MS ECHO: Highlights from the Consortium of Multiple Sclerosis Centers 2015 Annual Meeting Gary Stobbe, MD Medical Director, MS Project ECHO Clinical Assistant Professor, UW Neurology Conflicts of Interest • Dr. Stobbe has no conflicts of interest to disclose Objectives • Review topics of interest presented in posters and oral presentations at the CMSC 2015 Annual Meeting as well as AAN 2015 Annual Meeting • Discuss the importance of presented research as related to current clinical practice Benefits of Alemtuzumab when switching DMTs • Prospective, open label study (60 patients) – Median EDSS 5-5.5 – Short-term follow-up group (median – 10 mo; n-30) and long- term group (median – 82 mo; n-30) • EDSS improved by 0.4 in short-term group and by 1.0 in long-term group – Improvement seen with all prior DMTs (interferon-beta & glatiramer – 0.9, 82 mo; fingolimod – 0.4, 12 mo; natalizumab – 0.5, 49 mo) • Limitations – no MRI data; no patient-reported outcomes Hunter SF et al. Daclizumab HYP vs interferon Beta-1a in RRMS: primary results of the DECIDE study • Daclizumab high yield process (DAC HYP) – humanized monoclonal antibody against CD25, results in reversible modulation of IL-2 signaling • Study design – randomized, double-blind, active- controlled DAC HYP 150 mcg sq q4wks vs IFNβ-1a 30 mcg IM qweekly for 96-144 wks; 1° endpoint – annualized relapse rate (ARR) • Demographics – N=1841; mean age 36.3; mean EDSS 2.5; 41% prior DMT use Kaufman M. et al. Daclizumab HYP vs interferon Beta-1a in RRMS: primary results of the DECIDE study (cont.) • Results – – 45% reduction in the ARR (p<0.0001) – 41% reduction in proportion of patients that relapsed (p<0.0001) – 54% reduction in # of new/enlarging T2 lesions (p<0.0001) – 3-month confirmed disability reduction of 16% (p=0.158) – Improvement seen in all components of the MSFC and the SDMT (P=0.0274) Kaufman M. et al. BMI correlates with risk of MS disease progression • 150 patients (45.5 yrs, 79% female), retrospective analysis • 30% obese, 27% overweight • Logistic regression analysis of baseline BMI and MS progression over 5 years (EDSS, new MRI lesions, relapse rate, and timed 25-ft walk) • Controlling for age, gender, race, disease duration, MRI change, relapse rate, and MS type – odds 8x greater for obese patients in progressing EDSS by 1 point (p = 0.017); 6.2x greater for obese patients in having new brain MRI lesions (p < 0.0001) • Study does not inform causative relation • Others studies showing higher weight in youth associated with greater risk of developing MS and an earlier age of onset Ben-Zacharia A. et al. Current marijuana use by MS patients • Survey offered to participants of the North American Research Committee on Multiple Sclerosis (NARCOMS; 12,260 participants) • 5,665 respondents (78.3% women, mean age – 55.5 yrs); RRMS at onset – 90.2% (26.5% with relapse in past 2 years – “active”; 42.8% stable, 20.9% SPMS); PPMS were older, more men, and more disabled • Disability determined by Patient-Determined Disability Steps (PDDS) • 16% of all participants reported current marijuana use • Adjusted for age and gender, RRMS-S least likely for current marijuana use • PDDS of 0 less likely for current marijuana use (PDDS of 1 less likely than PDDS of 2-5) Cofield SS. Et al. Lymphopenia with Dimethyl Fumarate • Cross-sectional analysis of patient samples – patients stable (> 6 mo) on dimethyl fumarate (n-144), treatment-naïve MS patients, and healthy controls • Lymphopenia defined as < 800 (grade 2 or worse) – 14% of patients with persistent grade 2 or 3 lymphopenia (6% grade 3, ALC<500) – 4/14 (28.6%) grade 3 treated over 12 months – more common in patients over 55 (older patients excluded from phase III trials) • Prior DMT type did not influence • 1 patient with cellulitis • Multiple lymphocyte populations effected including CD4+ and T- reg; most profound was CD8+ which were almost entirely lost Longbrake EE et al. Anti-LINGO-1 monoclonal Ab (BIIB033) in acute optic neuritis: the RENEW trial • Background – LINGO-1 is a CNS-specific membrane glycoprotein that suppresses oligodendrocyte differentiation and myelination – BIIB033 is a fully human monoclonal Ab selectively antagonizes LINGO- 1 – Effective remyelination in preclinical studies; safe and well tolerated in Phase I trials • Methods – randomized, double-blind, placebo-controlled, parallel-group of patients with first episode of unilateral AON; – 18-55 yrs old (N=82) – BIIB033 100 mg/kg IV q4wks vs placebo x 6 doses Cadavid D. et al. Anti-LINGO-1 monoclonal Ab (BIIB033) in acute optic neuritis: the RENEW trial • Results – 34% improvement in EP latency recovery vs placebo week 24 (p=0.05) – 41% improvement in EP latency recovery vs placebo week 32 (p=0.01) – No effect on retinal layer thickness or vision (measured by low contrast letter acuity) – AEs – fatigue, nausea, paresthesia; 2 cases of hypersensitivity; 1 case