Phase 1 Studies of the Anti-Tau Monoclonal Antibody JNJ-63733657 in Healthy Participants and Participants with Alzheimer’s Disease

Background JNJ-63733657 (posdinemab) is a humanized IgG1/kappa monoclonal anti-phospho tau antibody that binds with high affinity to phosphorylated amino acid 217 (pT217) in the proline-rich domain. The parent molecule, PT3, was raised against Alzheimer’s disease brain purified paired helical filament, and preclinical studies with the humanized version, JNJ-63733657, have demonstrated reductions in tau seeding. The results of the first-in-human clinical trial of JNJ-63733657 and a separate single ascending dose study in Japanese participants are presented. Objectives To evaluate the safety and tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of JNJ-63733657 after single and multiple intravenous dose administrations in healthy participants and participants with prodromal or mild Alzheimer’s disease. Design A two part first-in-human, phase 1, randomized, double-blind, placebo-controlled trial: Single ascending dose (Part 1) and multiple ascending dose (Part 2). And a phase 1, randomized, double-blind, placebo-controlled single ascending dose trial in healthy Japanese participants. Setting 7 sites in Belgium, Netherlands, Spain, and Germany; 1 site in Japan. Participants A total of 40 healthy participants aged 55–75 were enrolled in Part 1 of the first-in-human study; a total of 16 healthy participants and 13 participants with prodromal or mild AD aged 55–80 years were enrolled in Part 2. In the Japanese trial, a total of 24 participants aged 55–75 were enrolled. Intervention In Part 1, single doses of 1, 3, 10, 30, or 60 mg/kg of JNJ-63733657 or placebo were administered to healthy participants. In Part 2, two dose levels of JNJ-63733657 (5 mg/kg or 50 mg/kg) or placebo were evaluated in healthy participants, and 2 dose levels (15 mg/kg or 30 mg/kg) or placebo were evaluated in participants with Alzheimer’s disease; doses were administered on Days 1, 29, and 57. In the Japanese trial, single doses of 3, 15, or 60 mg/kg of JNJ-63733675 or placebo were administered. All doses were administered intravenously. Measurements Safety assessments, serum and cerebrospinal fluid pharmacokinetic parameters, immunogenicity, and cerebrospinal fluid pharmacodynamic changes in free and total p217+tau, total tau, and p181tau were evaluated. Results JNJ-63733657 was generally safe and well-tolerated in healthy participants and participants with Alzheimer’s disease. In healthy participants and participants with Alzheimer’s disease, JNJ-63733657 demonstrated