Aducanumab titration dosing regimen: 24-month analysis from PRIME, a randomized, double-blind, placebo-controlled Phase 1b study in patients with prodromal or mild Alzheimer’s disease (S2.003)

Objective: We report 24-month data for fixed-dose and titration cohorts, including 12 months from the placebo-controlled period and 12 months from the long-term extension (LTE). Background: PRIME is an ongoing Phase 1b study evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics of aducanumab in patients with prodromal or mild AD. Design/Methods: Patients in PRIME, aged 50–90, had a positive florbetapir PET scan, and met clinical criteria for prodromal/mild AD. During the placebo-controlled phase, patients received aducanumab or placebo q4w for 52 weeks. Patients were randomized to fixed doses of aducanumab stratified by ApoE ɛ4 status. A protocol amendment added a cohort of ApoE ɛ4 carriers who received aducanumab titrated to 10 mg/kg or placebo. In the LTE, all patients received aducanumab 3, 6, or 10 mg/kg fixed or titrated. Excepting safety, all LTE endpoints, including measurement of Aβ reduction by PET and changes in clinical endpoints, were exploratory. Results: Consistent with fixed-dose cohorts, patients from the titration cohort continuing aducanumab to 24 months demonstrated reduced brain amyloid plaque levels, which was also observed in patients switching from placebo to aducanumab in the LTE. CDR–SB and MMSE data suggest clinical benefit in patients continuing aducanumab over 24 months. No new patients who continued at the same dose of aducanumab experienced ARIA-E. Four patients experienced more than one ARIA-E episode over 24 months. Recurrent ARIA was consistent with other ARIA reported to date. ARIA-E incidence at 24 months in patients switching from placebo to aducanumab was consistent with that reported at 12 months in active arms. Conclusions: In patients who completed the first year of the LTE, amyloid plaque levels continued to decrease in a dose- and time-dependent manner, and analyses of the clinical endpoints suggest continued benefit. These data support further investigation of aducanumab in ENGAGE/EMERGE Phase 3 trials. Study Supported by: Biogen Disclosure: Dr. Von Rosenstiel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Gheuens has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Chen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. O9Gorman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Chiao has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen; Cytel. Dr. Von Hehn has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Skordos has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with 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. Budd Haeberlein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Sandrock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Sandrock holds stock and/or stock options in Holds stock/options in Biogen.