Ascletis Announces Dosing of the First Patient in Phase II Clinical Trial of THRβ Agonist ASC41 for 52-Week Treatment of Liver Biopsy-Proven NASH

-- ASC41 is ranking first in China and third in the world in terms of clinical progress as a thyroid hormone receptor β (THRβ) agonist drug candidate for non-alcoholic steatohepatitis (NASH). ASC41 Phase II clinical trial is currently the most advanced 52-week Phase II clinical trial which is initiated by a China biotech company with enrollment of liver biopsy-proven NASH patients

-- The Phase II clinical trial will enroll approximately 180 liver biopsy-proven NASH patients to be randomized into two treatment arms and one placebo control arm at the ratio of 1:1:1 with oral administration of ASC41 (2 mg or 4 mg) or placebo once daily for 52 weeks. The enrollment is expected to be completed in the third quarter of 2023

-- The primary endpoint of the Phase II clinical trial is non-alcoholic fatty liver disease (NAFLD) activity score (NAS) improvement ≥2 points (improvement in inflammation or ballooning) and no worsening of fibrosis

HANGZHOU and SHAOXING,China,Oct. 5,2022 --Ascletis Pharma Inc. (HKEX: 1672,"Ascletis") announces dosing of the first patient in the 52-week Phase II clinical trial of thyroid hormone receptor β (THRβ) agonist ASC41 for treatment of liver biopsy-proven non-alcoholic steatohepatitis (NASH) patients. ASC41 Phase II clinical trial is currently the most advanced 52-week Phase II clinical trial which is initiated by China biotech company with enrollment of liver biopsy-proven NASH patients.

The randomized,double-blind,placebo-controlled and multi-center Phase II clinical trial intends to evaluate the safety and efficacy of ASC41 for treatment of liver biopsy-proven NASH patients,and will enroll approximately 180 liver biopsy-proven NASH patients to be randomized into two treatment arms and one placebo control arm at the ratio of 1:1:1 with oral administration of ASC41 (2 mg or 4 mg) or placebo once daily for 52 weeks. The enrollment is expected to be completed in the third quarter of 2023.

ASC41 is a liver-targeted prodrug,and its active metabolite is a selective THRβ agonist. THRβ is highly expressed in the liver,and THRβ agonists have demonstrated to be active in reducing low density lipoprotein (LDL),triglyceride (TG) and hepatic steatosis in humans. By promoting fatty acid breakdown and stimulating mitochondrial biogenesis,THRβ helps to reduce lipotoxicity and improve liver function,thereby reducing liver fat.

In January 2021,Ascletis announced the completion of a randomized,placebo controlled single- and multiple-ascending dose Phase I clinical trial in 65 subjects with elevated low-density lipoprotein cholesterol (LDL-C) (>110 mg/dL),in which subjects demonstrated clinically meaningful and statistically significant reduction in LDL-C and TG compared with placebo after 14 days treatment of once daily oral dosing of ASC41 tablet. At a very low dose of 1 mg,placebo-adjusted relative TG reduction from baseline was 39% (P=0.002) (https://www.ascletis.com/news_detail/175/id/454.html). Compared with THRβ agonist Resmetirom (MGL-3196),ASC41 has higher potency and requires lower dosage (1 mg) to reach over 30% relative TG reduction as placebo-adjusted.

In February 2021,Ascletis announced positive clinical results in overweight and obese subjects for ASC41. Preliminary data suggested that over 28 days of oral dosing of ASC41,subjects demonstrated sustainable,clinically meaningful and statistically significant reduction in LDL-C,TG and total cholesterol (TC),compared with placebo. High-density lipoprotein cholesterol (HDL-C) remained relatively unchanged (https://www.ascletis.com/news_detail/175/id/462.html).

