Investigative Treatment for Pulmonary Arterial Hypertension Fails to Meet Top Goal in Phase 2 Study

Gilead Sciences reported that selonsertib (also known as GS-4997), an investigational treatment for pulmonary arterial hypertension (PAH), did not achieve the primary endpoint in an analysis of ARROW, a Phase 2 clinical trial (NCT02234141) evaluating the drug’s efficacy, safety and tolerability.

The company also reported top-line data from two other Phase 2 clinical trials assessing selonsertib, one in people with nonalcoholic steatohepatitis (NASH), and the other in diabetic kidney disease (DKD) patients.

Selonsertib is an orally bioavailable inhibitor of apoptosis signal-regulating kinase 1 (ASK1), a protein that promotes inflammation, apoptosis (cell death), and fibrosis in settings of oxidative stress. It is being tested in Phase 2 trials as a therapy for PAH, NASH and DKD.

The ongoing, 24-week, randomized, dose-ranging ARROW trial compared the efficacy, safety, and tolerability of three doses (2 mg, 6 mg, or 18 mg once daily) of selonsertib to placebo in 151 patients with PAH (WHO Group 1).

Based on an analysis, Gilead reported that the trial did not achieve its primary endpoint. At week 24, treatment with selonsertib did not result in statistically significant changes from baseline in pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC). RHC is the most accurate test to measure pulmonary artery pressure and to officially diagnose PAH.

Due to the lack of efficacy evidence, the company said it will not move the drug into Phase 3 studies in PAH.

Separately, selonsertib showed anti-fibrotic activity in an open-label Phase 2 (NCT02466516) study in patients with NASH and moderate to severe (F2-F3) liver fibrosis.  In this trial, 72 people were treated with selonsertib (6 mg or 18 mg, orally once daily) alone or in combination with simtuzumab (SIM; a monoclonal antibody by Gilead being investigated for the treatment of fibrosis), or SIM alone (125 mg via subcutaneous injections) for 24 weeks. Results showed that treatment with selonsertib improved fibrosis compared to SIM alone, and reduced progression to cirrhosis (fibrotic liver). Selonsertib was generally well-tolerated, with no major treatment-related adverse events observed.

The results will be presented at The Liver Meeting, set for Nov. 11–15 in Boston.

“We are committed to advancing our pipeline of investigational molecules that separately target metabolic dysfunction, inflammation and/or fibrosis associated with NASH,” Norbert Bischofberger, PhD, executive vice president, Research and Development, and chief scientific officer, Gilead Sciences, said in a press release. “We are encouraged by these data demonstrating the anti-fibrotic effect of GS-4997 in patients with NASH after only 24 weeks of treatment, and look forward to sharing the complete results with the hepatology community. Additionally, pending discussions with regulatory agencies, we plan to initiate a Phase 3 clinical trial program of GS-4997 in patients with NASH.”

Gilead also reported that, based on a preliminary analysis of a Phase 2 study (NCT02177786) on patients with DKD, selonsertib did not achieve its primary endpoint. As in ARROW, due to the lack of efficacy evidence, Gilead said it does not plan to move the drug into Phase 3 trials for DKD at this time.