Efficacy and safety of ervogastat alone and in combination with clesacostat in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and F2-F3 fibrosis (MIRNA): results from a phase 2, randomised, double-blind, double-dummy study.

backgroundErvogastat, a diacylglycerol acyltransferase 2 (DGAT2) inhibitor, and clesacostat, an acetyl-coenzyme A carboxylase (ACC) inhibitor, have shown promise in reducing hepatic steatosis. Increased circulating triglycerides, a mechanistic consequence of ACC inhibitors, has been shown to be downregulated by DGAT2 inhibitor co-administration. We assessed the efficacy and safety of ervogastat alone and ervogastat plus clesacostat in adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stage 2 or 3.

methodsThis phase 2 double-blind, double-dummy, randomised study was conducted at 198 clinical sites across 11 countries. A computer-generated randomisation code (random permuted blocks method) was used to allocate patients to treatment groups in equal ratios, and stratified based on degree of fibrosis (F2 vs F3), using an interactive response technology system to ervogastat (25 mg, 75 mg, 150 mg, or 300 mg), ervogastat plus clesacostat (150 mg plus 5 mg or 300 mg plus 10 mg), or placebo, twice daily for 48 weeks. The primary endpoint was the proportion of patients achieving MASH resolution without fibrosis worsening, at least 1 stage fibrosis improvement without MASH worsening, or both, at week 48. Patients were analysed according to the treatment group they were assigned to. The primary endpoint was analysed based on the full analysis set (all randomly assigned patients who took at least one dose of study treatment who provided evaluable baseline biopsy data) in which patients missing a week 48 biopsy were considered non-responders. This completed trial was registered with ClinicalTrials.gov (NCT04321031).

findingsRecruitment began June 15, 2020; randomisation was completed Feb 22, 2023, with 255 patients randomly assigned and given treatment (73% of planned sample size; ervogastat 25 mg: N=35; ervogastat 75 mg: N=48; ervogastat 150 mg: N=42; ervogastat 300 mg: N=31; ervogastat 150 mg plus clesacostat 5 mg: N=35; ervogastat 300 mg plus clesacostat 10 mg: N=30; placebo: N=34). 13 (38%) patients in the placebo group achieved the composite primary endpoint, as did 16 (46%) in the ervogastat 25 mg group (difference from placebo in the proportion of patients achieving the primary endpoint 0·08 [90% CI -0·11 to 0·27]), 25 (52%) in the ervogastat 75 mg group (0·14 [-0·04 to 0·32]), 21 (50%) in the ervogastat 150 mg group (0·12 [-0·07 to 0·30]), and 14 (45%) in the ervogastat 300 mg group (0·07 [-0·12 to 0·27]). 23 (66%) patients in the ervogastat 150 mg plus clesacostat 5 mg group (difference from placebo 0·27 [90% CI 0·07 to 0·43]) and 19 (63%) of those in the ervogastat 300 mg plus clesacostat 10 mg group (0·25 [0·04 to 0·42]) achieved the composite primary endpoint. Thus, the primary endpoint was not met by any doses of ervogstat alone, but was met by both dose levels of ervogastat plus clesacostat. All experimental groups showed greater effects on MASH resolution without worsening of fibrosis than with placebo alone; improvement in fibrosis by one stage or more without worsening of MASH was not greater in any experimental group compared with placebo. Most adverse events were mild or moderate in severity and did not increase in frequency or severity with increasing dose; however, ervogastat plus clesacostat was associated with a likely undesirable fasting lipid and apolipoprotein profile. The most common adverse event was inadequate control of diabetes (placebo: 4/34 [12%]; ervogastat 25 mg: 6/35 [17%]; ervogastat 75 mg: 5/48 [10%]; ervogastat 150 mg: 3/42 [7%]; ervogastat 300 mg: 2/31 [6%]; ervogastat 150 mg plus clesacostat 5 mg: 2/35 [6%]; ervogastat 300 mg plus clesacostat 10 mg: 2/30 [7%]). There were no fatal events; 19/255 (7%) patients reported 20 serious adverse events (placebo: 1/34 [3%]; ervogastat 25 mg: 1/35 [3%]; ervogastat 75 mg: 5/48 [10%]; ervogastat 150 mg: 1/42 [2%]; ervogastat 300 mg: 4/31 [13%]; ervogastat 150 mg plus clesacostat 5 mg: 5/35 [14%]; ervogastat 300 mg plus clesacostat 10 mg: 2/30 [7%]).

interpretationThe combined efficacy, safety, and tolerability data with ervogastat supports continued investigation for its use in MASH. Larger and longer trials are needed to further assess ervogastat and ervogastat plus clesacostat for MASH treatment.

fundingPfizer.