A Single-Center, Randomized, Double-Blind, Placebo-Controlled, Six-Month Clinical Trial Followed by an Open-Label Extension to Evaluate the Safety, Tolerability and Clinical Endpoint Responsiveness of the Phosphodiesterase Type 4 (PDE4) Inhibitor Ibudilast (MN-166) in Subjects with Amyotrophic Lateral Sclerosis (ALS) - STEP-IBUDILAST-ALS-DB-OLE-1 (S50.005)

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OBJECTIVE: Ibudilast inhibiting PDE4(A)/PDE4(B)/PDE4(C)/PDE4(D) with IC50 values of 0.05μM/0.06μM/0.24μM/0.17 μM respectively, administered with Riluzole is safe/tolerable in ALS patients and improves ALS function and/or delays ALS progression. BACKGROUND: Vitamin E-promotes riluzole treatment by decreasing progression from early to middle stage of ALS(Desnuelle,2001)and decreasing loss of some functional measures(Graf,2005) without any added survival benefit. Riluzole slows the rate of loss of ALSFRS-R by 25-28[percnt] administered at 50mg-twice-daily achieving levels of 30-1552ng/mL[0.15-6.6 μM](Groeneveld,2003). Tissue levels are 10-fold higher(Milane, 2009) providing in vivo levels that permit pharmacological activities including CREB-mediated enhancement of neurotrophic factors(Tsuchioka,2011)/glutamate transport activation(Hayashida,2010). Ibudilast chronic daily oral administration at 30mg-twice-daily in humans achieves peak[0.25 μM] and trough[0.15 μM]serum levels(Yoon,2009)with higher brain and spinal cord levels(Sanftner, 2009). Ibudilast pharmacological mechanisms that may add to riluzole-induced CREB-mediated treatment effects include reduction in TNFalpha production by activated microglia(Kiebala,2011, Hama,2012) and astroctyes(Yoshikawa,2002)as well as inhibition of matrix metalloproteinase-9(Yagi,2010)which may be a key factor in ALS progression(Kaplan,2014). DESIGN/METHODS: ALS patients(40 subjects-MN-166 group; 20 subjects-placebo group)will be entered. Safety, tolerability, muscle strength, ALSFRS-R and respiratory function will be assessed at baseline, 3 and 6 months post randomization with monthly telephone follow-up. Upon completion of the Double-blind Phase, subjects randomized to the placebo arm will continue for an additional six months and will receive open-label MN-166. RESULTS: Patients have entered at 3-5 per week with assistance from the Center for Disease Control-Agency for Toxic Substances and Disease Registry National ALS Registry ALS Research Notification for Clinical Trials and Studies mechanism that has provided 20 patients per week for screening. CONCLUSIONS: Interim evaluation of the primary objective-safety/tolerability and secondary objective-clinical endpoint responsiveness of MN-166 60 mg/day versus placebo administered for six months with riluzole in subjects with ALS will be presented for the first 30 patients. Study Supported by: Medicinova and Carolinas ALS Research Fund

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