WEBINAR
Only
Emerging Research & Trial Strategies for Progressive Multiple Sclerosis
Monday, October 4, 2021, 10:25 AM - 5:20 PM EDT
Webinar
Despite being the most common progressive neurologic disease in young adults worldwide, no treatment is available for progressive forms of multiple sclerosis (MS). Furthermore, advances in disease modifying therapeutics for relapsing remitting MS have little to no efficacy for progressive MS. This is due in part to an incomplete understanding of the disease mechanism and lack of validated outcome measures for clinical trials.
To advance scientific understanding and therapies to treat progressive MS patients, this 1-day virtual symposium will convene physician-scientists, academics, industry leaders, and clinicians to discuss recent basic and clinical research and offer new targets and modalities to be tested as treatments. Session topics include research on innate immune response and cells as therapeutic targets, advances in biomarkers to assess disease progression and monitor response to therapy, and insights into Phase 2 and Phase 3 clinical trial design.
Registration
Scientific Organizing Committee
Gladstone Institutes and UCSF
Johns Hopkins Medicine
University College London
Cleveland Clinic
Biogen
Biogen
New York Academy of Sciences
Keynote Speaker
Cleveland Clinic
Speakers
Johns Hopkins University and Vita-Salute San Raffaele University, Milan
University College London
University of Cambridge
Harvard University and Brigham and Women’s Hospital
University of Genoa
Cleveland Clinic
Gladstone Institutes and UCSF
Johns Hopkins Medicine
University College London
Cleveland Clinic
Mayo Clinic
University College London
Columbia University School of Engineering and Applied Science
Monday
October 04, 2021
WELCOME REMARKS
Speakers
KEYNOTE PRESENTATION: Pathogenesis of Neurological Disability in MS
Speakers
Multiple sclerosis (MS) is a demyelinating disease of the CNS and the major cause of permanent neurological disability in young adults. Immune modifying therapies reduce disease progression in RRMS, but have minimal effect on the irreversible disability caused by axonal and neurodegeneration during progressive MS. This presentation will review settings/mechanisms that are thought to be responsible for axonal and neurodegeneration in progressive MS including degeneration of chronically demyelinated axons, cortical demyelination and expansion of chronic active white matter lesions. Increased energy demands of axonal conduction set the stage for degeneration of chronically demyelinated axons. Reduced ATP production associated with mitochondrial pathology increase axoplasmic Ca+, activate proteolytic enzymes, and eventually cause axonal degeneration. Cortical demyelination causes neuronal and axonal loss and is more prominent in PMS than in RRMS. Mechanisms proposed for subpial cortical demyelination include meningeal B cells and cortical microglia, but not infiltrating peripheral immune cells. Microglia are associated with the expansion of chronic active white matter lesions. These microglia have a distinct molecular phenotype compared to microglia in myelinated white matter and microglial that line the border of subpial cortical lesions. Compartmentation of microglial phenotypes, neuronal/axonal mitochondria and meningeal B cells are attractive targets for future PMS therapeutics.
Break
SESSION I: Research and Targets
Astrocyte Pathogenic Activities in Progressive MS
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Blood-Brain Barrier and Neurotoxic Innate Immunity in MS
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Remyelination and Aging — Reversing the Ravages of Time
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Break
SESSION II: Short Talks Selected from Submitted Abstracts
Subtyping and Predicting Disability Using Machine Learning to Expedite Progressive Multiple Sclerosis Clinical Trials
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Multiple sclerosis is a heterogeneous disease with an unpredictable course. We aimed to define subpopulations of patients at higher risk of disability progression and assess whether disability predictions could expedite patient recruitment in clinical trials. We used clinical and MRI data from 17 previously published clinical trials and observational cohorts and divided them into training and external validation data sets. At study entry, 5,483 patients in the training data set and 2,668 patients in the external validation data set were classified into three groups of high-risk, medium-risk and low-risk of disability progression. In the external validation data set, patients who were predicted to be in the high-risk group had a higher chance of developing CDP compared to those in the medium-risk (HR=1.51, p<0.0001) and low-risk groups (HR=1.51, 95% CI: 1.18 to 1.92, p<0.0001). When we looked at the model-derived risk scores, for every one standard deviation increase in the risk score at the study entry, there was 0.68 (standard error=0.03) increase in EDSS at baseline (p<0.001). Including patients predicted as high risk increased the statistical power by 6% for a trial of 1,200 participants (p<0.0001). Our model (an extension of the previously published "SuStaIn" model) can be used to expedite clinical trials by reducing sample sizes or duration and identify those who may benefit from more efficacious treatments because they have a greater risk of disability worsening.
Development of 1H MRS-visible Diagnostic Biomarkers for Progressive Multiple Sclerosis
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Multiple sclerosis (MS) diagnosis depends in part on invasive methods like lumbar puncture or contrast injection. These yield a broad range of sensitivities and specificities, some reported well below 80%. Proton magnetic resonance spectroscopy (1H MRS) measures disease-relevant small molecules in vivo and may therefore offer a noninvasive route to improving MS diagnostics, particularly the identification of progressive phenotypes. To this end, we applied supervised learning to seven age-corrected metabolite concentrations, including N-acetyl aspartate, choline, myoinositol, glutamate, glutamine, GABA, and glutathione, measured via 1H MRS at 7 Tesla in normal-appearing frontal cortex voxels of individuals with progressive (N=19) relapsing-remitting (N=25), or no (N=24) MS. Resultant models distinguished progressive from relapsing-remitting MS with up to 84% sensitivity and 74% specificity, and from control with up to 79% sensitivity and 68% specificity, exceeding diagnostic accuracies of many imaging- and CSF-based methods previously reported. Feature importances indicated the disproportionate contributions of glutamate, myoinositol, and GABA to distinguishing multiple sclerosis from control, but of glutamine, total choline, and glutathione to distinguishing progressive from relapsing-remitting MS. These results demonstrate that 1H MRS data from normal-appearing cortex can inform classifiers of progressive MS exhibiting some degree of both accuracy and interpretability.
SESSION III: Biomarkers and Endpoints
Fluid Biomarkers of MS Disease Activity and Treatment Response
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Biomarkers of MS activity have long been sought both for discovery biology to elucidate mechanisms of injury and for clinical application to predict and monitor clinical outcomes. MRI of the brain is now routinely used clinically to detect new and enlarging T2 lesions, which are associated with inflammatory disease activity but T2 lesion volume is only modestly associated with clinical measures of disability in MS and is insensitive to neuro-axonal loss. Neurofilaments are the dominant proteins of the neural cytoskeleton and are released into the extracellular space following neuro-axonal damage, and have thus been proposed as putative biomarkers of neuro-axonal injury. Neurofilament light chain (NfL) especially, has been shown to be a promising biomarker because of its high solubility, and increased NfL levels have been found in the blood and CSF in several neurological disorders with underlying neuro-axonal degeneration, including MS. NfL holds promise as a prognostic and monitoring biomarker, especially early on in the disease process when axonal transections are common in active lesions. In progressive MS the frequency of peripheral immune mediated infiltrates is reduced and secondary mechanisms of injury such as neurotoxic glial activation, synaptic pathology, metabolic dysfunction, and axon degeneration evolve with duration of disease highlighting the need for next generation biomarkers associated with slow insidious progression.
Imaging Biomarkers of the Spinal Cord in MS
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Paramagnetic Rim Lesion Assessment in Progressive Multiple Sclerosis
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Progressive MS: Pathologic and Therapeutic Implications
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Break
SESSION IV: Trial Considerations for Progressive MS
Clinical Trial Design for Progressive MS Trials
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Insights into Phase II Trials in Progressive MS
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Insights into Phase III Trials in Progressive MS
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Over the past two and half decades, dozens of positive Phase III trials have been conducted in relapsing MS. Despite this success in relapsing MS, the story with progressive MS has been very different with most trials failing to meet their primary outcome. This talk will review lessons learned from those trials, including therapeutic targets, patient selection, and outcome measures.
Closing Remarks
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