In September 2021,Ascletis completed the U.S. Phase I trial of drug-drug interactions in healthy subjects and pharmacokinetics (PK) in patients with non-alcoholic fatty liver disease (NAFLD) for ASC41 oral tablets. ASC41 is mainly metabolized by CYP3A4 to form an active metabolite ASC41-A,a selective THRβ agonist. This clinical study results demonstrated that clinically significant drug-drug interactions would be unlikely between ASC41/ASC41-A and antidepressants (selective-serotonin/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs),most of them are mild/moderate CYP3A4 inhibitors),which are commonly used in NASH patient population. It also revealed that the PK of ASC41/ASC41-A in healthy volunteers was not significantly different from that in patients with NAFLD (https://www.ascletis.com/news_detail/175/id/537.html).

"Non-alcoholic fatty liver disease (NAFLD) has become one of the most important causes of chronic liver disease,with a prevalence of 25% globally[1],one-fifth of which will progress to non-alcoholic steatohepatitis (NASH). NASH will become the major cause of liver transplant in a decade. According to statistics,there will be 48.26 million and 27 million NASH patients in China and the U.S. in 2030 [1],respectively.Despite the huge patient population,the U.S. Food and Drug Administration,European Medicines Agency and China National Medical Products Administration have not approved any NASH treatment,which indicates a huge unmet medical need. THRβ is a promising therapeutic target for treatment of NASH. Studies have shown that THRβ agonist can significantly improve NASH and inflammation[2]. I'm looking forward to advancing the clinical study and bringing more benefits to NASH patients." Said Dr. Junping Shi,Deputy Dean of the Affiliated Hospital of Hangzhou Normal University,Advisor of National Workshop on Fatty Liver and Alcoholic Liver Disease,Chinese Society of Hepatology,Chinese Medical Association and principal investigator of ASC41-NASH.

"Ascletis is at the frontier of NASH research in China and even in the world. Leveraging in-house R&D capabilities and global cooperation,Ascletis has established a broad pipeline of NASH candidates. Addition to the three promising single-drug candidates targeting fatty acid synthase (FASN),thyroid hormone receptor β (THRβ) and farnesol X receptor (FXR),respectively,Ascletis also developed three combination therapies. Dosing the first biopsy-proven NASH patient in ASC41 Phase II clinical trial marks a great milestone to us. Meanwhile,ASC40 (FASN),Ascletis' another NASH candidate will update topline results of interim analysis from the Phase IIb clinical trial in biopsy-proven NASH patients in the fourth quarter,2022. All these progresses once again demonstrate our in-depth insights and strong R&D capabilities. We will continue to advance clinical studies of our NASH pipeline and bring more benefits to patients worldwide." said Dr. Jinzi J. Wu,Founder,Chairman and CEO of Ascletis.

[1] YOUNOSSI Z,ANSTEE QM,MARIETTI M,et al. Global burden of NAFLD and NASH: Trends,predictions,risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol,2018,15(1): 11-20. DOI: 10.1038/nrgastro.2017.109.

[2]Harrison S A,Bashir M R,Guy C D,et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre,randomised,placebo-controlled,phase 2 trial [J]. Lancet (London,England) 2019,394(10213): 2012-24. DOI: 10.1016/s0140-6736(19)32517-6

About Ascletis

Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK),covering the entire value chain from discovery and development to manufacturing and commercialization. Led by a management team with deep expertise and a proven track record,Ascletis focuses on three therapeutic areas with unmet medical needs from a global perspective: viral diseases,non-alcoholic steatohepatitis (NASH) and oncology. Through excellent execution,Ascletis rapidly advances its drug pipeline with an aim of leading in global competition. To date,Ascletis has three marketed products,i.e. ritonavir tablets,GANOVO® and ASCLEVIR®,and 20 drug candidates in its R&D pipeline. The most advanced drug candidates include ASC22 (HBV functional cure),ASC10 and ASC11(oral small molecules for COVID-19 treatment),ASC40 (recurrent glioblastoma),ASC42 (PBC,primary biliary cholangitis),and ASC40 (acne).

For more information,please visit www.ascletis.com.