Interim findings boost therapeutic potential of lanifibranor for NASH

The pan-PPAR* agonist lanifibranor further advances into the NASH** treatment field, as more data from the phase IIb NATIVE*** study presented at AASLD 2021 unveil further histologic and therapeutic benefits for patients with NASH.

Initial reports demonstrated the therapeutic efficacy of lanifibranor on NASH resolution and fibrosis improvement. The study included 247 participants with active noncirrhotic NASH who were randomized 1:1:1 to receive lanifibranor 1,200 or 800 mg or placebo QD for 24 weeks. [N Engl J Med 2021;385:1547-1558]

Further histologic improvements

In participants who completed treatment (n=207), more lanifibranor vs placebo recipients had ≥1-point improvement in steatosis grading at week 24 (66 percent [800 mg] and 72 percent [1,200 mg] vs 32 percent; p<0.001 for both). The fractions of participants with ≥2-point improvement in steatosis grading were also greater with lanifibranor vs placebo (36 percent [800 mg] and 40 percent [1,200 mg] vs 5 percent [placebo]). [AASLD 2021, abstract 1920]

Week 24 also saw reductions in baseline CAP^# with both lanifibranor 800 mg (from 323 to 309 dB/m) and 1,200 mg (from 326 to 304 dB/m) but not with placebo (from 335 to 328 dB/m). Comparison of the reductions between the two lanifibranor doses and placebo were significant (p=0.028 [lanifibranor 800 mg vs placebo] and p=0.005 [lanifibranor 1,200 mg vs placebo]).

Compared with placebo, the fractions of patients with CAP ≤302 dB/m were twice as high with lanifibranor 800 mg (46 percent vs 24 percent; p=0.019) and 1,200 mg (50 percent vs 24 percent; p=0.009).

“After 24 weeks of treatment, lanifibranor induced a significant reduction in hepatic steatosis, as assessed by histology and by CAP,” noted Dr Michael Cooreman from Inventiva S.A., Daix, France, in the poster presentation.

A significant relationship was observed between CAP and histologic steatosis grade at both screening and week 24 (Spearman correlation p<0.001).

Among lanifibranor recipients, the CAP reductions significantly correlated with the changes in steatosis grading (Spearman correlation p=0.03) and improvements in triglyceride levels (Spearman correlation p<0.001) and HbA_1c (Spearman correlation p=0.09). These underline the potential of lanifibranor to deliver histologic improvements and improve biomarkers of lipid and glucose metabolism, noted Cooreman.

Improved glucose markers

Another analysis evaluated a cohort of nondiabetic individuals (n=144). Of these, 47 had prediabetes (fasting glucose level [FGL] 5.6–6.9 mmol/L) and 94 were normoglycaemic (FGL <5.6 mmol/L). In the prediabetic subgroup, 20, 16, and 11 participants respectively received lanifibranor 800 and 1,200 mg and placebo. [AASLD 2021, abstract 1921]

In normoglycemic patients who had completed treatment (n=83), none on either lanifibranor dose progressed to prediabetes at week 24; more than a quarter (26 percent) of placebo recipients did progress to prediabetes.

Conversely, in prediabetic participants who completed treatment (n=41), baseline FGL dropped by a mean –0.9 and –0.6 mmol/L with the respective lanifibranor 800- and 1,200-mg doses, while placebo increased FGL by +0.3 mmol/L. More lanifibranor recipients reversed to normoglycaemia (n=12 [800 mg] and 10 [1,200 mg]) as opposed to only one on placebo. Both lanifibranor doses also led to mean reductions in baseline fasting insulin levels (–144 [800 mg] and –264 pmol/L [1,200 mg]), HbA_1c (–0.32 percent and –0.38 percent, respectively), and HOMA-IR^## (–6.5 and –11.9).

NASH is tied to other manifestations of metabolic syndrome, including type 2 diabetes and cardiovascular disease (CVD). “Prediabetic individuals are at increased risk for CVD. [Therefore,] the reversal of prediabetes to normoglycaemia diminishes the risk for subsequent T2D, [as well as] risk for CVD,” noted Cooreman.

“The effect size on reversal to normoglycaemia and improvement of insulin resistance suggest a therapeutic benefit of lanifibranor on glucose metabolism in prediabetic patients that warrants further study,” said Cooreman. “Effective interventions for prediabetics may prevent or delay [progression of diabetes into] morbid complications.”

“These data further support the relevance of screening patients with NASH for both overt T2D and prediabetes,” he added.