Benzinga | Oct 21, 2021 12:11PM EDT

Inventiva Highlights Results Of Its NATIVE Phase 2b Trial With Lanifibranor In NASH Published In New England Journal Of Medicine

* In the Phase IIb NATIVE, lanifibranor met both the primary and key secondary endpoints, including NASH resolution with no worsening of fibrosis and improvement of liver fibrosis with no worsening of NASH

* NATIVE was the first clinical trial demonstrating an effect on the composite histology endpoint of NASH resolution and improvement of fibrosis

* NATiV31, a pivotal phase III trial of lanifibranor in NASH is currently ongoing with first clinical trial sites initiated and patients screened in the United States and if topline results, expected H2 2024, are positive, intent is to seek U.S. accelerated approval and EU conditional approval

Daix (France), Long Island City (New York, United States), October 20, 2021 -- Inventiva (NASDAQ:IVA), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of non-alcoholic steatohepatitis (NASH), mucopolysaccharidoses (MPS) and other diseases with significant unmet medical needs, today announced the publication of the results from its NATIVE (NAsh Trial to Validate IVA337 Efficacy) Phase IIb clinical trial evaluating lanifibranor for the treatment of NASH in the prestigious, peer-reviewed medical journal The New England Journal of Medicine (NEJM).

In the 24-week clinical trial, lanifibranor, an orally-available small molecule and the only pan-PPAR agonist currently in clinical development for the treatment of NASH, at 1200mg/day met the primary endpoint with a statistically significant reduction of the Steatosis Activity Fibrosis score (SAF), which combines assessments of hepatocellular inflammation and ballooning, with no worsening of fibrosis in the Intention To Treat (ITT2) and the Per Protocol populations (PP3).

Lanifibranor also met key secondary endpoints, including NASH resolution with no worsening of fibrosis4 and improvement of liver fibrosis with no worsening of NASH5 in both ITT and PP populations, as well as the composite endpoint of NASH resolution and improvement of liver fibrosis. With these latter results, lanifibranor is the first orally available drug candidate to achieve statistically significant results on the two U.S. Food and Drug Administration (FDA) and European Medicine Agency (EMA) primary endpoints relevant for seeking U.S. accelerated approval and EU conditional approval during Phase III clinical development.

The results of NATIVE were reported in June 2020 in accordance with the study protocol and Statistical Analysis Plan design using a single imputation method of missing data, a conservative method that consider missing end-of-study biopsy data as non-responders. The data presented in The New England Journal of Medicine showed additional analyses presented in accordance with the journal requirements using a multiple imputation method of missing end-of-study biopsy data.

The different statistical methods lead to similar results as shown in the table below, confirming the robustness of NATIVE results.

Primary and main secondary endpoints Intention to Treat Population (ITT) Single Imputation Method Multiple Imputation Method Placebo Lanifibranor Placebo Lanifibranor (N = 800mg 1200mg (N = 800mg 1200mg 81) (N = 83) (N = 83) 81) (N = 83) (N = 83) Decrease of ?2 points of SAF 27% 41% 49% 33% 48% 55%Primary activityendpoint score(1) Risk Ratio 1.52 1.82 1.45 1.69 [95%Cl](5) [0.98-2.12] [1.24-2.40] [1.00-2.10] [1.22-2.34] P=0.061 P=0.004 P=0.073 P=0.007 Resolution of NASH and no 19% 33% 45% 22% 39% 49% worsening of fibrosis (2) Risk Ratio 1.75 2.41 1.70 2.20 [95%Cl] (5) [1.02-2.68] [1.53-3.35] [1.07-2.71] [1.49-3.26] (6) P=0.043 P<0.001 P=0.039 P<0.001 Improvement of fibrosisSecondary by at leastendpoints one stage 24% 28% 42% 29% 34% 48% and no worsening of NASH (3) Risk Ratio 1.18 1.80 1.15 1.68 [95%Cl] (5) [0.68-1.86] [1.16-2.51] [0.72-1.85] [1.15-2.46] (6) P=0.530 P=0.011 P=0.561 P=0.017 Resolution of NASH and improvement 7% 21% 31% 9% 25% 35% of fibrosis (4) Risk Ratio 2.71 4.25 2.57 3.95 [95%Cl] (5) [1.16-5.40] [2.02-7.37] [1.2-5.51] [2.03-7.66] (6) P=0.017 P<0.001 P=0.018 P<0.001

(1). Response is defined as a decrease from baseline to week 24 of at least 2 points of the SAF Activity score (SAF-A) with no worsening of the CRN Fibrosis score (CRN-F). No worsening means that score remains stable or decreases.

(2). Resolution of NASH with no worsening of fibrosis at week 24: CRN-I = 0 or 1 (CRN-Inflammation), CRN-B = 0 (CRN-Ballooning) and no worsening of CRN-F from baseline.

