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The underlying studies aimed at characterizing the effects of the pan-PPAR agonist lanifibranor in two pre-clinical models of cirrhosis and in liver cells from cirrhotic patients
Lanifibranor showed clear beneficial effects leading to a marked improvement of fibrosis, portal hypertension and liver vascular resistance, three key elements of cirrhosis pathophysiology
Results in hepatic cells from cirrhotic patients further encourage the clinical evaluation of lanifibranor for the treatment of cirrhosis
Daix (France), December 7, 2020 – Inventiva (Euronext Paris and 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 need, today announced the publication of a scientific paper on the beneficial effects of lanifibranor on experimental advanced chronic liver disease (ACLD) by the peer-reviewed scientific journal Journal of Hepatology.
The article, entitled “The pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease”, discusses the effects of Inventiva’s lead drug candidate lanifibranor, a pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, in two distinct pre-clinical models of cirrhosis and in human liver cells from cirrhotic patients. The objective of the underlying studies was to evaluate the therapeutic potential of lanifibranor for the treatment of advanced cirrhosis.
Cirrhosis originates from a sustained hepatic injury that can vary in nature, with excessive alcohol consumption, unhealthy dietary habits and hepatitis B and C virus infections being the most common causes. As a consequence of long-term liver injury, tissue wound healing mechanisms may become deregulated, leading to hepatic fibrosis, which can ultimately progress to decompensated cirrhosis and, in some cases, hepatocellular carcinoma.1
The results of the pre-clinical studies show that lanifibranor improved portal hypertension, fibrosis and liver vascular resistance, three frequent and severe clinical syndromes associated with cirrhosis. The drug candidate also reduced ascites, sinusoidal capillarization, liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC) activated phenotypes as well as microvascular function and liver inflammation. Furthermore, the results show that all three PPAR isoforms were downregulated in both cirrhotic patients as well as in the
Moreover, differential expression of PPAR isoforms was observed in different liver cell types, emphasizing the importance of targeting all three isoforms for the treatment of cirrhosis. Finally, the findings also indicate that lanifibranor improved the phenotypes of isolated hepatocytes and hepatic stellate cells from cirrhotic patients, suggesting that the positive effects observed in both pre-clinical models could be translated to these patients.
Pierre Broqua, CSO and cofounder of Inventiva, commented: “We are very pleased to see our latest pre-clinical results on lanifibranor for the treatment of cirrhosis published in the renowned Journal of Hepatology. This scientific paper clearly illustrates that lanifibranor significantly improves key features of this severe disease, which still lacks a safe and effective treatment. The beneficial effects are based on our lead drug candidate lanifibranor’s capacity to target all three PPAR isoforms concomitantly and further encourage its clinical evaluation for the treatment of cirrhosis.”
Dr Jordi Gracia-Sancho, Head of the Liver Vascular Biology Team of IDIBAPS – Hospital Clínic de Barcelona and co-author of the article, added: “These studies, which combine two pre-clinical models of cirrhosis and human liver cells cultured in advanced in vitro systems, show that the pan-PPAR agonist lanifibranor improves the functionality of the cells that compose the liver microcirculatory system, leading to an improvement in portal hypertension and fibrosis. Considering the lack of treatments for advanced chronic liver disease, and its most deleterious complication portal hypertension, the findings included in this manuscript shed light on the way to develop novel therapies for patients with chronic hepatopathies.”
Title of scientific paper:
“The pan PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease”
Date of publication:
December 2, 2020
Zoe Boyer-Diaz2, Peio Aristu-Zabalza3, María Andrés-Rozas4, Claude Robert5, Martí Ortega-Ribera6, Anabel Fernández-Iglesias7, Pierre Broqua8, Jean-Louis Junien9, Guillaume Wettstein10, Jaime Bosch11, Jordi Gracia-Sancho12
Link to the article:
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 well‑balanced 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 pan‑PPAR agonist in clinical development. Inventiva believes that lanifibranor’s moderate and balanced pan‑PPAR binding profile contributes to the favorable tolerability profile that has been observed in clinical trials and pre‑clinical studies to date. The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy and Fast Track designation to lanifibranor for the treatment of NASH.
Inventiva is a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of NASH, MPS and other diseases with significant unmet medical need.
Leveraging its expertise and experience in the domain of compounds targeting nuclear receptors, transcription factors and epigenetic modulation, Inventiva is currently advancing two clinical candidates, as well as a deep pipeline of earlier stage programs.
Lanifibranor, its lead product candidate, is being developed for the treatment of patients with NASH, a common and progressive chronic liver disease for which there are currently no approved therapies. Inventiva recently announced positive topline data from its Phase IIb clinical trial evaluating lanifibranor for the treatment of patients with NASH and obtained Breakthrough Therapy and Fast Track designation for lanifibranor in the treatment of NASH.
Inventiva is also developing odiparcil, a second clinical stage asset, for the treatment of patients with subtypes of MPS, a group of rare genetic disorders. Inventiva announced positive topline data from its Phase IIa clinical trial evaluating odiparcil for the treatment of adult MPS VI patients at the end of 2019 and received FDA Fast Track designation in MPS VI for odiparcil in October 2020.
In parallel, Inventiva is in the process of selecting an oncology development candidate for its Hippo signalling pathway program. Furthermore, the Company has established a strategic collaboration with AbbVie in the area of autoimmune diseases. AbbVie has started the clinical development of ABBV‑157, a drug candidate for the treatment of moderate to severe psoriasis resulting from its collaboration with Inventiva. This collaboration enables Inventiva to receive milestone payments upon the achievement of pre-clinical, clinical, regulatory and commercial milestones, in addition to royalties on any approved products resulting from the collaboration.
The Company has a scientific team of approximately 70 people with deep expertise in the fields of biology, medicinal and computational chemistry, pharmacokinetics and pharmacology, as well as in clinical development. It also 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 C 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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1 Pellicoro A, Ramachandran P, Iredale JP, et al. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat Rev Immunol 2014;14:181–194.
2 Zoe Boyer-Diaz: MSc, Barcelona Liver Bioservices, Barcelona, Spain.
3 Peio Aristu-Zabalza: MSc, Barcelona Liver Bioservices, Barcelona, Spain.
4 María Andrés-Rozas: MSc, Barcelona Liver Bioservices, Barcelona, Spain.
5 Claude Robert: MSc, Inventiva, Daix, France.
6 Martí Ortega-Ribera: MSc, Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain.
7 Anabel Fernández-Iglesias: PhD, Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain & PhD, CIBEREHD, Madrid, Spain.
8 Pierre Broqua: PhD, Inventiva, Daix, France.
9 Jean-Louis Junien: PhD, Inventiva, Daix, France.
10 Guillaume Wettstein: PhD, Inventiva, Daix, France.
11 Jaime Bosch: MD & PhD, Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain, CIBEREHD, Madrid, Spain, Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland.
12 Jordi Gracia-Sancho: PhD, Barcelona Liver Bioservices, Barcelona, Spain, Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain, CIBEREHD, Madrid, Spain, Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland.