UB Dept of NeurologyUBMD Neurology/JNI

brains&GAINSNovember 2, 20139-12 a.m.Center For Tomorrow

http://ubnjacobsneuro.wordpress.com/home/

@wolfegil

https://www.facebook.com/UBMDNeurology

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

NMJ

Muscle

Axon

Myelin

Motor neuron

Neuronopathies& NeuropathiesALS, PLS, SMA, diabetic neuropathy, toxic neuropathy, GBS,CMT

MyopathiesMuscular dystrophy,polymyositis, dermatomyositis, IBM

Neuromuscular Junction DisordersMG, botulism

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

Shiraishi et al. Ann Neurol 2005;57:289 (biceps biopsies)

Control AChRAb

MuSKAb MuSKAb

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 wks900 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