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Background: GSK3532795/BMS-955176 has been evaluated through Phase 2b clinical trials. In Study 206220 evaluating the electrocardiographic effects (TQTS) of GSK3532795, two subjects receiving supratherapeutic doses of GSK3532795 developed neuropsychiatric serious adverse events (SAE). These isolated SAEs prompted an analysis of neuropsychiatric adverse events (AEs) across all clinical trials.
Methods: Thirteen trials involving healthy and HIV-1 infected adults receiving different GSK3532795 doses (5 mg QD to 240 mg BID) for varying duration (single dose to a maximum of 71 weeks), comparator drug, or placebo were included in this analysis which involved:
1) a clinical summary analysis of neuropsychiatric AEs and
2) an exploratory exposure-response (ER) analysis of most neuropsychiatric AEs in two trials: TQTS (Study 206220) and a Phase 2b study in HIV-1 infected adults (Study 205891).
Results: A total of 784 subjects received at least one dose of GSK3532795; 259 subjects received placebo/other treatments. For neurologic AEs, Grade 1 headache predominated in both groups. For psychiatric AEs, sleep abnormality AEs (abnormal dreams, insomnia, nightmare, sleep disorder, and difficulty sleeping) were the most common in both treatment groups but individually occurred at variable rates across studies. Other psychiatric AEs were infrequent and broadly similar across the two groups. Grade 3 AEs were rare and consisted of two cases at supra-therapeutic doses (240 mg QD and BID) in the TQTS; a single report of acute psychosis in one subject and another subject with homicidal ideation, suicidal ideation, and tachyphrenia. Finally, one HIV-1 infected subject had a Grade 3 nightmare (Study 205892). The ER analysis showed an increasing proportion of subjects having most neuropsychiatric AEs with increasing dose of GSK3532795. However, no significant ER relationship between GSK3532795 AUC(0-24) (Study 206220) or steady state AUC (Study 205891) and neuropsychiatric AEs was observed.
Conclusions: The overall incidence rates of neuropsychiatric AEs (mostly Grade 1) were similar between the GSK3532795 and placebo/comparator treatment arms. No significant ER relationship for neuropsychiatric AEs was observed with GSK3532795. Combined, the data from 13 clinical trials does not suggest a clinically significant signal for neuropsychiatric AEs in adults who receive the MI, GSK3532795.

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