Hangzhou and Shaoxing, China, December 21, 2022-- The enrollment of the 52-week Phase II clinical trial of thyroid hormone receptor β (THRβ) agonist ASC41 developed in house by Gannex Pharma Co., Ltd., a wholly owned subsidiary of Ascletis Pharma Inc. (HKEX: 1672, “Ascletis”), for treatment of liver biopsy-proven non-alcoholic steatohepatitis (NASH) patients is progressing as planned. 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 first patient was dosed in early October, 2022.The enrollment is expected to be completed by the end of the third quarter, 2023.
On December 19, 2022, Madrigal Pharmaceuticals, Inc. released the results from Phase III clinical trial of Resmetirom (MGL-3196) for the 52-week treatment of biopsy-proven NASH patients. Table 1 shows the comparison between the study designs of ASC41 and Resmetirom.
Table 1. Ascletis’ ASC41 Phase II VS Madrigal's Resmetirom Phase III
ASC41 Phase II |
Resmetirom Phase III |
|
Target |
THRβ |
THRβ |
Dosage |
Placebo, ASC41 2 mg, ASC41 4 mg, once daily |
Placebo, Resmetirom 80 mg, Resmetirom 100 mg, once daily |
Liver biopsy-proven? |
Yes |
Yes |
Treatments |
52 weeks |
52 weeks |
Enrollments |
180 patients |
around 1000 patients |
Ratio |
1:1:1 |
1:1:1 |
Inclusion |
NASH on liver biopsy: NASH F1 (up to 15%), F2, or F3, NAS≥4
|
NASH on liver biopsy: NAS≥4 with fibrosis stage 1A (up to 3%) 1B, total F1 up to 15%; F3, at least 50%, the rest F2 |
Histology efficacy endpoints |
Resolution of NASH at Week 52 with at least 2 point reduction in NAS (improvement in inflammation or ballooning) with no worsening of fibrosis; OR reduction in fibrosis stage by 1-point with no worsening of NAS |
Resolution of NASH at Week 52 with at least 2 point reduction in NAS with no worsening of fibrosis; OR reduction in fibrosis stage by 1-point with no worsening of NAS |
Key secondary endpoint |
LDL-C lowering at Week 12, Week 24 , and Week 52 |
LDL-C lowering at Week 24 |
ASC41 is a liver-targeted prodrug, and its active metabolite is a selective THRβ agonist. In January 2021, Ascletis announced the completion of a randomized, double-blind, 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 significant reduction in LDL-C after 14 days treatment of once daily oral dosing of ASC41 tablet (https://www.ascletis.com/news_detail/175/id/454/l/en-us.html).
In February 2021, Ascletis announced positive clinical results in overweight and obese subjects for ASC41. Data suggested that over 14 days of once daily oral dosing of ASC41, subjects demonstrated significant reduction in LDL-C (https://www.ascletis.com/news_detail/175/id/462/l/en-us.html). Table 2 shows the comparison data of LDL-C reduction after once daily oral treatment of ASC41 and Resmetirom at various doses, respectively.
Table 2. LDL-C Reduction after 14 Days of Once Daily Oral Dosing:
ASC41 VS Resmetirom (Not Head to Head)
LDL-C |
2 mg |
5 mg |
10 mg |
20 mg |
50 mg |
80 mg |
100 mg |
|
ASC41* |
ASC41* |
Resme tirom** |
ASC41*** |
Resme tirom** |
Resme tirom** |
Resme tirom** |
Resme tirom** |
|
% Change from baseline after 14-day (mean） |
-32.8% |
-40.8% |
3.2% |
-44.8% |
8.8% |
-11.3% |
-25.4% |
-20.9% |
* Data derived from ASC41 Phase 1 study
** Data derived from Taub et al. Atherosclerosis 230 (2013) 373-380
*** Data derived from ASC41 Phase 1b study
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/l/en-us.html).
