DAIX, France—Inventiva, a biopharmaceutical company developing therapies to treat fibrosis, has announced the peer-review publication of data on the effects of its lead drug candidate IVA337, a pan-PPAR (peroxisome proliferator-activated receptor) agonist currently in Phase 2b clinical development in various preclinical models of non-alcoholic steatohepatitis (NASH). The paper, “The New-Generation Pan-Peroxisome Proliferator-Activated Receptor Agonist IVA337 Protects the Liver From Metabolic Disorders and Fibrosis,” was published in the June 19 edition of Hepatology Communications.
The authors of the paper include several leading experts on NASH, including Prof. Isabelle Leclerc from University of Leuven, Belgium; Prof. Derek Mann from University of Newcastle, United Kingdom; and Prof. Sven Francque from University Hospital of Antwerp, Belgium, as well as Inventiva company scientists.
“We are pleased to announce this peer-review publication of our IVA337 data. These studies demonstrate that the molecule improves metabolic parameters and NASH histopathologic features, such as steatosis, ballooning, inflammation and fibrosis, in several relevant animal models,” said Dr. Pierre Broqua, chief scientific officer and co-founder of Inventiva. “Based on these results, together with a good safety profile differing from previously developed PPAR agonists, we believe that IVA337 is a promising candidate for NASH treatment. We are currently enrolling patients in a Phase 2b trial in NASH.”
Frédéric Cren, CEO and co-founder of Inventiva, tells DDNews, “PPAR are nuclear receptors involved in the regulation of cell metabolism and fibrosis that act through three subtypes: PPARα, δ and γ. IVA337 is a next-generation pan-PPAR modulator capable of acting on several key stages of fibrosis. IVA337 was designed to moderately and equipotently activate the three PPAR subtypes involved in the fibrotic process.”
“The combined action of modulating the three PPAR isoforms should enable IVA337 to slow down, block and even reverse the progression of fibrosis. IVA337 has demonstrated antifibrotic properties in several tissues and organs, including the liver, skin, lungs and kidneys,” says Cren. “It also offers therapeutic prospects for systemic sclerosis (SSc), which is characterized by fibrosis and vascular obliteration in the skin, lungs, heart, digestive system and kidneys, leading to a failure of these vital organs.” “In preclinical and clinical trials, IVA337 has shown an excellent tolerability and safety profile, as well as a beneficial effect on several metabolic parameters demonstrating its therapeutic potential: improvement of the insulin resistance; triglycerides decrease; adiponectin (an anti inflammatory adipocytokine playing a positive role in the insulin sensitivity) increase; and HDL cholesterol increase,” he continues. “We believe that these positive metabolic effects together with the anti-fibrotic activity of the product on the liver make IVA337 an ideal drug candidate.” According to Cren, Inventiva initiated the Phase 2b study NATIVE (NAsh Trial to Validate IVa337 Efficacy) in Europe in January. The effects of IVA337 were investigated on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine- and choline-deficient diet model; the foz/foz model; the CCl4-induced liver fibrosis model (prophylactic and therapeutic); and human primary hepatic stellate cells.
In the latter two models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ or PPARγ agonists. The diet-induced obesity model was used to evaluate the effect of IVA337 on insulin resistance and other parameters linked to metabolic syndrome. IVA337 dose dependently reduced body weight gain, normalized insulinemia and non-fasting glucose and reduced circulating leptin levels.
In mice fed with a methionine- and choline-deficient diet, IVA337 completely prevented steatosis and to a large extent reduced necroinflammatory changes. The effect of IVA337 was investigated in the Alsm1 mutant foz/foz mice, in which steatohepatitis occurs as a complication of severe obesity and insulin resistance. This model closely reproduces the natural history of NASH in humans. IVA337 largely attenuated steatosis and ballooning, and reduced macrophage recruitment and fibrotic gene expression.
IVA337 inhibited the expression of profibrotic and inflammasome genes while increasing the expression of β-oxidation-related and fatty acid desaturation-related genes in both the methionine and choline-deficient diet and the foz/foz model. IVA337 demonstrated both preventive and curative effects on fibrosis induced by CCl4. In-vitro experiments were also conducted to investigate the effect of IVA337 on human hepatic stellate cells. IVA337 inhibited proliferation and activation of these cells.
“If positive results are obtained, this Phase 2b study will be followed by a Phase 3 pivotal trial in Europe and the United States. We also believe that this Phase 3 study, if positive, will allow [us] to file for marketing approval application in these two geographical areas. IVA337’s anti-fibrotic effects also pave the way for the treatment of other fibrotic diseases. Inventiva has decided to develop IVA337 as the first treatment that can slow and even block the progression of SSc, a disease with significant sales potential, and for which IVA337 has been given orphan status in Europe and the United States, Cren continues.
“A Phase 2b trial (FASST: For A Systemic Sclerosis Treatment) was initiated [in] 2015. If positive results are obtained from the FASST study, we intend to discuss the possibility of a conditional marketing approval for IVA337 with the European regulatory authorities, based on the existence of an unmet medical need for the treatment of patients with SSc. This would allow the product to be marketed at the same time as the Phase 3 pivotal trial,” he concludes.