GSK2881078, a SARM, Produces Dose-Dependent Increases in Lean Mass in Healthy Older Men and Women.

Context: GlaxoSmithKline (GSK) 2881078 is a nonsteroidal, selective androgen receptor modulator (SARM) under investigation by GSK for treatment of reduced mobility and other functional limitation in men and women with muscle weakness associated with chronic and acute illnesses.

Objective: This was a phase 1b study intended to explore across a dose range the pharmacokinetics (PK)-pharmacodynamics relationship and further safety and tolerability data for GSK2881078. This study also evaluated effects of CYP3A4 inhibition on PK of GSK2881078.

Methods: This was a randomized, placebo-controlled, parallel-group, repeat-dose, dose-escalation study in healthy older males and postmenopausal females. A total of three cohorts of males and three cohorts of females were studied. Dosing at each dose level was twice daily for the first 3 days followed by once daily for up to 53 days. Repeated dual-energy X-ray absorptiometry and MRI cross-sectional thigh scans were performed. The effect of CYP3A4 inhibition on GSK2881078 PK was evaluated in a separate cohort.

Results: GSK2881078 was generally well tolerated and no serious adverse events were reported. Compared with placebo, there was greater lean mass accrual with all dose levels of GSK2881078. Females exhibited a greater response at lower doses than did males. Transient elevations of alanine aminotransferase were observed. The effect of CYP3A4 inhibition on GKS2881078 PK was unlikely to be of clinical significance.

Conclusions: GSK2881078 yielded dose-dependent increases in lean mass with evidence of enhanced sensitivity in women. The compound was well tolerated.