The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis

Abstract

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.

Fig. 1. Time courses for CMH and hepatic markers absolute change from baseline, by to treatment groups.

A Triglycerides (n = 242 patients at W4, 231 at W14 and 217 at EOT), B HDL-C (n = 243 patients at W4, 232 at W14 and 218 at EOT), C LDL-C (n = 239 patients at W4, 227 at W14 and 213 at EOT), D APO-B (n = 208 patients), E fasting glucose (n = 242 patients at W4, 232 at W14 and 216 at EOT), F HbA1c (n = 243 patients at W4, 233 at W14 and 218 at EOT), G hs-CRP (n = 218 patients), H ferritin (n = 218 patients), I diastolic blood pressure (n = 243 patients at W4, 233 at W14 and 218 at EOT) and J NT-proBNP (n = 212 patients). Data are plotted as mean ± 95%CI. Treatment groups are indicated as follows: placebo, blue circle and solid line; lanifibranor 800 mg, red plus and dash line; lanifibranor 1200 mg, green cross and mixed line. *p < 0.01, **p < 0.001, from two-sided Mixed Model for Repeated Measures using change from baseline as endpoint, the time, treatment, the diabetic status, the interaction (treatment*time) and the baseline value as fixed effects, a time repeated measure within each subject and an unstructured variance covariance matrix. No adjustment for multiple comparisons was performed. Source data are provided as a Source Data file. APO apolipoprotein, CI confidence interval, EOT end of treatment, HbA1c hemoglobin A1c, HDL high density lipoprotein, hs-CRP high-sensitivity C-reactive protein, LDL low density lipoprotein, p = p value, NT-proBNP N-terminal pro b-type natriuretic peptide, W week.

Fig. 2. Hepatic steatosis.

A CRN-S improvement, defined as at least one-point improvement of CRN-S at EOT compared to screening (n = 207 patients). Point-improvement groups are indicated as follows: 1 point, blue; 2 points, red; 3 points, green. p-values from two-sided Cochran-Mantel-Haenszel test, stratified on the diabetic status at Baseline. B Correlation between CAP™ and CRN-S (n = 294 pooled pre- and post-treatment biopsies). The box’s length represents the IQR, the diamond inside the box represents the mean, the horizontal line inside the box represents the median, the whiskers extend to the minimum and maximum values included in [Q1-1.5*IQR; Q3 + 1.5IQR], the circles outside the whiskers represent the outliers. P value from two-sided Spearman correlation test. C CAP™ at screening and EOT, by treatment group (n = 153 patients). Data are plotted as mean ± 95%CI. Treatment groups are indicated as follows: placebo, blue circle and solid line; lanifibranor 800 mg, red plus and dash line; lanifibranor 1200 mg, green cross and mixed line. *p < 0.05, from two-sided Wilcoxon-Mann-Whitney test. D CAP™ ≤302^a dB/m at screening and EOT (n = 153 patients). P values from two-sided Chi² test ^a Youden optimal cutoff of the CAP™ as a diagnosis marker of steatosis ≥S1 versus S0. No adjustment for multiple comparisons was performed. Source data are provided as a Source Data file. CAP™ controlled attenuation parameter, CI confidence interval, Coef. coefficient, CRN Clinical Research Network, EOT end of treatment, IQR interquartile range.

Fig. 3. Time courses for CMH and hepatic markers absolute change from baseline according to weight-change groups at EOT, by treatment group.

A HOMA-IR (n = 169 patients), B ferritin (n = 217 patients), C ALT (n = 217 patients at W4 and W14, 216 at EOT), D adiponectin (n = 217 patients), E CAP™ (n = 142 patients), F diastolic blood pressure (n = 217 patients at W4, W14 and EOT) and G NT-pro-BNP (n = 210 patients). Data are plotted as mean ± 95%CI. Weight-change groups are indicated as follows: stable (≤2.5%), blue circle and solid line; moderate (within 2.5% and 5%), red plus and dash line; increase (≥5%), green cross and mixed line for lanifibranor-treated patients, and stable (≤2.5%), blue circle and solid line; increase (>2.5%), red plus and dash line for placebo-treated patients. Only two weight relative change groups defined for placebo due to few patients ≥5% (n = 4). For HOMA-IR related figures, patients treated with sulphonylureas were removed from the analyses. Source data are provided as a Source Data file. ALT alanine aminotransferase, BL Baseline, CAP™ controlled attenuation parameter, CI confidence interval, EOT end of treatment, HOMA-IR homeostatic model assessment of insulin resistance, NT-proBNP N-terminal pro b-type natriuretic peptide, W week.

Fig. 4. Time courses for CMH and hepatic markers from baseline according to adiponectin-change groups at EOT in lanifibranor treated patients.

Absolute changes in levels of A HDL-C, B HbA1c, D ALT, (n = 139 patients at W4, W14, EOT) and levels of C AST (n = 139 patients at baseline, W4, W14, EOT), E CAP^TM (n = 90 patients at screening and EOT). Data are plotted as mean ± 95%CI. Adiponectin increase groups are indicated as follows: unchanged (<1.5-fold), blue circle and solid line; moderate (within 1.5- and 4-fold), red plus and dash line; high (>4-fold), green cross and mixed line. Source data are provided as a Source Data file. AST aspartate aminotransferase, ALT alanine aminotransferase, CAP™ controlled attenuation parameter, CI confidence interval, EOT end of treatment, HbA1c hemoglobin A1c, HDL high density lipoprotein.

Fig. 5. Histological improvement according to adiponectin-change groups at EOT, in lanifibranor-treated patients.

A CRN-NAS score, B CRN-I, C CRN-B and D CRN-F (n = 128 patients). Histological improvement is indicated as follows: improvement of at least one point at EOT compared to screening according to NASH-CRN grading and staging, red; and no improvement otherwise; blue. Adiponectin increase groups are defined as unchanged (<1.5-fold), moderate (within 1.5- and 4-fold) and high (>4-fold). Source data are provided as a Source Data file. B ballooning, CRN Clinical Research Network, EOT end of treatment, F fibrosis, I inflammation, NAS  NAFLD activity score.