June 23, 2020
- Inventiva has released topline results from the phase 2b NATIVE trial of its pan-PPAR agonist, lanifibranor, for the treatment of NASH.
- The primary endpoint of the trial, the Steatosis Activity Fibrosis (SAF) score at Week 24 was met, along with all other secondary outcomes at the same time point, including NASH resolution with no worsening of fibrosis and improvement of liver fibrosis with no worsening of NASH.
- The proportion of patients achieving a reduction in SAF score of ≥2 at Week 24 was 41% and 49% in the lanifibranor 800mg and 1200mg treatment groups respectively, compared with 27% in the placebo group (p=0.061 and p=0.004).
- Lanifibranor is the first drug candidate to achieve significant effects on NASH resolution with no worsening of fibrosis and improvement of fibrosis with no worsening of NASH, the FDA and EMA primary endpoints relevant for seeking accelerated approval during future phase 3 clinical development.
- Statistically significant results were also obtained in both dose groups on decrease of insulin, fasting glucose and glycated haemoglobin (HB1AC) in patients with T2DM, decrease in triglycerides, increase in high density lipoprotein cholesterol (HDL) and decrease in liver enzymes (ALT, AST and GGT).
- Lanifibranor continued to show a favorable tolerability profile, consistent with observations from previous clinical trials.
- Full results of the study will be presented at the AASLD meeting in November.
These positive data enter a mixed PPAR environment for NASH after Genfit’s PPARα/δ agonist elafibranor failed an interim analysis of the phase 3 data and CymaBay did a U-turn on its own PPARδ agonist seladelpar and resurrected its development after previously terminating it due to abnormal histology findings. The major difference between lanifibranor and the other two PPAR agonists is its lack of selectivity, with moderate and well‐balanced activity on all three PPAR isoforms (α, γ, δ). Pan-PPAR agonism indirectly inhibits hepatic macrophage infiltration, decreasing the pro-inflammatory activation of macrophages via PPARδ agonism.
If and how the isoform-specific effects on hepatic macrophage biology translate to a differential effect on clinical outcomes remains to be seen, but it must be noted that elafibranor also achieved success at the phase 2 stage before failing its interim phase 3 analysis. Regardless, the investigators of this trial are optimistic about lanifibranor’s robust efficacy across FDA and EMA regulatory endpoints and it potential in phase 3 development.
Source: Inventiva Press Release