MS Summit 2020 MS Research Update

Peiqing Qian, MD MS Center at Swedish Neuroscience Institute 6/13/20 Overview

• Pregancy,Breast feeding, smoking and Marijuana • Biomarker NFL • S1P1 receptor –Ponesimod • B cell depleting agents • BTK inhibitors • Biotin high dose • Anti-Lingo study • Beat MS –AHSCT • Therapy approach, Treat MS study

Exclusive Breast-Feeding -Lower Rates of Early Postpartum Relapse in Multiple Sclerosis • Within the first 6 months postpartum, women who breast-fed >2M exclusively were less likely to experience relapses (9%) than those who breast-fed nonexclusively (17%) or not at all (25%). • Exclusive breast-feeding was associated with lower risk for relapse compared with no breast-feeding (AHR, 0.33; 95% CI, 0.15–0.69). • ¾ had no postpartum relapse. ARR returns to prepregnancy by 6M. • Population is unique: 30% never used DMT. Half had discontinued DMTs the year prior, half had no relapse 2yrs prior to pregnancy. • DMT during the year prior to pregnancy: 93% injectable therapy, 5% infusion • Hard to disentangle cause from effect with Registry data • Stable postpartum MRI can help assess disease activity as a factor in encouraging decisions about breast-feeding for several months

Neurology® 2020;94:e1939-e1949 Blood neurofilament light levels segregate treatment effects in multiple sclerosis • 1,261 Swedish patients with RRMS starting novel DMTs • pNfL concentrations as a function of clinical variables • DMTs (alemtuzumab, dimethyl fumarate, fingolimod, , rituximab, and teriflunomide). • pNfL concentrations were determined using antibodies from UmanDiagnostics (Umeå, Sweden) and the SIMOA Immunoassay using the Quanterix Kit

Bénédicte Delcoigne et al. Neurology 2020;94:e1201-e1212 Unweighted and weighted baseline log–neurofilament light in plasma (pNfL)N40 Baseline and on-treatment mean neurofilament light in plasma (pNfL)N40 levels in the disease-modifying therapy groups

Bénédicte Delcoigne et al. Neurology 2020;94:e1201-e1212

Ponesimod- Phase III study, OPTIMUM

• Selective sphingosine-1-phosphate receptor 1 (S1P1) modulator • Eliminated with 1 wk after stopping (t1/2=31h), rapidly reversible • OPTIMUM -Compare the effectiveness and safety of posenimod to teriflunomide in reducing relapses in RRMS patients for 108 wks • 1,133 adult patients with relapsing MS at 162 sites in 28 countries. The average age of participants was about 37; and 51% were from EU. • Ponesimod started at 2 mg once daily and was titrated up to 20 mg for 14 days to mitigate potential cardiac effects. Ponesimod- Phase III study, OPTIMUM

• Primary endpoint of a significant 30% reduction in ARR at 108 weeks • Ponesimod reduced the number of new inflammatory lesions on MRI by 56% compared with teriflunomide • Ponesimod also showed effects on fatigue compared with teriflunomide (mean difference -3.57, P=0.0019) at 108 weeks • Common adverse events included hepatobiliary disorders and liver enzyme abnormalities, hypertension, and pulmonary events Current and Investigative B-cell MS Therapies Targeting Different B-cell Surface Markers

Bone Marrow Peripheral Lymphoid Tissue and Brain (antigen-independent) (antigen-dependent) Short-lived CD20+CD27+(high)CD40L plasma cell (Early plasmablast) CD19+IgD+C + ++ CD19+IgM+ CD19 CD138 or CD38+CD138+ IgM D27- IgM CD19+CD27+CD38++ IgG

IgE IgA IgE Stem Cell Pre B Cell B Cell Immature B Cell Mature Naïve Activated Memory Late Plasmablast Plasma cell (autoreactive receptors) (Drivers of MS pathogenesis) (germinal C) (Produce antigen-specific (Produce antigen-specific antibodies) antibodies) CD19 Inebilizumab CD20 Rituximab Ublituximab Ofatumumab CD138 BAFF-R BR3Fc BAFF Antagonist BCMA APRIL-specific BCMA IgG TACI Atacicept Atacicept

Figure adapted from: Dalakas M et al. Nat Clin Pract Neurol 2008 • Specific CD (cluster of differentiation) markers such as CD20, CD27, BAFF-R, CD38 and CD138 are helpful for distinguishing the transitional phases, including stem cells, memory B cells and plasma cells, through which B cells pass during maturation

Phase III- Asclepios I and II

Subcutaneous (SC) formulation of Ocrelizumab (co- mixed with recombinant human hyaluronidase PH20

• rHuPH20 is a human hyaluronidase for injection that has been developed by Halozyme Therapeutics, Inc.

