--No pruritus observed during 14-day treatment of the once-daily human therapeutic dose of 15 mg.
--FXR target engagement biomarker FGF19 increased 1632% on Day 14 of treatment with 15 mg, once-daily.
--FXR target engagement biomarker C4 decreased 93% on Day 14 of treatment with 15 mg, once-daily.
--Mean LDL-C values remained within the normal range during 14-day, once daily treatment with 15 mg.
--There were no treatment-emergent ALT and AST elevations during 14-day, once daily treatment with 15 mg.
--Doses selected for Phase II trial in patients with NASH, which will be initiated by the end of 2021.
Shanghai, China, June 16, 2021-- Gannex, a wholly owned company of Ascletis Pharma Inc. (HKEX: 1672), fully dedicated to the R&D and commercialization of new drugs in the field of non-alcoholic steatohepatitis (NASH), today announces positive topline results of safety and pharmacodynamic biomarkers from the U.S. Phase I trial of NASH drug farnesoid X receptor (FXR) agonist ASC42.
The ASC42 Phase I trial in the U.S. was a first-in-human, randomized, placebo-controlled, double-blind single-ascending dose (SAD), multiple-ascending dose (MAD), and food effect trial in 64 healthy subjects receiving ASC42 or matching placebo. Doses in the SAD portion ranged from 5 to 200 mg doses and in the MAD portion ranged from 5 to 50 mg administered once-daily for 14 days. The food effect on ASC42 pharmacokinetics was studied with a dose of 15 mg. The primary objective was to evaluate the safety, pharmacokinetics and pharmacodynamics of ASC42 versus placebo. Biomarkers for FXR target engagement were assessed through measurement of 7α-hydroxy-4-cholesten-3-one (C4), a blood biomarker of bile acid synthesis that decreases with FXR activation, and Fibroblast Growth Factor 19 (FGF19), a hormone produced after FXR activation in the intestine that regulates bile acid synthesis as well as glucose and lipid metabolism.
Based on both mouse and rat NASH animal models, the predicted human therapeutic dose was 15 mg once-daily. ASC42 Phase I topline data showed that during 14-day treatment with15 mg once-daily, Day 1 and Day 14 FGF19 levels increased 1195% and 1632% from the pre-dose level, respectively; Day 1 and Day 14 C4 levels decreased 88% and 93% from the baseline, respectively. Based on these data, 15 mg once-daily dose has been selected as one of 3 doses to be studied in the Phase II trial in patients with NASH, that will be initiated by the end of 2021. The magnitude of FGF19 increase and/or C4 decrease may be used to project potential levels of liver fat reduction in patients with NASH, with a ≥30% relative liver fat reduction on MRI-PDFF potentially correlating with an increased likelihood of histologic benefit.
Overall, ASC42 was safe and tolerated and there were no study drug related SAEs or premature discontinuations. Notably, there was no pruritus, mean LDL-C values remained within normal limits and there were no treatment-emergent ALT and AST elevations for 14-day, once daily dosing with 15 mg.
In addition, there was no significant food effect on the pharmacokinetic profile of ASC42 with a high fat meal.
Melissa Palmer, M.D., Chief Medical Officer of Gannex, said, “We are excited about the safety and tolerability profile of ASC42 and looking forward to initiating a Phase II trial by the end of 2021.”
Handan He, Ph.D., Chief Scientific Officer of Ascletis, said, “We are thrilled by our discovery team’s successful prediction of the ASC42 human therapeutic dose using the preclinical PK/PD data. This expertise has enabled us to accelerate many of our internal discovery programs.”
ASC42 is an in-house developed, novel non-steroidal, selective, potent FXR agonist with best-in-class potential. ASC42 is an oral tablet formulation developed with in-house proprietary technology and is stable at room temperature. ASC42 is expected to be used alone and in combination with thyroid hormone receptor beta (THR-β) agonist ASC41 or fatty acid synthase (FASN) inhibitor ASC40.
Ascletis is an innovative R&D driven biotech and listed on Hong Kong Stock Exchange (1672.HK). Ascletis is committed to developing and commercializing innovative drugs in the areas of NASH, cancer lipid metabolism and oral checkpoint inhibitors, viral hepatitis and HIV/AIDS for unmet medical needs in China and globally. Led by a management team with deep expertise and a proven track record, Ascletis has developed into a fully integrated platform covering the entire value chain from discovery and development to manufacturing and commercialization.
Ascletis has three marketed products and seventeen R&D pipeline drug candidates or combination therapies (eleven of them developed in-house). 1. NASH: Gannex, a wholly-owned company of Ascletis, is fully dedicated to the R&D and commercialization of new drugs in the field of NASH. Gannex has three clinical stage drug candidates against three different targets – FASN, THR-beta and FXR, and three combination therapies. 2. Cancer lipid metabolism and oral checkpoint inhibitors: focus on a pipeline of oral inhibitors targeting FASN which plays a key role in cancer lipid metabolism and a pipeline of oral PD-L1 small molecule inhibitors as the next generation checkpoint inhibitors. 3. Viral hepatitis: (i) Hepatitis B: focus on breakthrough therapies for HBV clinical cure with subcutaneously injected PD-L1 antibody - ASC22 and Pegasys® as cornerstone drugs. (ii) Hepatitis C: successfully launched all oral regimen of ASCLEVIR® and GANOVO® combination (RDV/DNV regimen); and ASC18 fixed dose combination (FDC) is an upgraded version of RDV/DNV regimen with bridging study finished. 4. HIV/AIDS: ASC09F is a FDC treatment of HIV targeting protease. The clinical trial application of ASC09F has been approved. For more information, please visit www.ascletis.com.
Ascletis Pharma Inc.
Chenlin Li, +86-159-6815-8530