Gilead Science announced on February 12 that NASH’s research drug, ASK1 inhibitor selonsertib (GS4997), missed the primary endpoint in its first phase III clinical trial (STELLAR-4).
STELLAR-4 is a phase III randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of the NASH new drug selonsertib in patients with compensated cirrhosis (F4) caused by NASH. A total of 877 NASH-induced compensatory cirrhosis patients were enrolled, and the effects of selonsertib and placebo on fibrosis were compared between the two dose groups.
Eligible adults aged 18 to 70 were randomized to receive selonsertib 18 mg (n=354), selonsertib 6 mg (n=351) or placebo (n=172) for up to 240 weeks; selonsertib or placebo was administered orally once a day. The primary endpoint of the study was a comprehensive assessment of the proportion of patients with no improvement in grade 1 fibrosis (fibrosis improvement ≥1) in patients who did not have NASH deterioration at week 48 and who achieved event-free survival at week 240 according to the NASH CRN classification. .
The results of the STELLAR-4 trial showed that 14.4% of patients treated with selonsertib 18 mg and 5% of patients treated with selonsertib 6 mg achieved a fibrosis improvement of ≥1 in the study of 877 subjects receiving the study drug. NASH did not worsen after 48 weeks of treatment; patients receiving placebo achieved a fibrosis improvement of ≥1, which was 12.8%. Selonsertib is generally well tolerated and the safety results are consistent with previous studies. However, the pre-set 48-week clinical endpoint was missed.
Gilead said that further in-depth analysis of the findings is in progress and the data will be submitted to the upcoming scientific meeting and will work with the data monitoring committee and researchers to complete the STELLAR-4 study in a manner that is in the best interest of each patient. .
“Although we are disappointed that the STELLAR-4 study did not reach its primary endpoint, we remain committed to advancing treatment for patients with advanced fibrosis caused by NASH, especially in this area where there is a significant unmet need for effective and well tolerated treatment. Gilead Chief Scientific Officer John McHutchison, MD, revealed in a press release that “Gilead is also collecting research data on compensated cirrhosis caused by NASH, including a large number of biomarkers, which will further enhance The disease is recognized and informs the broader NASH development program.”
Selonsertib is an ASK1 inhibitor and is a highly selective kinase inhibitor. The full name of ASK1 is an apoptosis signal-regulating kinase that activates key regulatory proteins such as JNK and P38 to induce inflammation and fibrosis.
NASH is a chronic and progressive liver disease characterized by accumulation of fat and inflammation in the liver, which can lead to scarring or fibrosis that impairs liver function. Individuals with advanced fibrosis, including bridging fibrosis (F3) or compensatory cirrhosis (F4), have a significantly increased risk of liver-related mortality and all-cause mortality.
Gilead is advancing a variety of new research compounds for the treatment of advanced fibrosis caused by NASH, evaluating single-agent and combination therapies for NASH. In recent years, it has acquired ACC2 inhibitor GS-0976, FXR agonist GS-9674, ASK1 inhibitor selonsertib, and LOXL2 inhibitor SIM. At the end of 2018, he purchased an exclusive pre-emptive right to acquire the global interest in three TGFbeta antibodies from Scholar Rock.
John McHutchison also said that he expects the results of Phase II ATLAS trials of another phase III STELLAR-3 trial of selonsertib and bridging fibrosis (F3) patients in combination with selonsertib, cilofexor (GS-9674) and firsocostat (GS-0976).