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AIMThe objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. METHODSSingle doses (0.1, 0.3,1,3,10, and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. RESULTSABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4-to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. CONCLUSIONSBased on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Histamine H3 receptor antagonists increase the release of the brain neurotransmitters that are known to modulate cognitive processes. H3 receptor antagonists have demonstrated pro-cognitive effects in preclinical studies. ABT-288 is a highly selective histamine H3 receptor antagonist designed for symptomatic treatment of cognitive disorders. WHAT THIS STUDY ADDS• In the present article, we present the safety, tolerability and pharmacokinetics of ABT-288 in healthy young adults and in elderly human subjects. Results from these trials, along with preclinical data, were the basis for advancing ABT-288 to proof-of-concept phase 2 evaluation in Alzheimer's disease and the presented studies guided dose selection for phase 2 testing. In general, results presented in the current article provide the most comprehensive characterization of the safety and tolerability profiles of pharmacological H3 receptor antagonism in young adults and elderly human subjects.

Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

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 four weeks. The primary endpoint was the change from baseline up to Week 96 in the Clinical Dementia Rating-Sum of Boxes 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 (standard deviation [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.

AIMSABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. METHODSThis was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. RESULTSOf the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. CONCLUSIONSABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake.