Multiple Ascending Dose Study of the Tau-Directed Monoclonal Antibody BIIB092 in Patients with Progressive Supranuclear Palsy (S27.004)

Objective: To assess the safety, tolerability, pharmacokinetic and pharmacodynamic effects of BIIB092 (formerly BMS-986168) on free extracellular tau (eTau) after every 4 week intravenous infusions (Q4W) in patients with progressive supranuclear palsy(PSP). Background: BIIB092 is a humanized monoclonal antibody that binds to tau at the N-terminal domain. In a phase I study, single dose BIIB092 (up to 4200 mg) safely and effectively suppressed free eTau in healthy subject CSF. Design/Methods: Randomized, double-blind, placebo-controlled, multiple ascending dose trial in 48 patients with PSP. In each cohort, BIIB092 (150 mg, 700 mg, or 2100 mg) or placebo was administered in a 3:1 ratio (n=8 patients/cohort) intravenously Q4W for 12 weeks; an additional expansion panel (24 patients) received 2100 mg or placebo Q4W for 12 weeks. After 12 weeks, completed participants were eligible for an open-label extension study. Safety assessments and serum and CSF samples were collected over 12 weeks. Pharmacokinetic parameters (serum and CSF) and absolute and percent change from baseline in pharmacodynamic measures (concentrations of CSF free eTau) were evaluated. Results: Mean age was 67.4 ± 5.5 years; 54.2% were female. BIIB092 serum and CSF concentrations increased with dose. Mean suppression of CSF free eTau was ~90–96% (Day 29) and 91–97% (Day 85). There were no deaths or discontinuations due to AEs. The percentages of patients experiencing adverse events (AEs) were similar in the treatment and placebo groups (~75%); most were mild and unrelated to study drug. Conclusions: Administration of multiple doses of BIIB092 was safe and well tolerated at doses up to 2100 mg in patients with PSP. The suppression of CSF free eTau concentrations in this study is consistent with target engagement in the CSF and further supports the potential utility of BIIB092 in the treatment of human tauopathies. Research is ongoing in PSP (efficacy, NCT03068468) and in development for Alzheimer’s disease. Study Supported by: The study was funded by Bristol-MyersSquibb, Lawrenceville, NJ, USA and Wallingford, CT, USA. Writing and editorial support for the preparation of this poster was provided by Excel Scientific Solutions (Southport, CT, USA): funding was provided by Biogen. Disclosure: Dr. Boxer has nothing to disclose. Dr. Qureshihas received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BMS, Biohaven. Dr. Qureshiholds stock and/or stock options in former BMS employee: Biohaven Pharmaceutical employee. Dr. Grundman holds stock and/or stock options in Prothena Biosciences Inc., which sponsored research in which Dr. Grundman was involved as an investigator. Dr. Grundman has received research support from Prothena Biosciences Inc. Dr. Tirucherai has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of BMS. Dr. Tirucherai holds stock and/or stock options in BMS. Dr. Bechtold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BMS. Dr. Ahlijanian has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BMS employee,. Dr. Ahlijanian has received research support from Bristol-MyersSquibb, Pinteon Therapeutics, FORMA Therapeutics. Dr. Kolaitis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BMS employee. Dr. Kolaitis holds stock and/or stock options in BMS, which sponsored research in which Dr. Kolaitis was involved as an investigator. Dr. Kolaitis holds stock and/or stock options in BMS. Dr. Golbe has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BMS, AbbVie, USB. Dr. Golbe has received research support from research funds went to university. Dr. Honig has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Miller Medical Communications (webinar presenter). Dr. Honig has received personal compensation in an editorial capacity for JAMA Neurology (assoc. ed). Dr. Isaacson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultancy and/or promotional speaker fees: Acadia, Acorda, Adamas, Allergan, Amarantus, Biotie, Britannia, Cynapsus, GE Pharma, Impax, Ipsen, Kyowa, Lundbeck, Teva, UCB, and US WorldMeds. Research funding: AbbVie, Acadia, Acorda, Adamas, Addex, Allergan. Dr. Grossmanhas received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GE Whitney. Dr. Grossmanhas received personal compensation in an editorial capacity for Neurology. Dr. McFarland has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis. Dr. Litvan has received personal compensation for serving onthe scientific steering committeeof the Biotie/Parkinson Study Group clinical trial Dr. Geldmacher has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Axovant, BrownGreer, Clearview Partners, Grifols, Pennside Partners. Dr. Geldmacher has received research support from Abbvie, Avanir, Biogen, BMS, Eisai, Janssen, Lilly, Lundbeck. Dr. Xie has nothing to disclose. Dr. Bordelon has nothing to disclose. Dr. Tuite has nothing to disclose. Dr. O9Suilleabhain has received research support from BMS. Dr Zesiewicz has nothing to disclose.