Study data published in the New England Journal of Medicine suggest that investigative drug lanifibranor reduces disease activity in nonalcoholic steatohepatitis (NASH).
Lanifibranor is a pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist with demonstrated effects on the metabolic and inflammatory pathways involved in NASH. To test the utility of this drug in reducing disease activity, investigators conducted a phase 2b, randomized, double-blind, placebo-controlled trial of patients with active severe NASH.
Patients were randomly assigned in a 1:1:1 ratio to receive 1200 mg of lanifibranor, 800 mg of lanifibranor, or placebo once daily for 24 weeks. The primary endpoint was a decrease of at least 2 points in the activity subscale of the Steatosis, Activity, Fibrosis (SAF-A) scoring system without worsening of fibrosis. Resolution of NASH and fibrosis regression were assessed as secondary endpoints. Safety events were also captured.
A total of 247 patients were randomly assigned: 83 to lanifibranor 1200 mg, 83 to lanifibranor 800 mg, and 81 to placebo. Mean patient age was 53.6±12.5 years, 144 (58%) were women, 232 (94%) were white, and 103 (42%) had type 2 diabetes mellitus. The majority of patients (76%) had moderate or advanced fibrosis.
The proportion of patients who achieved a decrease of ≥2 points in SAF-A scores without a worsening of fibrosis was significantly greater in the lanifibranor 1200 mg group vs the placebo group (55% vs 33%; P =.007). The difference between the lanifibranor 800 mg and placebo groups was not statistically significant (48% vs 33%; P =.07). Resolution of NASH was also more prevalent in the lanifibranor 1200 mg (49%) and 800 mg (39%) groups compared with placebo (22%).
Improvement in fibrosis stage of ≥1 plus resolution of NASH was observed in 35%, 25%, and 9% of the lanifibranor 1200 mg, lanifibranor 800 mg, and placebo groups, respectively. The majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. Liver enzyme levels also decreased significantly from baseline in the 1200 mg and 800 mg groups compared with the placebo group.
Adverse events were more common with lanifibranor compared with placebo, though attrition was similar across groups. The dropout rate due to adverse events was 4% in the lanifibranor 1200 mg group, 5% in the 800 mg lanifibranor group, and 4% in the placebo group. The most common side effects were diarrhea, nausea, peripheral edema, anemia, and weight gain, which occurred more commonly with lanifibranor. A reduction in hemoglobin levels was observed in patients taking lanifibranor. No effect on kidney function or bone turnover was observed.
These data suggest that daily lanifibranor at 1200 mg may improve NASH in patients with severe active disease. A phase 3 trial of longer duration is warranted to better assess the efficacy and safety of this treatment option.
“In this phase 2b trial of patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg once-daily dose of lanifibranor than with placebo,” investigators wrote. “The results of this trial also support the potential for benefits with lanifibranor with respect to many secondary end points, including hepatic fibrosis, lipid profile, and glycemic control.”
Disclosure: This research was supported by Inventiva Pharma. Please see the original reference for a full list of authors’ disclosures.
Francque SM, Bedossa P, Ratziu V, et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385(17):1547-1558. doi: 10.1056/NEJMoa2036205