Ascletis Reports Positive Phase I Results for Obesity Drug ASC47 in Australia

Data from a Phase I study in Australia involving subjects with elevated low-density lipoprotein cholesterol (LDL-C) demonstrated that ASC47, administered subcutaneously, has a half-life of 21 days, suggesting that once-monthly dosing could be effective for patients with obesity. In diverse preclinical studies using a diet-induced obese (DIO) mouse model, ASC47 showed promising results in promoting healthy weight loss while preserving muscle mass.

In a head-to-head preclinical study comparing ASC47 to semaglutide in a DIO mouse model, ASC47 significantly reduced total fat mass by 63.5%, as opposed to 39.6% with semaglutide. Additionally, ASC47 increased total muscle mass by 5.8%, while semaglutide led to a 9.3% decrease in muscle mass. Both drugs showed a similar reduction in total body weight, although mice treated with ASC47 had a considerably lower reduction in caloric intake compared to those treated with semaglutide.

When compared to tirzepatide in another head-to-head preclinical study using a DIO mouse model, ASC47 reduced total fat mass by 68.0%, a significant improvement over the 50.4% reduction seen with tirzepatide. In the same study, ASC47 increased total muscle mass by 8.1%, whereas tirzepatide led to a 3.8% decrease in muscle mass. The reduction in total body weight was comparable between ASC47 and tirzepatide, despite a less pronounced decrease in caloric intake with ASC47.

ASC47 was designed with unique properties to facilitate targeted delivery to adipose tissue, leading to high drug concentrations in a dose-dependent manner. In DIO mice, a dose of 15 mg/kg administered subcutaneously every two weeks resulted in drug concentrations in adipose tissue that were seven times higher than the predicted efficacious concentration in humans.

One of the primary mechanisms through which ASC47 reduces fat and preserves muscle mass is via uncoupling protein 1 (UCP-1)-mediated thermogenesis in adipose tissue.

The Phase I single ascending dose (SAD) study in Australia included subjects with elevated LDL-C, who received doses of ASC47 ranging from 10 mg to 360 mg or a placebo through subcutaneous injections. Participants had multiple outpatient visits over eight weeks following the injections. The initial three cohorts (10 mg, 30 mg, and 90 mg) included 20 subjects in total, and ASC47 demonstrated a favorable tolerability profile with no serious adverse events (SAEs) or discontinuations due to adverse events (AEs). Most AEs were mild, with only two subjects reporting mild injection site reactions and no gastrointestinal or cardiac AEs. No abnormal liver enzymes or clinically significant findings in laboratory tests, electrocardiograms, vital signs, or physical examinations were observed.

Building on the safety, pharmacokinetic, and target engagement data from the SAD study, a second Phase I study focusing on ASC47 monotherapy in patients with obesity has commenced in Australia. Topline results are anticipated in the first quarter of 2025.

Additionally, two more Phase I studies are underway in Australia: a multiple ascending dose (MAD) study of ASC47 monotherapy and a MAD study of ASC47 in combination with either tirzepatide or semaglutide in patients with obesity. Detailed clinical data from these studies are expected to be presented at medical conferences in 2025.

Preclinical efficacy data of ASC47 monotherapy indicated dose-dependent healthy weight loss in DIO mouse models. When compared to semaglutide and tirzepatide, ASC47 consistently showed superior results in reducing fat mass and preserving muscle mass.

ASC47 is an adipose-targeted thyroid hormone receptor beta (THRβ) selective small molecule agonist developed by Ascletis. It is designed to achieve high concentrations in adipose tissue, which is crucial for effective weight loss in metabolic diseases like obesity. Unlike other THRβ selective agonists that primarily target the liver, ASC47's adipose-targeted delivery distinguishes it, enabling the use of lower and clinically relevant doses for obesity treatment.

One of ASC47’s key mechanisms involves UCP-1-mediated thermogenesis in adipose tissue. In a head-to-head study with semaglutide in DIO mice, ASC47 significantly increased UCP-1 expression in adipose tissue, differentiating it from incretin-based drugs and other muscle-preserving candidates.

The detailed mechanisms of action, preclinical efficacy, and other relevant data are expected to be shared at medical conferences in 2025.