Gilead Reports Success, Failures in Investigational Drug Across Multiple Diseases

Phase 2 studies of GS-4997 presented successful results in patients with non-alcoholic steatohepatitis.

Gilead recently announced that its experimental drug GS-4997 (selonsertib) performed well in phase 2 clinical trials of non-alcoholic steatohepatitis, and did not perform optimally in trials of pulmonary arterial hypertension and diabetic kidney disease.

GS-4997 is an investigational inhibitor of apoptosis signal-regulating kinase 1 in these 3 diseases. This protein promotes inflammation, apoptosis, and fibrosis, especially in oxidative stress settings, according to Gilead.

The phase 2 study GS-US-384-1497 determined the safety, tolerability, and efficacy of GS-4997 as a monotherapy, or in combination with simtuzumab, an investigational antibody against lysel oxidase-like-2.

Included in the study were 72 patients with moderate-to-severe fibrosis resulting from non-alcoholic steatohepatitis. Patients received a 6-mg or 18-mg dose of GS-4997 alone, or in combination with 125-mg of simtuzumab. Some patients also received treatment with simtuzumab alone.

Scientists reported that 43% of patients taking 18-mg of GS-4997 monotherapy had a fibrosis improvement of at least 1 stage. Only 1 patient progressed to cirrhosis on the drug, Gilead reported.

For the combination therapy, 30% of patients’ fibrosis improved, and 7% progressed to cirrhosis. Approximately 20% of patients taking situzumab monotherapy had improved fibrosis, and 20% progressed.

In another phase 2 study, GS-US-223-1015, the drug was tested in 334 patients with type 2 diabetes with stage 3 or 4 renal impairment and albuminuria. Patients either received 6-mg or 18-mg of GS-4997 or placebo on top of their diabetic kidney disease therapy for 48 weeks, according to Gilead.

The primary endpoint for the study was the change in glomerular filtration rate from baseline.

The last study, ARROW, investigated GS-4997 in 151 patients with pulmonary arterial hypertension. Patients received 2-mg, 6-mg, or 18-mg of the drug or placebo, in addition to pulmonary arterial hypertension treatment.

The primary endpoint was change in pulmonary vascular resistance at week 24, which it did not reach. Overall, the drug was well tolerated, and no adverse events were seen with increasing doses. Common adverse events included headache, nausea, and sinusitis.

Gilead reported that efficacy data was not strong enough to pursue phase 3 studies for patients with diabetic kidney disease or pulmonary arterial hypertension. However, they do plan to conduct phase 3 trials for non-alcoholic steatohepatitis (NASH).

“We are committed to advancing our pipeline of investigational molecules that separately target metabolic dysfunction, inflammation and/or fibrosis associated with NASH,” said Norbert Bischofberger, PhD, executive vice president, Research and Development and chief scientific officer, Gilead Sciences. “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.”