Interim Analyses of Fixed-Dose and Titration Cohorts from PRIME: A Randomized, Double-Blind, Placebo-Controlled Phase 1b Study of Aducanumab (S9.006)

Objective: We report 36-month data from fixed-dose and titration cohorts and 48-month data for fixed-dose cohorts from the ongoing PRIME study. Cumulative safety data is presented. Background: Aducanumab is a human monoclonal antibody that binds to both soluble and insoluble aggregated forms of amyloid beta, including oligomers, protofibrils, and fibrils. PRIME (NCT01677572) is an ongoing Phase 1b study evaluating aducanumab in patients with prodromal AD and mild AD dementia. Design/Methods: During the 12-month placebo-controlled period of PRIME, patients (aged 50–90; positive florbetapir PET scan) were randomized to placebo or fixed-dose aducanumab (1, 3, 6, or 10 mg/kg), stratified by ApoE-e4 status (q4w; 52 weeks). An added cohort of ApoE-e4 carriers received aducanumab titrated to 10 mg/kg or placebo. In the long-term extension (LTE), all patients received aducanumab (3, 6, or 10 mg/kg, fixed or titrated). Except safety, LTE endpoints were exploratory. Results: Amyloid plaque levels (SUVR change from baseline) decreased in a dose- and time-dependent manner in patients receiving aducanumab over 36 or 48 months. CDR–SB and MMSE data suggest continued clinical benefit in patients continuing aducanumab in the LTE. Since the start of PRIME, 46 of 185 (25%) patients dosed with aducanumab experienced ARIA-E, and of those patients, the majority (61%) were asymptomatic. When they occurred, symptoms associated with ARIA-E were typically mild to moderate in severity. 8 patients experienced more than one ARIA-E event. The clinical and imaging characteristics of recurrent ARIA were similar to the ARIA previously reported in the PRIME study; typically asymptomatic, and most patients continued the study. Conclusions: In patients treated with aducanumab in the PRIME LTE, amyloid plaque levels continued to decrease, and analyses of clinical endpoints suggest continued benefit. The safety profile of aducanumab remains unchanged. These data continue to support investigation of aducanumab in the Phase 3 trials ENGAGE and EMERGE. Disclosure: Dr. Castrillo-Viguera has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Castrillo-Viguera has received research support from Biogen. Dr. Budd Haeberlein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Budd Haeberlein holds stock and/or stock options in Biogen. Dr. Von Rosenstiel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Von Rosenstiel holds stock and/or stock options in Biogen. Dr. Chen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Chen has received personal compensation in an editorial capacity for Shareholder of Biogen. Dr. O’Gorman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. O’Gorman holds stock and/or stock options in Biogen. Dr. Rajagovindan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Rajagovindan holds stock and/or stock options in Biogen. Dr. Patel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Patel holds stock and/or stock options in Biogen which sponsored research in which Dr. Patel was involved as an investigator. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Wang holds stock and/or stock options in Biogen which sponsored research in which Dr. Wang was involved as an investigator. Dr. Chalkias has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Chalkias holds stock and/or stock options in Biogen. Dr. Skordos has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Skordos holds stock and/or stock options in Biogen which sponsored research in which Dr. Skordos was involved as an investigator. . Dr. Prada has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Prada holds stock and/or stock options in Biogen. Dr. Hock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurimmune. Dr. Nitsch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Neurimmune. Dr. Sandrock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Sandrock holds stock and/or stock options in Biogen.