Selonsertib improves NASH fibrosis; does not meet goals in DKD, PAH

Gilead Sciences announced that Selonsertib, its investigational drug for the treatment of nonalcoholic steatohepatitis, improved fibrosis stage in a majority of patients with NASH after 24 weeks of treatment. Endpoints were not met in diabetic kidney disease or pulmonary arterial hypertension.

Selonsertib (GS-4997, Gilead Sciences) is a small molecule inhibitor of apoptosis signal-regulating kinase 1. In a randomized open-label clinical trial, researchers tested the safety, tolerability and efficacy of GS-4997 alone or in combination with simtuzumab for 24 weeks in 72 patients with NASH and fibrosis stages F2 to F3, according to a press release.

Patients received either 6 mg (n = 20) or 18 mg (n = 22) of GS-4997 alone; 6 mg of GS-4997 plus 125 mg of simtuzumab (n = 10); 18 mg of GS-4997 plus 125 mg of simtuzumab (n = 10); or 125 mg of simtuzumab alone (n = 10). GS-4997 was given once daily and simtuzumab was given weekly via subcutaneous injection.

After 24 weeks of therapy, 43% of patients who received 18 mg of GS-4997 with or without simtuzumab and 30% of patients who received 6 mg of GS-4997 with or without simtuzumab experienced an improvement of at least one stage of fibrosis from baseline, according to the release. In addition, only one patient who received 18 mg of GS-4997 and two who received 6 mg of GS-4997 had disease progress to cirrhosis.

Overall, the drug was well-tolerated with no dose-related increase in the incidence of treatment-related adverse events or serious adverse events. The most commonly reported events were headache, nausea and sinusitis.

“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 of research and development and chief scientific officer at Gilead Sciences, said in the 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.”

Gilead plans to initiate a phase 3 clinical trial program of GS-4997 in patients with NASH, pending conversations with regulatory agencies, according to Bischofberger.

In two separate phase 2 studies of GS-4997 for pulmonary arterial hypertension and diabetic kidney disease, preliminary analyses showed primary endpoints were not met. Gilead will not pursue phase 3 studies of GS-4997 for the treatment of pulmonary arterial hypertension and diabetic kidney disease at this time, according to the release.

Complete study results of GS-4997 for patients with NASH and fibrosis will be presented at The Liver Meeting in Boston next month.

Disclosure: Bischofberger is employed by Gilead Sciences.