Date: 2017-06-20
Type of
information: Publication of results in a medical journal
phase: preclinical
Announcement: publication of results in Hepatology Communications
Company: Inventiva Pharma (France)
Product: IVA337 - lanifibranor- 1-(6-benzothiazolylsulfonyl)-5-chloro-1H-indole-2-butanoic acid)
Action
mechanism:
- PPAR modulator. This compound is a peroxisome proliferator activated receptors (PPAR) modulator. It has demonstrated anti-fibrotic properties in several tissues alongside good clinical tolerance. Its unique mechanism of action goes through the activation of all three alpha, gamma and delta PPARs to slow, halt or reverse the progression of fibrosis.
- IVA337 has received orphan drug status for the treatment of systemic sclerosis in Europe and the United States.
- Inventiva is currently conducting Phase IIb clinical trials with IVA337 in both NASH and systemic sclerosis, and results are expected in the second half of 2018.
Disease: NASH (non-alcoholic steatohepatitis)
Therapeutic
area: Liver diseases - Hepatic diseases
Country:
Trial
details:
Latest
news:
- • On June 20, 2017, Inventiva announced the peer review publication of data on the effects of IVA337 in various preclinical models of NASH. The paper "The New-Generation Pan-Peroxisome Proliferator-Activated Receptor Agonist IVA337 Protects the Liver From Metabolic Disorders and Fibrosis" is published in the June 19th, 2017 edition of the peer -reviewed journal Hepatology Communications. The authors of the paper include several leading experts on NASH, including Professor Isabelle Leclerc from the University of Leuven (Belgium), Professor Derek Mann from the University of Newcastle (UK), Professor Sven Francque from the University Hospital of Antwerp (Belgium), as well as company scientists.
Summary of Key Findings from Preclinical NASH Studies:
The effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH were investigated. These models comprised a diet-induced obesity model (high-fat/highsucrose diet); a methionine- and choline-deficient diet (MCD model); the foz/foz model; the CCl4-induced liver
fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. In the two latter models, IVA337 displayed an antifibrotic efficacy superior to selective PPAR?, PPAR? or PPAR?
agonists.
HF/HS model: This 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.
MCD model: In mice fed with a methionine- and choline-deficient diet, IVA337 completely prevented steatosis and to a large extent reduced necroinflammatory changes.
HFD foz/ foz model: 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.
CCL4- liver fibrosis: IVA337 demonstrated both preventive and curative effects on fibrosis induced by CCl4.
IVA337 inhibited the expression of profibrotic and inflammasome genes while increasing the expression of oxidation-related and fatty acid desaturation-related genes in both the methionine and choline-deficient diet and the foz/foz model.
In vitro experiments were conducted to investigate the effect of IVA337 on human hepatic stellate cells (HSCs) which are the key cells driving liver fibrogenesis in NASH. IVA337 was shown to inhibit proliferation and activation of these cells.
Is
general: Yes
