A Randomized Trial of the Efficacy and Safety of the H3 Antagonist ABT-288 in Cognitive Impairment Associated With Schizophrenia

Abstract

Introduction: ABT-288 is a highly potent histamine-3 receptor antagonist that has demonstrated pro-cognitive effects in preclinical models relevant to schizophrenia. This study evaluated the efficacy and safety of two doses of ABT-288 in the treatment of cognitive impairment associated with schizophrenia. Methods: A randomized, double-blind, placebo-controlled, parallel-group 12-week study was conducted at 23 centers in the United States. Clinically stable subjects with schizophrenia were randomized in an equal ratio to ABT-288 10 mg, ABT-288 25 mg, or placebo once daily while continuing their antipsychotic regimen. The primary efficacy measure was the change from baseline to day 84 evaluation on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) composite score vs placebo. Secondary measures included cognitive functioning and psychiatric scales. Safety assessments and sparse pharmacokinetic sampling were also conducted. Results: A total of 214 subjects were randomized. The mean baseline MCCB composite score was 28.4. Approximately 80% of subjects completed the study. The MCCB composite score mean change from baseline to day 84 was numerically worse for both the 10 mg (1.90, P = .618) and 25 mg (0.64, P = .946) doses of ABT-288 vs placebo (2.19). Results from the secondary measures were consistent with the primary analysis. Subjects' schizophrenia symptoms remained stable throughout the study as evidenced by stable Positive and Negative Syndrome Scale scores. Overall, study medication was tolerated; however, an increased incidence of psychosis-related and sleep-related adverse events was associated with ABT-288. Discussion: Neither dose of ABT-288 resulted in cognitive improvement in clinically stable adults with schizophrenia.

Monoaminergic neuropathology in Alzheimer’s disease

“…Seven H 3 R antagonists showed beneficial effects on cognition in preclinical models: thioperamide, BF2.649, ABT-239, ABT-288, GSK189254, JNJ-10181457 and PF-03654746 (see Table 3; for review, see Brioni et al, 2011). In clinical studies, the H 3 R antagonist ABT-288 was shown to be safe in healthy elderly subjects and demonstrated efficacy across several cognitive domains (Haig et al, 2014). However, the drug failed in patients with mild to moderate AD (Haig et al, 2012).…”

Procognitive Properties of Drugs with Single and Multitargeting H3 Receptor Antagonist Activities

“…ABT‐288 demonstrated good pharmacokinetics (37% oral BA, t 1/2 : 1.3 h) and CNS penetration (B/P ratio = 1.5) in rat models, a safe preclinical profile in rodent and dog studies and has advanced to clinical studies for the treatment of cognitive deficits in AD and schizophrenia . However, a recent report indicated that while safe and well tolerated in humans, ABT‐288 failed to show procognitive effects in AD and schizophrenic patients . The GSK‐239512 (pKi(hH 3 R = 10.0) displayed acceptable pharmacokinetics (51% oral BA, t 1/2 : 1.2 h) and CNS penetration (B/P ratio = 1.8) in rats and in patients with AD, exhibited evidence for positive effects on attention and memory .…”

Histamine H3 receptor ligands by hybrid virtual screening, docking, molecular dynamics simulations, and investigation of their biological effects

“…As a result of relevant investigations in animal models of CNS diseases, administration of anti‐H 3 R ligands enhances the synaptic neurotransmission and improves the corresponding neurophysiological processes (Hancock & Fox, ). There are lines of evidence suggesting the usefulness of H 3 ‐antagonists/inverse agonists in the treatment of neurological disorders (Haig et al., ; Herring et al., ; Jarskog et al., ; Passani, Cangioli, Bacciottini, Mannaioni, & Blandina, ; Schwartzbach et al., ). Due to the important physiological role of H 3 R in controlling neurotransmitters, special attention has been dedicated to the development of novel H 3 antagonists for their potential therapeutic applicability in neurological diseases.…”