Inventiva announces positive results from the Phase II, LEGEND, Proof-of-Concept study combining lanifibranor with empagliflozin in patients with MASH/NASH and T2D

LEGEND achieved its primary efficacy endpoint by significantly lowering HbA1c level in both the lanifibranor arm and in the lanifibranor with empagliflozin arm compared to placebo.

Statistical significance was also achieved on several markers of liver injury, markers of glucose and lipid metabolism, as well as hepatic steatosis.

Patients treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24 weeks study, addressing the moderate, metabolically healthy, weight gain that has been observed in some patients treated with lanifibranor.

Treatment with lanifibranor alone and in combination with empagliflozin decreased the ratio of visceral abdominal fat to subcutaneous fat, reflecting a shift from pro-inflammatory visceral fat towards metabolically healthy adipose tissue.

The treatment with lanifibranor 800mg/once daily alone or in combination with empagliflozin for 24 weeks was well tolerated, with no safety concerns reported.

Inventiva will host an investor webcast Tuesday, March 19th at 8am ET (details below).

March 18, 2024 – Inventiva (Euronext Paris and Nasdaq: IVA), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), and other diseases with significant unmet medical needs, today announces positive results of its interim analysis of the Phase II, Proof-of-Concept clinical trial, LEGEND, evaluating lanifibranor in combination with empagliflozin in patients with MASH/NASH and poorly controlled Type 2 Diabetes (T2D).

The LEGEND trial has been designed as a multi-center, randomized, 24-week treatment, placebo-controlled Phase II Proof-of-Concept trial to assess the safety and efficacy of lanifibranor in combination with the SGLT2 inhibitor empagliflozin for the treatment of patients with non-cirrhotic MASH/NASH and T2D. The trial is double-blind for the placebo arm and lanifibranor (800mg daily) arm, and open-label for the combination of lanifibranor (800mg daily) and empagliflozin (10 mg daily) arm. The diagnosis of non-cirrhotic MASH/NASH was based on historic histology evaluation or a combination of non-invasive methods including diagnostic methods including imaging. As planned per protocol, the interim analysis was done once half of the 63 planned randomized patients with MASH completed the 24-week treatment period or prematurely discontinued from treatment.

The study achieved the primary efficacy endpoint with an absolute reduction in Hemoglobin A1c (HbA1c) of 1.14% and 1.59% in patients with MASH and T2D treated with lanifibranor (800mg daily) or in combination with empagliflozin (10mg daily) at week 24 compared to an increase of 0.26% observed in the placebo arm.

The study also demonstrated a statistically significant reduction in hepatic steatosis measured by MRI-PDFF1, in patients treated with lanifibranor alone and in combination with empagliflozin, -47% and -38% respectively, compared to placebo (0%). 83% and 67% of patients treated with lanifibranor alone or in combination with empagliflozin respectively, showed a reduction greater or equal to 30% of their hepatic fat, compared to 0% in the placebo arm. In addition, the study demonstrated a statistically significant effect on several secondary and exploratory endpoints, including liver enzymes (alanine aminotransferase (“ALT”) and aspartate aminotransferase (“AST”)), insulin resistance (HOMA-IR), HDL, and adiponectin (see tables below). Markers of liver inflammation and fibrosis (corrected T1 relaxation time (cT1) assessed by LiverMultiScan®) were assessed for the first time with lanifibranor and showed a significant effect with lanifibranor alone and in combination with empagliflozin.

The study also demonstrated that patients treated with lanifibranor in combination with empagliflozin maintained a stable weight throughout the 24 weeks study, addressing the moderate, metabolically healthy, weight gain that can be observed in some patients treated with lanifibranor alone. Furthermore, these results demonstrated a significant relative reduction in the VAT/SAT ratio (visceral and subcutaneous adipose tissue) in patients treated with lanifibranor alone or in combination with empagliflozin, -5% and -17% respectively, compared to an increase of 11% in patients under placebo. This result reflects a shift from pro-inflammatory visceral fat towards metabolically healthy adipose tissue.

The treatment with lanifibranor 800mg/daily alone and in combination with empagliflozin 10mg/daily for 24 weeks appears to be well tolerated, with no safety concerns reported.

Dr. Michael Cooreman, M.D., Chief Medical Officer of Inventiva: “The results of the LEGEND study announced today further illustrate the potential of lanifibranor to address the broad spectrum of the disease biology of MASH and T2D. These data complement the already published dataset of lanifibranor demonstrating fibrosis improvement and MASH resolution but also its role as a potent insulin sensitizer. With roughly 50% of the U.S. population estimated to have either prediabetes or diabetes, and the well-established correlation between MASH and T2D, lanifibranor has a unique mechanism of action to potentially address the medical need of patients with both MASH and T2D. We wish to thank the patients who participated in the study and the investigators of LEGEND.”

