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Tau accumulation in patients with Alzheimer's disease tracks closely with cognitive decline and plays a role in the later stages of disease progression. This phase 2 study evaluated the safety and efficacy of tilavonemab, an anti-tau monoclonal antibody, in patients with early Alzheimer's disease. In this 96-week, randomized, double-blind, placebo-controlled study (NCT02880956), patients aged 55-85 years meeting clinical criteria for early Alzheimer's disease with a Clinical Dementia Rating-Global Score of 0.5, a Mini-Mental State Examination score of 22 to 30, a Repeatable Battery for the Assessment of Neuropsychological Status-Delayed Memory Index score of ≤85, and a positive amyloid PET scan were randomized 1:1:1:1 to receive one of three doses of tilavonemab (300 mg, 1000 mg, or 2000 mg) or placebo via intravenous infusion every 4 weeks. The primary end point was the change from baseline up to Week 96 in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Safety evaluations included adverse event monitoring and MRI assessments. A total of 453 patients were randomized, of whom 337 were treated with tilavonemab (300 mg, n = 108; 1000 mg, n = 116; 2000 mg, n = 113) and 116 received placebo. Baseline demographics and disease characteristics were comparable across groups. The mean age was 71.3 (SD 7.0) years, 51.7% were female, and 96.5% were White. At baseline, the mean CDR-SB score was 3.0 (1.2), which worsened through Week 96 for all treatment groups. The least squares mean change from baseline at Week 96 in the CDR-SB score with tilavonemab was not significantly different compared with placebo [300 mg (n = 85): -0.07 (95% confidence interval, CI: -0.83 to 0.69); 1000 mg (n = 91): -0.06 (95% CI: -0.81 to 0.68); 2000 mg (n = 81): 0.16 (95% CI: -0.60 to 0.93); all P ≥ 0.05]. The incidence of any adverse event and MRI findings were generally comparable across groups. Tilavonemab was generally well tolerated but did not demonstrate efficacy in treating patients with early Alzheimer's disease. Further investigations of tilavonemab in early Alzheimer's disease are not warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Alicapistat is an orally active selective inhibitor of calpain 1 and 2 whose overactivation has been linked to Alzheimer disease (AD). Three studies were conducted in healthy subjects (18-55 years), 1 in healthy elderly subjects (≥65 years), and 1 in patients with mild to moderate AD. Four studies assessed pharmacokinetics, 1 study in healthy subjects assessed pharmacodynamics (sleep parameters, particularly rapid eye movement [REM], as a measure of central nervous system [CNS] penetration and activity), and all studies assessed safety. Participants received single doses or multiple twice-daily doses of alicapistat for up to 14 days. Maximum alicapistat plasma concentrations were reached in 2 to 5 hours; half-life was 7 to 12 hours postdose. Alicapistat exposure was dose proportional in the alicapistat 50- to 1000-mg dose range. Exposure of the alicapistat R,S diastereomer was approximately 2-fold greater than exposure of the R,R diastereomer in healthy young and elderly subjects and patients with AD. Alicapistat at 400- or 800-mg twice-daily doses had no effect on REM sleep parameters, whereas the active control, donepezil at 10 mg twice daily, affected sleep parameters. Across all trials, the incidence of treatment-emergent adverse events was similar in the placebo and alicapistat groups. There were no clinically significant changes in vital signs and laboratory measurements. The lack of an effect of alicapistat on sleep suggests that concentrations in the CNS were inadequate or that preclinical studies do not predict alicapistat effects in humans., (© 2018, The American College of Clinical Pharmacology.)