of elevated LFT Cadavid D. et al. Spontaneous remyelination has a major impact on clinical disability in MS: a PET study • Objectives – quantitative imaging of remyelination is needed to understand disease pathophysiology and evaluate potential remyelinating therapies – positron emission tomography (PET) with the marker [11C]-PIB is shown to bind myelin in the CNS • Methods – 24 patients with active MS underwent MRI and PET at baseline and again at 2 or 4 months – myelin content in T2 lesions determined – dynamic demyelination and remyelination was determined in comparing baseline to subsequent image – each index was correlated with the EDSS and MS Severity Scale Bodini, B. et al. Spontaneous remyelination has a major impact on clinical disability in MS: a PET study (cont.) • Results – index of dynamic demyelination did not correlate with EDSS or MSSS – Index of dynamic remyelination showed strong correlation with EDSS (r=-0.8, p=0.0001) and MSSS (r=-0.57, p=0.009) Bodini, B. et al. High dose vitamin D supplementation in MS patients • Objective – determine the effect of vitamin d on cytokine production and memory phenotype of CD4+ T-cells • Background – vitamin D is a potent in vitro immunomodulator, but little in vivo data • Design – peripheral blood mononuclear cells isolated at baseline and 6 months in a randomized, double- blind study of low (800 IU/day; n=17) vs high dose (10,400 IU/day; n=15) vitamin D in 32 MS patients Bhargava P. et al. High dose vitamin D supplementation in MS patients (cont.) • Results – – baseline demographic/immunologic markers similar between groups – Rise in serum vit D level, high vs low dose – 33.67 ng/mL vs 5.35 ng/mL (p<0.0001) – 3.27% decrease from baseline in IL-17+ CD-4+ cells in high dose (p<0.027); no change in low dose group – 10.4% decrease in T-effector memory cells in high dose (p<0.013); no change in low dose group – Correlation seen between rise in serum vit D levels and reduction in IL-17 production (only seen in patients with rise > 20ng/mL) • Future direction - 2 large clinical trials underway Bhargava P. et al. References • Ben-Zacharia A. Abstract DX12. The effects of body-mass index on multiple sclerosis progression. Presented at: Consortium of Multiple Sclerosis Centers Annual Meeting 2015; May 27-30, 2015; Indianapolis, IN. • Bhargava P et al. Abstract S38.001. High-dose vitamin D supplementation reduced IL-17-producing CD-4+ T-cells and effector-memory CD-4+ T-cells in multiple sclerosis patients. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C. • Bodini B. et al. Abstract S29.008. Spontaneous remyelination has a major impact on clinical disability in multiple sclerosis: a longitudinal PET study with 11C-PIB. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C. • Cadavid D. et al. Abstract P7.202. Efficacy analysis of the anti-LINGO-1 monoclonal antibody (BIIB033) in acute optic neuritis: the RENEW trial. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C. References (cont.) • Cofield SS. Et al. Oral Presentation DX02. Current marijuana usage by multiple sclerosis status and disability in the NARCOMS registry. Presented at: Consortium of Multiple Sclerosis Centers Annual Meeting 2015; May 27-30, 2015; Indianapolis, IN. • Hunter SF et al. Oral Presentation DX03. Alemtuzumab (ALE) improves disability after switch from other disease modifying therapies in a high disability treatment-refractory relapsing MS cohort. Presented at: Consortium of Multiple Sclerosis Centers Annual Meeting 2015; May 27- 30, 2015; Indianapolis, IN. • Kaufman M. et al. Oral Presentation DX01. The effect of daclizumab high- yield process (DAC HYP) on patient-centered functional outcomes: results from the DECIDE study. Presented at: Consortium of Multiple Sclerosis Centers Annual Meeting 2015; May 27-30, 2015; Indianapolis, IN. • Longbrake EE et al. Abstract DX49. Dimethyl fumarate effects on lymphocyte phenotype. Presented at: Consortium of Multiple Sclerosis Centers Annual Meeting 2015; May 27-30, 2015; Indianapolis, IN. Jean Thomas’s Case • 62 yo Female with memory complaints and abnormal MRI • One year hx: forgets how to spell and stops in mid sentence with loss of thought. Forgets long known procedures at work • Works as a claims representative for S.S. • Supervisor told her she is not fast enough Jean Thomas’s Case • Age 42 saw neurologist for headaches. Work up revealed MRI that she says “ it looked like I started to get MS but didn’t, there were some little white spots but he couldn’t find anything wrong” • No LP at that time • Denies any symptoms in adult life of focal numbness, weakness, tingling, unilateral loss of vision, diplopia, perineal numbness, vertigo • She is exhausted when she gets home from work daily • Family history pos for Mom and Maternal Grandfather with dementia • PMH: severe depression-well controlled • Diabetes & Metabolic syndrome • Neurologic exam normal.