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 and effective treatment.
Progressive MS includes different subtypes. Primary progressive MS (PPMS) is characterized by a gradual but continuous worsening of the disease over time. Approximately 15% of people with MS are diagnosed with primary-progressive MS (PPMS). PPMS differs from the more commonly diagnosed relapsing-remitting MS (RRMS represents about 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 eventually over time, people may transition to a progressive course which may or may not be classified as active (accompanied by relapses) or non-active (no relapses). Before the availability of disease-modifying therapies (DMTs), studies indicated that approximately half of all people with RRMS will eventually develop SPMS within 10-20 years following their initial diagnosis. There is evidence suggesting that early treatment with a DMT may alter MS disease course and delay transition to SPMS, however further investigation is needed to determine the extent to which current medications impact disease progression.
Progressive MS Research Challenges
An enormous surge in research and available treatments for MS has emerged in the last 20 years. Health Canada has approved more than a dozen DMTs for treatment of MS to date. These therapies, which focus largely on targeting inflammation in the central nervous system, are demonstrated to be safe and effective in treating relapsing forms of MS, including one medication for early PPMS and several medications for active SPMS. Inflammation has been shown to play a smaller role in progressive MS, which is characterized primarily by neurodegeneration and failure of repair mechanisms (i.e. remyelination). These characteristics help explain in part, why the anti-inflammatory therapies for relapsing MS are largely ineffective in altering the course of progressive MS.
While robust research and well-designed clinical trials continue to expand to investigate and develop novel treatments for progressive MS, researchers face a number of 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 people with RRMS. In progressive MS, such outcomes have not been found as useful due to differences in disease characteristics. This not only creates challenges for assessing treatments, but also for detecting disease progression in people with progressive MS versus relapsing MS. Identifying biomarkers (a biological marker that can detect disease and/or treatment effectiveness) that specifically detects progression in MS has yet to be found though there have been promising advancements in this research area.
Compounding this difficulty is the likelihood of small sample sizes and dropout rates of clinical trials. Additionally, as people living with progressive MS are typically older and have other comorbid diseases (conditions that occur alongside MS), this may complicate the interpretation of results. With that said, Canadian and international research has a number of active and promising studies in progressive MS to help identify biomarkers, genetic risk factors, treatments, rehabilitation, and understanding the underlying disease pathology. Please read on for more information.
Treatments for Progressive MS
The mechanisms of progression primarily involve neurodegeneration (loss of neurons that may or may not result from an inflammatory process) and failure of repair mechanisms such as remyelination; hence, further investigation into these non-inflammatory mechanisms is important in identifying new therapeutic targets for progressive MS. There are some treatment options for people living with early PPMS and active SPMS. To date, OcrevusTM (ocrelizumab) is the only DMT conditionally approved for the treatment of early PPMS in Canada. Early PPMS is defined by duration of disease and level of disability (measured using Expanded Disability Status Scale, EDSS), in addition to MRI features characteristic of inflammatory activity. Ocrevus acts as an immunomodulatory drug by targeting and removing potentially harmful B cells (a type of white blood cell) in people living with MS. Please see the Ocrevus page for more information.
Health Canada has also approved Mayzent® (siponimod) for the treatment of adults with active SPMS, as evidenced by relapses or MRI features characteristic of MS inflammatory activity, to delay the progression of physical disability. Please see the Mayzent page for more information.
In addition to Mayzent, some of the interferon formulations carry a Health Canada indication for active SPMS, these include interferon beta 1a (Avonex, Rebif) and interferon beta 1b (Extavia and Betaseron).
People living with secondary progressive or primary progressive MS can also manage their disease through rehabilitation and symptom management strategies. In particular, exercise has demonstrated to be a cost-effective and feasible intervention that benefits motor and cognitive function in MS. People living with progressive MS are encouraged to speak to their health care team for more information on treatment options.
To learn more about the recent research and treatments in the pipeline for progressive MS, please see the Treatments in Development page.