Dr. Onno Holleboom, MD PhD, endocrinologist and associate professor at Amsterdam UMC, co-principal investigator of the LEGEND Phase II clinical trial: “It is a big step seeing these positive results of LEGEND demonstrating the impact of lanifibranor on steatosis, inflammation and fibrosis while stabilizing weight with empagliflozin in patients with poorly controlled T2D and MASH. The study was designed as a proof of concept and these results are significant and strengthen confidence in the potential of lanifibranor to address the specific metabolic unbalance in patients with T2D while also addressing steatosis and fibrosis, a hepatic consequence of insulin resistance.”

Prof. Michelle Lai, M.D., Ph.D., Beth Israel Deaconess Medical Center and co-principal investigator of the LEGEND Phase II clinical trial, said: “These LEGEND results provide valuable insights on the complementary mechanisms of action of an SGLT2 inhibitor and the panPPAR agonist, lanifibranor. MASH is a multifaceted disease that we believe will benefit from combination therapies in order to properly address the full cardiometabolic spectrum of the disease. These results of LEGEND suggest that lanifibranor in combination with empagliflozin could be an ideal combination for patients we care for in our clinic who suffer from T2D and MASH.”

Given that the primary endpoint of LEGEND was met, and statistically significant results were achieved on several key additional markers, the Company has decided to stop the recruitment as defined per protocol. More details on these results are expected to be presented in upcoming scientific conferences and submitted for publication.

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来源: GlobeNewswire-Health Care

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来源: GlobeNewswire-Health Care

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来源: GlobeNewswire-Health Care

Conference call

Inventiva will host a conference call and webcast with slide presentation on Tuesday, March 19, 2024 at 8:00 am ET (New York time) 1:00 pm CET (Paris time).

Introduced by Frederic Cren, Chairman, CEO and cofounder of Inventiva, this event will be as follow:

Presentation of LEGEND Results - Michael Cooreman, M.D., CMO of Inventiva

Metabolic and hepatic benefits of lanifibranor - Stephen Harrison, M.D., Pinnacle Clinical Research and principal investigator of the exploratory cohort of NATiV3, Phase III clinical trial

Vascular benefits of lanifibranor - Sven Francque, M.D., University Hospital Antwerp, co-principal investigator of NATiV3, Phase III clinical trial

Opportunity for lanifibranor - Frederic Cren, CEO and cofounder of Inventiva

The conference call and the slides of the presentation will be webcast live at: https://edge.media-server.com/mmc/p/hyuvxf9a and will also be available on Inventiva’s website: Investor Presentations - Inventiva Pharma. In order to receive the conference access information necessary to participate to the conference call, it is required to register in advance using the following link: https://register.vevent.com/register/BI334d62953abb41cea27de99dc5da974c . Participants will need to use the conference access information provided in the e-mail received at the point of registering (dial-in number and access code).

About lanifibranor

Lanifibranor, Inventiva’s lead product candidate, is an orally-available small molecule that acts to induce anti-fibrotic, anti-inflammatory and beneficial vascular and metabolic changes in the body by activating all three peroxisome proliferator activated receptor (PPAR) isoforms, which are well characterized nuclear receptor proteins that regulate gene expression. Lanifibranor is a PPAR agonist that is designed to target all three PPAR isoforms in a moderately potent manner, with a ‑wellbalanced‑ activation of PPARα and PPARδ, and a partial activation of PPARγ. While there are other PPAR agonists that target only one or two PPAR isoforms for activation, lanifibranor is the only panPPAR‑ agonist in clinical development for the treatment of MASH/NASH. Inventiva believes that lanifibranor’s moderate and balanced panPPAR‑ binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and preclinical studies to date. The FDA has granted Breakthrough Therapy and Fast Track designation to lanifibranor‑ for the treatment of MASH/NASH.

About Inventiva

Inventiva is a clinical-stage biopharmaceutical company focused on the research and development of oral small molecule therapies for the treatment of patients with MASH/NASH, and other diseases with significant unmet medical need. The Company benefits from a strong expertise and experience in the domain of compounds targeting nuclear receptors, transcription factors and epigenetic modulation. Inventiva is currently advancing one clinical candidate, has a pipeline of two preclinical programs and continues to explore other development opportunities to add to its pipeline.

Inventiva’s lead product candidate, lanifibranor, is currently in a pivotal Phase III clinical trial, NATiV3, for the treatment of adult patients with MASH/NASH, a common and progressive chronic liver disease for which there are currently no approved therapies.

Inventiva’s pipeline also includes odiparcil, a drug candidate for the treatment of adult MPS VI patients. As part of Inventiva’s decision to focus clinical efforts on the development of lanifibranor, it suspended its clinical efforts relating to odiparcil and is reviewing available options with respect to its potential further development. Inventiva is also in the process of selecting a candidate for its Hippo signaling pathway program.

The Company has a scientific team of approximately 90 people with deep expertise in the fields of biology, medicinal and computational chemistry, pharmacokinetics and pharmacology, and clinical development. It owns an extensive library of approximately 240,000 pharmacologically relevant molecules, approximately 60% of which are proprietary, as well as a wholly-owned research and development facility.

Inventiva is a public company listed on compartment B of the regulated market of Euronext Paris (ticker: IVA, ISIN: FR0013233012) and on the Nasdaq Global Market in the United States (ticker: IVA). www.inventivapharma.com

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