Clinical trials for a new progressive MS therapy can take up to five years and require millions of Euros. But people living with progressive MS simply can’t wait that long to see if a new treatment is viable. That is why it’s critically important to be able to test multiple approaches in a shorter time span with a lower level of investment required.

Additionally, there are challenges that must be addressed to improve clinical trials.  There is a vital need for biomarkers in progressive MS that can measure progression and indicate if a potential treatment is effective.  Clinical trials also need to be designed that can provide deeper insights into the biology of progression which will lead to targeting areas where a drug intervention could be successful in preventing disease progression or stimulating nervous system repair.  Finally, clinical trials need to include a broader spectrum of people with progressive MS and people affected by MS need to be involved in the design of trials.

The Alliance is working in multiple ways to speed up and improve clinical trials:

  • MRI Imaging Biomarker International Collaborative Research Network – Artificial Intelligence can lead to new tools that can predict, via MRI’s, the changes in the brain as MS progresses. Such tools could be used to quickly evaluate whether a potential treatment is effective and ultimately be used in a clinical setting for customizing an individual’s treatment.  The Alliance has invested €4 million in a research network that is using machine learning to create tools that would be a major advancement in progressive MS clinical trials.
  • Serum Neurofilament light chain (sNfL) – a fluid biomarker – If sNfL is further confirmed as a biomarker for progressive MS, a blood test could help predict the future course of the disease and indicate whether a treatment is working.  The Alliance has formed an expert panel that has published a set of recommendations and is working with the FDA, EMA and the MS scientific community to further this effort.
  • Expert panel recommendations – the Alliance has convened a panel of experts to give recommendations on ways to improve progressive MS clinical trials. This panel has produced a paper that provides a number of steps for the design of trials in progressive MS that will not only effectively test new treatments but also lead to new understandings of the biology of progression. The panel also describes the importance of including different cohorts of people with progressive MS in trials and that people affected by MS should be involved in trial design.  Next steps in this work include Alliance funding initiatives that would support the testing of new clinical trial approaches.

Mobility is a major issue for me. Without people to take me out, I am pretty much housebound. Leaving the house requires very careful planning, it involves investigating the accessibility of the place I’m going, including the toilet facilities, deciding what to wear, and so on.

Christelle from South Africa, living with progressive MS

Identifying a biomarker of disability progression for use in clinical trials

Goal: Predicting progression using MRI – An international Research Collaboration Network.

Principal Investigator: Douglas Arnold, M.D., McGill University (Canada) in collaboration with 16 investigators from The Netherlands, U.K., U.S., and Switzerland.

Led by Professor Doug Arnold from Canada, this network is working to develop imaging tools and computer programs that will predict changes in the brain as MS progresses and provide an understanding of how progression affects the brain. Such tools could be used in clinical trials to measure if a treatment is slowing or stopping disease progression. Something that currently takes a long time and is expensive.

The research examines the underlying idea that brain injury-associated disease progression in MS is detectable by MRI prior to its identification by physicians in a clinic visit at a later stage.

Using cutting-edge advances in artificial intelligence and machine learning, the tools could be used to evaluate whether a potential treatment is effective—is the treatment slowing or reversing damage in the brain—thus addressing a major barrier in current treatment development.

Potentially, researchers would know much faster whether a prospective treatment is working and need far fewer patients involved in a trial for less time. Together, this would reduce time and cost in developing new treatments.

The overall goal of this network is to accelerate Phase 2 clinical trials for progressive MS by:

  • Bringing together MRI and clinical data from Phase 3 clinical trials and natural history cohorts to make them available for collaborative research projects​
  • Identifying new MRI markers that are associated with progression​
  • Developing a biomarker to assess treatment effects over short periods of time​
  • Developing robust MRI processing techniques that are more sensitive to changes in brain structures in individual patients over time

A large number of scans are needed to train the AI software. To date, the team has received data from approximately 13,500 subjects that include more than 72,000 MRI scans. A recent request was made for the use of the data from a new trial that would add data from an additional 650 progressive MS patients.

An MRI Scan of a brain on a computer screen

The goal of this project is to allow shorter, less expensive clinical trials through optimized MRI image analysis using artificial intelligence.

Serum Neurofilament light chain (sNfL)

Goal: A routine blood test could predict and measure progression

The International Progressive MS Alliance has formed an expert panel led by Robert Fox MD and Kathy Smith. Their goal is to develop recommendations to advance a novel biomarker for progressive MS found in blood ─ neurofilament light or NfL.