Canadian Contribution to Progressive MS Research
The MS Society of Canada (MSSC) has identified progressive MS as among its top research priorities. Below are some of the key research studies currently supported by the MSSC and the MS Scientific Research Foundation (MSSRF), with potential implications for progressive MS across key focus areas: cause and risk factors of MS, diagnosis, progressive MS, repair and remyelination, cognition and mental health, and life-modifying therapies.
1. Project Title: Characterizing Inflammatory and Neurodegenerative Pathways Driving Clinical Disease in Primary Progressive MS
Dr. Jacqueline Quandt (University of British Columbia) and team are characterizing the first mouse model of MS based on a human mutation that causes PPMS in families. Developing a new animal model that mimics human disease will provide researchers with a needed tool to understand the underlying mechanisms of PPMS and identify novel therapeutic targets.
The CogEx study led by Dr. Anthony Feinstein (Sunnybrook Health Sciences Centre) and his international team of investigators are testing if cognitive rehabilitation, or aerobic exercise, or a combination of both, will improve cognitive function in people progressive MS.
3. Project Title: Unravelling Immune Cell – Microglial Interactions in Progressive MS
A collaborative team grant led by Drs. Jennifer Gommerman (University of Toronto) and Alexandre Prat (Centre hospitalier de l'Université de Montréal) will study the molecular factors that govern MS progression. This project aims to shed light on how most people with RRMS transition to SPMS and will help explain why many of the current MS drugs are unable to effectively treat SPMS.
For more information on MSSC funded research, please see the Research We Fund page.
International Progressive MS Alliance – An Unprecedented Global Collaboration
More than 2.8 million people worldwide currently live with MS. Up to 65% of people with relapsing-remitting MS will eventually develop secondary progressive MS.
In 2012, the International Progressive MS Alliance (known as the “Alliance”) was established by six founding members (MS Societies of Canada, Italy, the Netherlands, the UK and USA, and MS International Federation). They came together to make a joint commitment to raise the profile and accelerate progress in treatments to end progressive MS. The Alliance began by bringing together the world’s leading experts in MS 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.
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, and 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.
In 2016, the Alliance announced the recipients of the ‘Collaborative Network Awards’, support for global collaborative networks of excellence engaged in transformative research. In total, three of the most promising collaborative networks were awarded to receive a total of € 12.4 million (approximately $18.6 million CAD) over three years:
1. Project Title: Identifying a Biomarker of Disability Progression for use in Clinical Trials
This network is led by Dr. Douglas Arnold, M.D., McGill University (Canada)
in collaboration with 16 investigators from The Netherlands, U.K., U.S., and Switzerland. Dr. Arnold is developing the next generation of tools for measuring disease progression in progressive MS. The team is pioneering the development of magnetic resonance imaging (MRI) markers that signal disease progression, and adapting these for use in early clinical trials for progressive MS treatments.
2. Project Title: Bioinformatics and Cell Programming to Develop an In Vitro Platform to Discover New Drugs for Progressive Multiple Sclerosis (BRAVEinMS)
This network is led by Dr. Gianvito Martino, M.D., Division of Neuroscience, San Raffaele Hospital Milan (Italy) in collaboration with 13 Investigators from Italy, France, Germany, Europe, Canada and the U.S. This team is working to identify molecules with a greater chance of being therapeutics for progressive MS. These molecules may have a protective role in nerve cells and/or have the capacity to promote myelin repair. They anticipate having several good candidates for clinical trials at the end of this project.
3. Project Title: Development of a Drug Discovery Pipeline for Progressive MS
This network is led by Dr. Francisco Quintana, Ph.D., Brigham and Women’s Hospital (U.S) in collaboration with 8 Investigators from the U.S., Canada, Israel and Sanofi Genzyme. This team aims to identify drug candidates that may be effective therapies for progressive MS at the end of this project.
For more information on the Alliance collaborative research networks, please visit here.
What is the PMSA up to today?
In May 2019, the Alliance convened a meeting of the three collaborative research networks to mark the mid-point of these ambitious projects, to hear an update on their results and progress to-date, and to explore potential relationships and opportunities to accelerate their progress. For more information on networks progress refer to this blog.
