brains&GAINS November 2, 2013 9-12 a.m. Center For Tomorrow UB Dept of Neurology UBMD Neurology/JNI http://ubnjacobsneuro.wordpress.com/home/ https://www.facebook.com/UBMDNeurology @wolfegil

Gil I. Wolfe, MD Irvin and Rosemary Smith Professor and Chair since Jan 2012 9 new Dept. of Neurology faculty 3 stroke 1 multiple sclerosis 1 adult epilepsy 1 child neurology 1 neurocritical care 2 neuroimaging (100% research) Clinical and investigative career in neuromuscular medicine Myasthenia Gravis (MG) ECU-MG-301: Double-blind, placebo –controlled trial of eculizimab in refractory generalized MG Clinical chair of international, NIH supported study of thymectomy in MG Peripheral Neuropathy GBS longitudinal follow-up study (IGOS) Others INSIGHTS IV immunoglobulin usage patterns across U.S.

Aging, Alzheimer’s Disease & Memory Kinga Szigeti, MD, PhD Director, Memory Disorders Program

Disease Classification Motor neuron Neuronopathies & Neuropathies ALS, PLS, SMA, diabetic neuropathy, toxic neuropathy, GBS, CMT Axon Myelin Neuromuscular Junction Disorders MG, botulism NMJ Myopathies Muscular dystrophy, polymyositis, dermatomyositis, IBM Muscle

Eculizimab in MG Monoclonal antibody that binds complement C5, preventing cleavage to C5a Complement activation is key component to damage of muscle membrane in MG Cobra venom blocks complement and prevents induction of experimental autoimmune MG (EAMG) Membrane attack complex (MAC) present on muscle membrane in EAMG animals and MG patients Up to 10% of MG patients refractory

MG and complement-mediated injury Control AChRAb MuSKAb MuSKAb Shiraishi et al. Ann Neurol 2005;57:289 (biceps biopsies)

Phase II Study of Eculizimab n=14 (30-72 yrs) AChRAb+ and failed 2 immunosuppressives, including prednisone, for ≥ 1 yr No IVIg for 8 weeks or plasma exchange for 12 weeks Results Reduction by >3 QMG points during eculizimab vs. placebo marginally significant (p=0.0577) Side effects Mild to moderate Nausea, back pain, headache, pharyngitis 3 serious adverse advents on both active and placebo treatment Howard JF et al. Muscle Nerve 2013;48:76--84 600 mg IV qwk for 4 wks 900 mg IV at 5th q2wks for 12 wks

ECU-MG-301: Eculizimab in refractory generalized MG Phase 3, randomized (1:1), double-blinded, placebo-controlled trial Treatment duration 26 wks AChRAb+, age ≥ 18 yrs MG-ADL score ≥ 6 MG-ADL is the primary outcome measure QMG, MGC, QOL also measured Failed ≥2 immunotherapies for at least 1 yr No IVIg or PE within 4 wks Can continue on current immunosuppressive treatments without dose changes