Neurofilaments are structural proteins found within neuronal cells of the central nervous system. sNfL is a component of neurofilaments that is released following axonal damage and neuronal degeneration. This type of tissue damage occurs in MS, as well as in brain injuries and other neurodegenerative diseases. sNfL can be detected and measured in the bloodstream. If sNfL is further confirmed as a biomarker for progressive MS, a blood test could help predict the future course of the disease and indicate whether a treatment is working.

A paper published in the September 8, 2020, issue of Neurology®, the medical journal of the American Academy of Neurology, notes that sNfL is a plausible marker for measuring neurodegeneration accurately, sensitively and reproducibly, but standard procedures for blood sample collection and assay methods need to be established. Further challenges must be overcome to understand differences in sNfL in active inflammation in MS (i.e., relapse) versus disease progression. Data is also needed to understand the effects of age and comorbidities on sNfL levels.

The next steps are to engage regulators and the broader scientific community to address key issues and consider standards for use.

The International Progressive MS Alliance is engaged with regulatory bodies regarding the use of sNfL measurement in clinical trials and is also convening MS scientific experts to address the challenges noted above.

3D illustration of node structures in the central nervous system.

If sNfL is further confirmed as a biomarker for progressive MS, a blood test could help predict the future course of the disease and indicate whether a treatment is working.


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Improving Early Clinical Trials Initiative

Making phase II clinical trials more consistent, comparable, and informative of the biology underlying MS are among the International Progressive MS Alliance’s key goals for speeding new therapies for progressive MS. 

  • An expert panel of the Alliance has taken a crucial step in this direction by publishing a paper recommending changes in the way these trials are designed and conducted. 
  • The Alliance also proposes to launch a new funding program to advance trials that follow these recommendations, after gaining feedback from the broader MS community. 
  • The paper was published in Nature Reviews Neurology on January 22, 2021.


Phase II trials are the stage of testing that comes before the larger phase III trials that are required to seek regulatory approval of a therapy. Generally, phase II trials are short studies conducted to look for signs that an experimental medicine is beneficial and appears safe. How its benefit is determined can vary greatly, from imaging scans and blood tests to clinical measures of disease activity. The choice of outcome measures is critical because the decision to launch laborious and expensive phase III trials depends on whether the phase II trial is considered a success or a failure. 

An expert panel of the International Progressive MS Alliance formed to encourage consistency and improve comparability in how phase II trials are currently conducted. Under the leadership of co-chairs Drs. Marco Salvetti (Sapienza University and a member of the Alliance’s Scientific Steering Committee) and Fernando Dangond (EMD Serono and a member of the Alliance’s Industry Forum), the team developed the recently published recommendations.


Phase II trials can and should be informative about disease mechanisms even if their results are considered negative. Specific direction has been developed related to study designs, types of outcome measures, and disease activity markers. Recommendations for best practices for phase II trials include: 

  • Testing multiple medicines at the same time using advanced trial designs;
  • Testing new therapies in combination with an approved MS therapy to reduce the potential interference of inflammation on trial results;
  • Using diverse measures of disease biology, on top of a core set of outcome measures to track an experimental medicine’s effects. Core measures include: 
    • Clinical measures (such as upper limb dexterity) to track disability, and composite clinical outcomes, and could also include ancillary testing of mobility, vision, cognition and others (depending on characteristics of study population)
    • Paraclinical tests (such as imaging, blood markers) to measure disease activity 
    • Tests of biological response indicators, related to mechanism of action
    • Exploratory measures, such as gene transcriptomics
  • Using less restrictive criteria for characteristics of people to be included in a trial;
  • Using alternative clinical trial designs; and
  • Soliciting feedback on the feasibility of trial designs from people living with MS.
Two arrows make a circular review process between Iterative Review, comparability, Comparison of Trial Results and innovation.

Future funding program

Another aspect of initiative focuses on a proposed future funding program to be supported by the Alliance. This program would provide grants for phase II experimental medicine trials that explore treatments and targets while generating hypotheses about disease mechanisms, using biological and clinical measures in alignment with these published recommendations.

A multi-stage review of the grant proposals would be an iterative process to encourage innovation, while improving and aligning trial designs and outcome measures so that ultimately it would be possible to compare or even combine the results of trials that were conducted separately.

Feedback on recommendations

Through a variety of forums, the Alliance will be inviting comments on these recommendations in preparation of releasing a targeted Request for Applications on Experimental Medicine Phase IIa clinical trials in progressive MS.