SHANGHAI—Gannex Pharma Co., Ltd., a wholly owned company of Ascletis Pharma Inc., recently announced that the company has filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for its non-alcoholic steatohepatitis (NASH) drug candidate ASC42.
“We are excited about US IND filing of the in-house developed ASC42 that has the potential to be a best-in-class FXR agonist,” stated Dr. Handan He, chief scientific officer of Ascletis. “ASC42 IND filing demonstrated again our confidence and capability to develop first-in-class or best-in-class NASH drug candidates through our internal effort.”
ASC42 is a Farnesoid X Receptor (FXR) agonist. In two NASH animal models, ASC42 demonstrated significant improvements in liver steatosis, inflammation and fibrosis. Gannex also has two other drug candidates at the clinical stage in its NASH pipeline — ASC40 and ASC41. ASC42 is expected to be used alone or in combination with ASC40 or ASC41.
ASC40 is an oral fatty acid synthase (FASN) inhibitor. In the Phase 2 FASCINATE-1 randomized, placebo-controlled trial of 99 patients in the U.S., clinicians evaluated the safety and efficacy of oral, once-daily dosing of ASC40 (TVB-2640) for 12 weeks. The preliminary data showed that ASC40 significantly reduced liver fat — the primary efficacy endpoint of the trial — with a 61% responder rate in the 50 mg group. Participants also showed improvement in markers of liver function and fibrosis.
On August 28, FASCINATE-1 data were presented as a Late Breaker at the virtual European Association for the Study of the Liver International Liver Congress 2020.
ASC41 is an oral thyroid hormone receptor beta (THR-beta) agonist which recently received IND approval from China’s National Medical Products Administration (NMPA) to conduct clinical trials for NASH indication. Topline data of Phase 1 safety, pharmacokinetic and preliminary efficacy (LDL-C) in healthy volunteers with LDL-C > 110 mg/dL is expected to be available by the end of 2020.
On September 9, Gannex Pharma also reported that the company has entered into a research agreement which aims at a combination therapy of ASC41 and Aramchol for the treatment of NASH with Galmed Pharmaceuticals Ltd. The financial details of the transaction were not disclosed.
“There is a significant medical need and a large potential pharmaceutical market for NASH treatment. There are currently no drugs licensed for the treatment of NASH in [the] U.S., Europe and China,” Dr. Jinzi J. Wu, founder, chairman and CEO of Ascletis, noted in a press release. “ASC41 is a THR-beta agonist that improves steatosis, inflammation and fibrosis, and Aramchol, an SCD 1 inhibitor, reduces glycemic index and fibrosis. Therefore, combination therapy of the two drug candidates could result in synergistic effect for the treatment of NASH.”
ASC41’s active moiety selectively activates THR-beta, resulting in the improvement of steatosis/lipotoxicity, inflammation, ballooning and fibrosis. In two NASH animal models, ASC41 demonstrated the same improvement in liver steatosis, inflammation and fibrosis at 1/10 dose of Resmetirom (MGL-3196), another THR-beta agonist currently in Phase 3 clinical trial.
Aramchol is a novel synthetic small molecule, a conjugate of cholic acid and arachidic acid linked by a stable amide group. The drug candidate exerts its anti-steatotic and anti-fibrotic effects via inhibition of SCD 1 expression in hepatocytes and hepatic stellate cells (HSCs). In hepatocytes, reduction of SCD 1 results in elevation of AMPK, FA oxidation and Glutathione ratio. In HSCs, inhibition of SCD 1 results in specific up regulation of PPARγ, which blocks collagen production.
In Phase 2 clinical trials for NASH, Aramchol significantly reduced liver fat, improved liver histology, hepatic biochemistry and glycemic parameters with a favorable safety and tolerability profile. Aramchol is currently in a Phase 3 registrational study for NASH and fibrosis (ARMOR). It has been granted Fast Track designation status by the FDA for the treatment of NASH.
“By combining ASC41, THR-beta agonist, which is clinically proven to rapidly reduce liver fat and improved blood lipids profile, with Aramchol, SCD 1 inhibitor, which is clinically proven to reduce glycemic index and fibrosis, physicians will have good and solid toolbox and will be able to normalize NASH patients for life and control the disease. We believe that combining these two distinct and selective compounds with complementary mechanisms will provide a perfect treatment for NASH,” added Allen Baharaff, president and CEO of Galmed.