(3). Improvement of liver fibrosis ? 1 stage and no worsening of NASH at week 24: Improvement of CRN-F ? 1 stage and no increase of CRN-S, CRN-I or CRN-B.

(4). Resolution of NASH and improvement of fibrosis at week 24: CRN-I = 0 or 1, CRN-B = 0 and an improvement of CRN-F ? 1 stage.

(5). Risk ratio was calculated using the Cochran--Mantel--Haenszel method stratified by diabetic status at baseline, and can be interpreted as the ratio of % responders in lanifibranor to % responders in placebo.

(6). As per recommendations of the New England Journal of Medicine, p values were not included on secondary endpoints and will not appear in the publication.

Throughout the Company's NATIVE Phase IIb clinical trial, lanifibranor also showed an overall favorable tolerability profile, consistent with observations from previous clinical studies. The drop-out rates for adverse events were 3.6% in 1200mg, 4.8% in 800mg, and 3.7% in placebo, with the vast majority being mild or moderate in intensity. The rate of severe treatment-emergent adverse events (TEAE) was similar in the three arms (<4%) and two serious TEAEs were assessed as drug-related (mild heart failure; urticaria), both occurring in the placebo group.

The Native phase IIb results contributed in obtaining FDA Breakthrough Therapy designation in NASH in 2020 and allowed Inventiva to start a pivotal phase III trial which is currently ongoing following the activation of first clinical sites and start of patient screening in the United States in September 2021.. Topline results of this study are expected H2 2024 and, if positive, should allow us to seek U.S. accelerated approval and EU conditional approval.

Pierre Broqua, Chief Scientist Officer and cofounder of Inventiva, commented "We are delighted to see the results of our NATIVE Phase IIb clinical trial in NASH published in the renowned and influential The New England Journal of Medicine, which reflects the clinical significance and scientific rigor of our lanifibranor development program. Backed by these strong Phase IIb results and following the recent initiation of the Phase III clinical trial, we are convinced that lanifibranor, with its unique characteristics as a pan-PPAR agonist, is ideally positioned in the NASH field and we now look forward to advancing with its pivotal development phase."

Prof. Sven Francque, M.D., Ph.D., Antwerp University Hospital and co-principal investigator of the Phase IIb NATIVE clinical trial, said "The publication of the results of the Phase IIb NATIVE in The New England Journal of Medicine is an important scientific accomplishment and represents a milestone for the patients who have committed to this trial and those waiting for a treatment. The Inventiva team and all the investigators, including myself, are deeply grateful for all the patients who have participated to NATIVE and the ones who will be participating in NATiV3. This publication is a major contribution to the field of NASH."

Prof. Manal Abdelmalek, M.D., M.P.H., Duke University and co-principal investigator of the Phase IIb NATIVE clinical trial, added "It is important when considering treatment strategy to have a therapeutic available that will target not only NASH but also fibrosis, the primary predictor of mortality in patients with NASH. NATIVE was the first phase IIb to meet the composite histology endpoint of NASH resolution and fibrosis improvement, achieving both FDA and EMA regulatory endpoints. While a modest increase in body weight was observed during the trial, patients receiving lanifibranor were metabolically healthy and had better lipids and glycemic profiles which are key for cardiovascular risk reduction in patients at increased risk of cardiovascular disease . The Phase IIb data certainly give us great optimism and enthusiasm for NATiV3, the phase III clinical trial."

Jean-Louis Junien, Chairman of Inventiva's Scientific Advisory Board, commented "This article translates the expertise and deep understanding of the Inventiva team of the mechanism of actions of nuclear receptors, and more specifically of PPARs, which associated with their strong experience in biology, chemistry and pharmacology has allowed Inventiva to develop lanifibranor."

Publication details

Publication ?A Randomized Controlled Trial of the panPPAR agonist lanifibranortitle: in NASH?Date of October 21, 2021publication: Sven M. Francque, Pierre Bedossa, Vlad Ratziu, Quentin M. Anstee, Elisabetta Bugianesi, Arun J. Sanyal, Rohit Loomba, Stephen A. Harrison, Rozalina Balabanska, Lyudmila Mateva, Nicolas Lanthier,Authors: Naim Alkhouri, Christophe Moreno, Jo:rn M. Schattenberg, Diana Stefanova-Petrova, Luisa Vonghia, Re'gine Rouzier, Maeva Guillaume, Alexander Hodge, Manuel Romero-Go'mez, Philippe Huot-Marchand, Martine Baudin, Marie-Paule Richard, Jean-Louis Abitbol, Pierre Broqua, Jean-Louis Junien, Manal F. Abdelmalek.Online http://www.nejm.org/doi/full/10.1056/NEJMoa2036205version: Print October 21, 2021 vol. 385 no. 17edition: