Slide 1: Progressive MS: A Major Unmet Need
Progressive MS: A Major Unmet Need Mechanisms, role of EBV and Biomarkers Sept 10, 2024 Amit Bar-Or, MD, FRCPC Melissa and Paul Anderson President’s Professor Director, Center for Neuroinflammation and Experimental Therapeutics Chief, Multiple Sclerosis Division, Department of Neurology Perelman Sch
Slide 2: Outline
Outline Progressive biology of MS: an under-estimated unmet need Mechanisms contributing to progressive MS biology Emerging roles of EBV How to measure relevant biologies: key to providing biological proof-of-principle insight
Slide 3: Outline
Outline Progressive biology of MS: an under-estimated unmet need Mechanisms contributing to progressive MS biology Emerging roles of EBV How to measure relevant biologies: key to providing biological proof-of-principle insight
Slide 4: Revisiting the Clinical Spectrum of MS
Revisiting the Clinical Spectrum of MS RMS SPMS
Slide 5: Revisiting the Clinical Spectrum of MS
Revisiting the Clinical Spectrum of MS RMS SPMS PPMS
Slide 6: Revisiting the Clinical Spectrum of MS
Revisiting the Clinical Spectrum of MS RMS SPMS PPMS Both ‘Relapsing’ and ‘Progressive’ biologies exist across MS spectrum Both mostly sub-clinical, and exhibit substantial clinical heterogeneity
Slide 7: Outline
Outline Progressive biology of MS: an under-estimated unmet need Mechanisms contributing to progressive MS biology Emerging roles of EBV How to measure relevant biologies: key to providing biological proof-of-principle insight
Slide 8: Simplified model of MS Immune Pathogenesis
Simplified model of MS Immune Pathogenesis 1. Activation 4. Invasion B Cell 3. Attraction Th B Cell 2. Adhesion 5. Reactivation 6. Neural/glial responses Periphery Barriers CNS
Slide 9: Simplified model of MS Immune Pathogenesis
Simplified model of MS Immune Pathogenesis Compartmentalized 1. Activation 4. Invasion B Cell Immune-Brain 3. Attraction Interactions in Th Progressive MS B Cell Peripheral 2. Adhesion Cellular Immune 5. Reactivation Interactions Drive MS Relapses 6. Neural/glial responses Periphery Barriers CNS
Slide 10: Treatments impacting only peripheral inflammation: modest efficacy at best for progressive MS
Treatments impacting only peripheral inflammation: modest efficacy at best for progressive MS Compartmentalized 1. Activation 4. Invasion B Cell Immune-Brain ?EBV 3. Attraction Interactions in Th Progressive MS B Cell Peripheral 2. Adhesion Cellular Immune 5. Reactivation Interactions Drive MS Relap
Slide 11: Elucidating mechanisms of Progressive ('non relapsing') MS
Elucidating mechanisms of Progressive (‘non relapsing’) MS Potential underlying mechanisms: Inflammation: meningeal; sub-ependymal; perivascular; diffuse microglial Bidirectional Immune:CNS interactions propagate injury Mitochondrial (hypoxia; demand > supply; innate/adaptive immunity) ‘Toxic substa
Slide 12: Elucidating mechanisms of Progressive ('non relapsing') MS
Elucidating mechanisms of Progressive (‘non relapsing’) MS Potential underlying mechanisms: Inflammation: meningeal; sub-ependymal; perivascular; diffuse microglial Bidirectional Immune:CNS interactions propagate injury Mitochondrial (hypoxia; demand > supply; innate/adaptive immunity) ‘Toxic substa
Slide 13: Outline
Outline Progressive biology of MS: an under-estimated unmet need Mechanisms contributing to progressive MS biology Emerging roles of EBV How to measure relevant biologies: key to providing biological proof-of-principle insight
Slide 14: Outline
Outline Progressive biology of MS: an under-estimated unmet need Mechanisms contributing to progressive MS biology Emerging roles of EBV How to measure relevant biologies: key to providing biological proof-of-principle insight
Slide 15: Reinvigorated interest in EBV role/s across MS spectrum
Reinvigorated interest in EBV role/s across MS spectrum Nat Med, 2022 1. Development of MS 2. Triggering of Relapses 3. Progressive Disease Propagation (In the Periphery) (Within the CNS)
Slide 16: Schneider-Hohendorf et al., JEM, 2022
Schneider-Hohendorf et al., JEM, 2022
Slide 17: Broader EBV T cell repertoire in MS and Treatment Responses
Broader EBV T cell repertoire in MS and Treatment Responses Discovery cohort Validation cohort Schneider-Hohendorf et al., JEM, 2022
Slide 18: Broader EBV T cell repertoire in MS and Treatment Responses
Broader EBV T cell repertoire in MS and Treatment Responses Discovery cohort Validation cohort Schneider-Hohendorf et al., JEM, 2022 Schneider-Hohendorf et al., Brain, 2024
Slide 19: Assessing effect of therapies on (MS-implicated) EBV biology
Assessing effect of therapies on (MS-implicated) EBV biology Need to measure EBV ‘biology/state’ broadly: ie. study both EBV-infected B cells and EBV-reactive T cells Assays to detect EBV and EBV infected B-cells ddPCR (EBV DNA viral load) RTddPCR (EBV RNA viral transcripts: lytic + latent) PrimeFlo
Slide 20: Outline
Outline Progressive biology of MS: an under-estimated unmet need Mechanisms contributing to progressive MS biology Emerging roles of EBV How to measure relevant biologies: key to providing biological proof-of-principle insight NfL: neurofilament light chain; GFAP: glial fibrilary acidic protein … fl
Slide 21: Neurofilament Light Chain (NfL)
Neurofilament Light Chain (NfL) Non-specific marker of neuroaxonal injury 1-7 Neuroaxonal Source: Neuroaxonal damage → elevated NfL Structural Cytoskeleton Component First-generation and Third-generation and (MS, AD, ALS, PD, and Trauma) second-generation fourth-generation neurofilament assays neuro
Slide 22: NfL elevation in MS Patients on High Efficacy Therapy reflect injury from progressive MS biology
NfL elevation in MS Patients on High Efficacy Therapy reflect injury from progressive MS biology OPERA I and II (OCR arm) 50 DB: OCR OLE: OCR Year 2 Year 5 OLE baseline OLE Y3 P = .018 P = 1.1e-5 40 Cumulative Probability of CDP24 on EDSS, % H 30 20 10 Year 9 OLE Y7 log-rank P = 2.6e-5 0 0 24 48 72
Slide 23: GFAP + NfL: Results of EmBioProMS1
GFAP + NfL: Results of EmBioProMS1 Patients followed over a mean of 29.3 months • Prospective multicenter PPMS observational study (n = 135) High GFAP + low NfL followed patients with PPMS and SPMS levels could identify high progression risk • Goal: define the in patients with association between no
Slide 24: Outline
Outline Progressive biology of MS: an under-estimated unmet need Mechanisms contributing to progressive MS biology Emerging roles of EBV How to measure relevant biologies: key to providing biological proof-of-principle insight
Slide 25: Progressive MS: A Major Unmet Need
Progressive MS: A Major Unmet Need Mechanisms, role of EBV and Biomarkers Sept 10, 2024 Amit Bar-Or, MD, FRCPC Melissa and Paul Anderson President’s Professor Director, Center for Neuroinflammation and Experimental Therapeutics Chief, Multiple Sclerosis Division, Department of Neurology Perelman Sch