The panPPAR agonist lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the native phase 2b trial.
Multimechanism Drug Improves NASH and Fibrosis in 24-Week Trial
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Lanifibranor, an experimental agent directed against several mechanisms behind nonalcoholic steatohepatitis (NASH), both reduced NASH activity and improved fibrosis in a 247-person, 24-week, phase 2b, placebo-controlled trial [1]. The novel panPPAR agonist also improved markers of liver damage, inflammation, and glucose control.
Metabolic, inflammatory, and fibrosis-related factors combine to worsen NASH and complicate attempts to reverse this sometimes fatal liver disease. Peroxisome proliferator-activated receptors (PPAR) play roles in governing all three mechanisms. The panPPAR agonist lanifibranor affects all three types of PPAR [2] and thus may simultaneously address several factors involved in NASH progression.
To assess the safety and efficacy of lanifibranor in people with NASH, researchers conducted a phase 2b, double-blind, placebo-controlled trial [3]. Participants had to have biopsy-proven NASH with high activity denoted by a steatosis-activity-fibrosis (SAF) score of 1-3 for steatosis, 3-4 for activity, and below 4 for fibrosis. They could not have cirrhosis.
Researchers randomized participants in a 1-1-1 ratio to 800 or 1200 mg of lanifibranor once daily (by mouth with food) or to placebo. The primary endpoint was a decrease of 2 or more points in the SAF activity score by week 24. Researchers assessed outcomes in two groups: the full analysis set of 247 people who received at least one dose of lanifibranor or placebo, and a per-protocol set of 194 people with biopsies before and after the 24 weeks of treatment and without deviations from the trial plan that could affect results.
The 83 people randomized to 800 mg of lanifibranor, the 83 randomized to 1200 mg, and the 81 randomized to placebo did not differ substantially in age (average 53.6 overall), proportions of whites (94% overall), body mass index (average 32.9 kg/m2 overall), or proportions with diabetes (42% overall). Women made up 65% of the 800-mg lanifibranor group, 59% of the 1200-mg group, and 51% of the placebo group. SAF activity score was similar in the three study arms, averaging 3.3 overall.
In the 247-person full-analysis set, 49% getting 1200 mg of lanifibranor had at least a 2-point drop in SAF activity score and no worsening of fibrosis, compared with 27% in the placebo group, a significant difference (P = 0.004). In the 800-mg lanifibranor group, 41% achieved this goal, through the difference from the placebo group fell just short of statistical significance (P = 0.061). In the 194-person per-protocol group, response rates were 55% in the 1200-mg lanifibranor group (P = 0.015 vs placebo), 51% in the 800-mg group (not significant at P = 0.058 vs placebo), and 34% in the placebo group. Responses were consistent in people with versus without diabetes and in an analysis limited to people with F2-F3 fibrosis.
In the 247-person full-analysis set, response rates for secondary endpoints always proved significantly greater with 1200 mg of lanifibranor than with placebo: resolution of NASH with no fibrosis worsening (45% vs 19%, P < 0.001), improvement in fibrosis by at least 1 stage and no NASH worsening (42% vs 24%, P = 0.011), and resolution of NASH and improvement in fibrosis (31% vs 7%, P < 0.001). Response rates in the 800-mg group were significantly greater versus placebo for the first and third of those endpoints. Results were similar in people with or without diabetes.
Absolute change from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) improved significantly with either dose of lanifibranor versus placebo by treatment week 4, and those differences remained significant through 24 weeks. These results remained consistent in people with or without diabetes.
Compared with the placebo group, people receiving lanifibranor had significant improvements through 24 weeks in fibrosis biomarkers (ProC3, TIMP1/TIMP2 ratio), an apoptosis marker (CK18M30), and inflammation markers (ferritin, hsCRP). “Good” high-density lipoprotein cholesterol rose significantly in both lanifibranor groups and stayed largely flat in the placebo arm over 24 weeks, while triglycerides fell significantly with lanifibranor while remaining unchanged with placebo. Low-density lipoprotein cholesterol did not change significantly in any study arm. Glucose control indicated by fasting glucose, fasting insulin, and HbA1c improved significantly in both lanifibranor groups versus placebo through 24 weeks.
Rates of drug-related treatment-emergent adverse events were 27.7% with 1200 mg of lanifibranor, 30.1% with 800 mg, and 23.5% with placebo. Respective rates of drug-related adverse events leading to drug withdrawal were 2.4%, 1.2%, and 2.5%. Two people in the placebo group and none receiving lanifibranor had a drug-related serious adverse event.
The researchers concluded that lanifibranor is the first drug to improve both NASH and fibrosis—and in only 24 weeks. They also noted that this is the first trial to use the SAF activity score to define study inclusion criteria, and that resulted in a study population with more active NASH and significant fibrosis. Phase 3 trials of lanifibranor are planned for 2021.
References
1. Francque S, Bedossa P, Ratziu V, et al. The panPPAR agonist lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the native phase 2b trial. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 12.
2. Boubia B, Poupardin O, Barth M, et al. Design, synthesis, and evaluation of a novel series of indole sulfonamide peroxisome proliferator activated receptor (PPAR) α/γ/δ triple activators: Discovery of lanifibranor, a new antifibrotic clinical candidate. J Med Chem. 2018;61:2246-2265.
3. ClinicalTrials.gov. Phase 2b study in NASH to assess IVA337 (NATIVE). ClinicalTrials.gov identifier NCT03008070.