.
The Alliance announced the successful awardees for the Planning Awards, which represent the first stage of the Collaborative Network Award. These short-term grants will provide start-up funds and resources for networks to form, develop a shared strategy and formulate more extensive projects and applications towards the common goal of understanding and treating progressive MS. The Alliance received a total of 52 applications from research networks spanning the globe; following a rigorous scientific review by a panel of international reviewers including representatives from the MS Society of Canada, these applications were narrowed down to 11 strong research networks, including two from Canada, representing a broad range of key research topics in progressive MS.
The impact of these awards will be felt in these three key areas:
- Drug discovery programs that identify molecular and cellular targets for new or repurposed therapeutic strategies.
- Discovery, advancement and validation of new or existing biological or imaging biomarkers.
- Designing and conducting clinical trials testing therapeutic strategies including remyelination, neuroprotection, and rehabilitation through neuroplasticity.