• Increasing the dispersion and absorption of other injected drugs and is used primarily as a permeation enhancer – Allows for transient hydrolyze hyaluronan, a component of the SC matrix, leading to reduced viscosity of the extracellular matrix of the hypodermis – Improved delivery of drugs SC and at larger volumes

• Ocarina I study will use a formulation of rHuPH20, which will be co-mixed with SC Ocrelizumab at the clinic at the time of administration Overview of Study Design

• Phase Ib

• Open label, PPMS and RMS

• Treatment phases: – Dose Escalation: to determine SC dose of ocrelizumab (comparable to approved 600-mg IV formulation of ocrelizumab) – Dose Continuation: SC Ocrelizumab dosing every 24 weeks up to 3 years

• Safety follow-up phase: up to 1 year after the last Ocrelizumab administration Ublituzumab

Glycoengineered chimeric anti-CD20 Greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab Target a specific receptor on the CD20 antigen found on mature B- cells Phase II trial showed both a favorable safety profile and an ability to be dosed in a rapid 1-hour infusion. Ongoing Phase III clinical trials with comparison to teriflunomide New B cell depleting treatment in clinical trials

Binding Epitopes of Anti-CD20 Antibodies ULTIMATE I & II -Phase 3 randomized, double blinded, double dummy, active controlled trials

Oral BTK Inhibitor in MS -Evobrutinib

• Bruton’s tyrosine kinases is expressed in B cells, macrophages, and monocytes but not in T cells • Evobrutinib is a selective, covalent, oral inhibitor of BTK (particularly to EGFR) that blocks B-cell activation and cytokine release • It inhibits the activation, differentiation, and polarization of proinflammatory M1 Macrophage and their release of cytokines in vitro. • Evobrutinib has shown in vivo efficacy against experimental autoimmune encephalomyelitis regardless of B-cell activity. • The irreversible binding of evobrutinib to BTK results in a pharmacodynamic effect that is longer than the pharmacokinetic plasma half-life of evobrutinib. B cell receptor and signaling

Evobrutinib in RRMS and active SPMS- Phase II

Panel A: total number of gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (primary end point) in the five trial groups

Panel B shows the relapse rate ratio and annualized relapse rate at 24 weeks (a key secondary end point). The relapse rate ratio is based on a negative binomial model for the relapse count that was adjusted for patients’ relapse activity at baseline.

Panel C shows the annualized relapse rate at weeks 24 and 48. All the analyses were performed in the modified intention-to-treat population

N Engl J Med 2019; 380:2406-2417 Oral BTK Inhibitor in MS –Evobrutinib Safety

• Evobrutinib 75-mg QD and BID doses were associated with higher rates of adverse events than the 25-mg dose or placebo. • Higher evobrutinib doses were associated with a higher frequency of elevations in ALT, AST, or lipase levels at 52 weeks. • Adoption of hepatic risk-mitigation strategies and stopping rules in future clinical trials may be appropriate. • Limitations: population was older, the disease duration was longer, higher baseline EDSS and fewer relapses within 2 years before baseline. Phase IIb BTK inhibitor SAR442168

Opicinumab- Anti-Lingo-1

Opicinumab is a fully human IgG1 aglycosylated monoclonal antibody against LINGO-1 LINGO-1 blockade with antibodies against LINGO-1 (anti-LINGO-1) facilitates axonal myelination in vitro and remyelination in several in vivo demyelination models through enhanced differentiation of oligodendrocyte precursor cells RENEW study: ON, improvement on VEP SYNERGY study: RMS and SPMS, no difference in improvement in disability or a slowdown in disability progression vs placebo Opicinumab- Anti-Lingo Beat MS study--BAT vs AHSCT

• Best Available Therapy (BAT) Versus Autologous Hematopoietic Stem Cell Transplant (AHSCT) for MS (BEAT-MS) • Compare the efficacy, safety, immunologic effects, and cost- effectiveness of AHSCT versus BAT over 72 months in relapsing MS and continued MS disease activity despite treatment with DMTs. • Prospective 1:1 randomized controlled trial of 156 participants • Age ≤ 55, EDSS≤5.5 • Primary Endpoint: MS relapse free survival • BAT agents: natalizumab, alemtuzumab, ocrelizumab, or rituximab Early vs. Late High-Efficacy Therapy in Multiple Sclerosis • Retrospective international observational study • Two distinct registries (MSBase registry and the Swedish MS registry) • Evaluate patients on high-efficacy therapy with complete data from diagnosis to at least 6 years. • High-efficacy therapies included rituximab, ocrelizumab, alemtuzumab, mitoxantrone, and natalizumab. • Compare patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset.

Lancet Neurol 2020 Apr; 19:307 Early vs. Late High-Efficacy Therapy in Multiple Sclerosis • Matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. • Primary outcome was disability, measured with the Expanded Disability Status Score at 6–10 years after disease onset, assessed with a linear mixed-effects model.

Lancet Neurol 2020 Apr; 19:307 Early vs. Late High-Efficacy Therapy in Multiple Sclerosis

Lancet Neurol 2020 Apr; 19:307 Treat MS Study-PCORI

• Treat MS study --PCORI funded randomized, controlled studies • High risk group vs low risk group • High efficacious vs platform DMT • Aim 1: To evaluate higher risk vs. lower risk patients for disability accumulation, whether an “early aggressive” therapy approach, versus starting with a lower-efficacy therapy • Aim 2: To evaluate lower risk patients who start on first-line MS therapies but experience breakthrough disease, those who switch to a higher-efficacy therapy versus a new first-line therapy Treat MS Study-PCORI