Scientific Steering Committee member, Jon Strum, commented on the network awards and the progress, “this took me back two years ago when we were announcing the Network awards. It was a highly conceptual conversation. But here we are at half circle today, and we can see so much real progress and science that’s been achieved. It is an understatement to say that this work is impressive. Progress fuels hope. This could not be a more hopeful convening about what’s being done.”
In 2019, the Alliance launched the ‘Challenges in Progressive MS Awards’ to support research proposals that uncover new mechanisms driving progressive MS that can be used to identify therapeutic targets that will ultimately slow or stop disability progression. In 2021, the Alliance announced a total of 1,425,00 euros in funding for 19 projects, including Canadian researcher, Dr. Jennifer Gommerman (University of Toronto). Representing 13 countries around the world, the proposals were chosen based on their innovative and collaborative concepts that challenge current approaches and thinking. The projects focus on a breadth of areas, ranging from identifying novel insights into axonal loss in progressive MS to molecular pathways that promote neuroprotection and myelin repair. For more information, refer to news and Alliance.
Additionally, the Alliance has taken on new strategic initiatives to accelerate activities and progress and have assembled implementation teams that bring together Scientific Steering committee members, industry forum members, global experts and persons affected by MS. The implementation teams are focused on progressive MS in three key areas:
Understanding how to accelerate clinical trials in progressive MS
- In February 2021, the Alliance expert panel makes recommendations for improving early phase clinical trials. In the publication, the panel recommends changes in the way progressive MS clinical trials are designed and conducted to encourage consistency and improve comparability. Refer to publication here.
Identifying biomarkers for progressive MS
- In September 2020, the Alliance’s biomarkers implementation team published their first paper in the journal of Neurology, highlighting evidence for one of the most promising biomarkers called ‘neurofilament light (NfL)’, an important component of nerve cells that is released into the blood stream following damage or as a result of neurodegeneration. Recent clinical trials in MS have demonstrated that NfL levels as a possible indicator of treatment effect in both relapsing and progressive forms of MS. NfL levels are able to predict relapse rates, brain tissue loss, disability progression and can be used as indicators of treatment response. This publication and the ongoing work from the Alliance will help advance the goal of accelerating new treatments for people with progressive MS. For more information on NfL, please see our MS update.
Enhancing well-being for people living with progressive MS (non-drug approaches)
- In April 2021, the enhancing well-being expert panel convened by the Alliance published a paper outlining their recommendations on research priorities to address MS symptoms: fatigue, impairment of mobility and upper limb function, pain, and cognitive impairment. The authors found minimal research funding is currently directed toward these symptoms and there is a need for more investment to identify solutions. The paper outlines key knowledge gaps and priority research questions in each of these four symptoms. Refer to publication here.
In December 2021, the Alliance maps out the global research agenda to end progressive MS in this published paper. The Alliance is proposing a global research strategy to prioritize and coordinate efforts needed to find more and better treatments and improve quality of life for people living with progressive MS. Three gap areas are identified as holding potential for accelerating progress, with suggestions for research approaches and critical steps to tackle them:
- Understanding mechanisms that drive progression: Having deeper knowledge of the underlying causes of progression will uncover plausible treatment targets to slow, prevent, and even reverse disability. Increasing data sharing and application of machine learning may support progress in this area, as will having disease descriptors that are based on biological phenotypes, an effort already underway.
- Speeding clinical trials: MS progression is generally slow and there is no quick way to detect whether an experimental therapy is working. To increase testing of novel agents, new trial designs that require fewer participants are needed, as well as fluid and imaging biomarkers and clinical outcome measures that give early reflections of treatment response.
- Improving wellbeing: More attention is needed to test and disseminate effective approaches to address the physical, cognitive, and emotional health symptoms experienced by people living with progressive MS. This necessitates an increase in the trained workforce and investments in high-quality research in these areas.
Watch the 2021 Progress Report (video):
