Highlights from the AAN 2015 Annual Meeting

MS ECHO: Highlights from the AAN 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 AAN 2015 Annual Meeting • Discuss the importance of presented research as related to current clinical practice MS relapse, disability progression after

stopping DMT • Prospective study from MSBase (30,000 patients globally - observational registry for MS) • 303 eligible patients, age 40 and older at time of discontinuation • No relapses or EDSS progression in prior 5 years • DMT for at least 3 years • Followed 3 years after stopping DMT

Kister I. et al. MS relapse, disability progression after stopping DMT (cont.)

• 198 of 303 restarted DMT (65.4%) – subsequent 46% risk reduction in 3 month sustained disability progression – Rate of restarting decreased by 25% for every 10 year increase in age – Gender, age of onset, history of subsequent relapse, and identity of DMT were not associated with rate of DMT restart • Subgroup of 181 patients (?criteria of subgroup) – 24% relapsed – 32% with EDSS 3 month sustained progression (1.5 steps if baseline 0; 1 step if baseline 0.5 – 5.5; 0.5 step if baseline 6 – 6.5) – 10.6 % both

Kister I. et al.

High dose biotin in progressive MS • Background – biotin is water-soluble vitamin, coenzyme for carboxylases involved in energy metabolism and fatty acid synthesis – Activates acetylCoA carboxylase, potentially key-enzyme in myelin synthesis – Previous open-label study (n=23) found high dose biotin (100-600 mg/d; RDA is 30-100 mcg/d) resulted in progressive/sustained improvement of disability in PPMS/SPMS • Methods – Randomized, double-blind, multi-center, placebo controlled (2:1) of oral biotin, 300 mg/d – SPMS or PPMS patients, EDSS 4.5-7, EDSS progression in previous 2 yrs – Treatment duration 48 wks – Primary endpoint – proportion improved at M9 and confirmed at M12 Tourbah A. et al. High dose biotin in progressive MS (cont.) • Results – Patient demographics - 154 pts (41% PPMS; 59% SPMS)16 sites: mean age – 51.4 yrs; mean disease duration 16.6 yrs; mean EDSS – 6.1 – 12.6% of biotin treated patients met endpoint (1 point for baseline /=6.0 OR 20% improvement on timed 25-ft walk) vs 0% for placebo group (p=0.0051) – Overall improvement in EDSS of -0.03 vs. 0.13 in placebo (p=0.014) – 4% of biotin group progressed on EDSS vs. 13% on placebo (p=0.07) – Well tolerated; SAE of hyperthyroidism in 5% Tourbah A. et al. Safety and efficacy of extended dose

natalizumab in MS • Hypothesis – less frequent dosing may result in sub- maximal α4β1-integrin receptor saturation, adequate to exclude auto-reactive T-cells from CNS entry but sufficiently permissive to enable CNS lymphocyte scavenging of JC virus to occur • Methods – recurrent retrospective chart review of NTZ treated patients from 6 MS Centers stratified in 4 groups – Standard dosing (n = 674) – Early extended dosing (n = 231) – q4-7 weeks – Late extended dosing (n = 245) – q7-8.5 weeks – Variable extended dosing (n = 208) – alternating EED and LED

Zhovtis Ryerson L. et al. Safety and efficacy of extended dose

natalizumab in MS (cont.) • Results – groups show comparable efficacy across bot clinical and radiological measures – ED groups show annualized relapse rate of 0.12 compared to 0.14 for SD group – 83% of ED groups with no radiologic activity vs 82% in SD cohort – 2 PML cases in SD; 0 cases in ED groups (861 JCV antibody positive person years – need 1248 for statistical significance)

Zhovtis Ryerson L. 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. The topographical model of multiple sclerosis: a

new visualization of disease course

• Objective – develop a new unified MS clinical course model – Account for inflammatory and neurodegenerative processes as well as heterogeneity • Model design encapsulates 5 factors – Topographical distribution of lesions – Relapse frequency, severity, and recovery – Progression rate

Krieger SC. The topographical model of multiple sclerosis: a new visualization of disease course (cont.)

Krieger SC. 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. 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 Kappos L. 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)

Kappos L. 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. References

• 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. • Kappos L. et al. Abstract S4.003. Daclizumab HYP versus interferon beta-1a in relapsing-remitting multiple sclerosis: primary results of the DECIDE study. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C.

References

• Kister I. et al. Abstract P5.192. ‘Doctor, can I stop my medicine?' Analysis of disease course after stopping disease-modifying therapy in stable MS patients. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C. • Krieger SC. Abstract P4.013. The topographical model of multiple sclerosis: a new visualization of disease course. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C. • Tourbah A. et al. Abstract PL2.002. Effect of MD1003 (high doses of biotin) in progressive multiple sclerosis: results of a pivotal phase III randomized double blind placebo controlled study. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C. • Zhovtis Ryerson L et al. Abstact P3.267. Safety and efficacy of extended dose natalizumab in multiple sclerosis: an ongoing multicenter study. Presented at: American Academy of Neurology Annual Meeting 2015; April 18-25, 2015; Washington, D.C.

Dr. Mitchell’s Case

• 42 yo male • Uncertain initial clinical picture • MRI brain – multiple enhancing lesions • Started avonex • Also amantadine for fatigue; baclofen for spasticity Dr. Mitchell’s Case (cont.)

• 4/2002 – f/u MRI – no enhancement; slight progression in size/number • 2010 – stable visual complaints; trial of IV steroids for R leg numbness/increased instability – no response noted; viagra added

Dr. Mitchell’s Case (cont.)

• 2015 – stable visual field cut, gradual progression of visual “fuzziness” – not particularly interested in changing DMT • Exam unremarkable except visual field cut • MRI – numerous lesions; single enhancing lesions near R lat vent

Dr. Mitchell’s Case (cont.)

• Questions: – What is reasonable frequency for MRI monitoring? – Is single enhancing lesion reason to change? If so, to what? – Is it reasonable for community internist to sign up for the Tysabri TOUCH program?

Jamie Barns week 11 case - update

Jamie Barn’s case • 63 yo female • Otherwise healthy on ASA, MVI, Vit D • Clinical presentation – – 2 months dizziness on changing positions – Dizzy on/off for a few years – Dull ache LLE with sitting; “charlie horse” left calf – Hx wavy lines in vision followed by dull h/a; trouble remembering names; numb hands 15 min once – PMHx – concussion 20 yrs ago Jamie Barn’s case (cont.)

• Exam – 4/5 L hip flexor, otherwise WNL • MRI – 12/2014 – white matter changes c/w MS • CSF – positive OCBs; VEPs - WNL • Labs – vitamin D – 19; ANA – pos (1:40) • could this be CIS or could her symptoms of tingling/squeezing represent ongoing symptoms? • treatment plan to start Copaxone appropriate?

Dr. Kieran Case

• 61 year old female • Diagnosed with RA 2 years ago • Initially on MTX and then switched to adalimumab (Humira) in 2014 • RA symptoms dramatically improved Dr. Kieran Case (cont.) • 9 months after treatment started with adalimumab - developed saddle anesthesia that spread to all extremities • Brain MRI - 9 enhancing lesions in the subcortical white matter • Spine MRI - enhancing lesions in the cervical spine and conus medularis • CSF was unremarkable (not completely done for an MS profile). • Symptoms have almost completely resolved at this point after a course of IV and oral steroids

Dr. Kieran Case (cont.) Questions • Does she have MS? • Can TNF inhibitors per se cause this? • Would anyone treat with DMTs? • Would further testing be helpful now or in the future if she has no further symptoms?