Ascletis Pharma is making strides in obesity treatment with its novel small-molecule oral GLP-1 receptor agonist (RA), ASC30. Positive results from a Phase Ia single ascending dose (SAD) study and interim data from an ongoing Phase Ib multiple ascending dose (MAD) trial indicate promising potential for this drug.
The Phase Ia SAD study, involving 40 patients with obesity across five dose cohorts (2 mg, 5 mg, 10 mg, 20 mg, and 40 mg) under fasting conditions, demonstrated dose-proportional pharmacokinetics (PK) and a long half-life of up to 60 hours. This supports the possibility of once-daily or less frequent oral dosing. A cross-trial comparison showed that a 5 mg single dose of ASC30 resulted in 2.2 times the drug exposure compared to a 6 mg dose of orforglipron, another oral GLP-1 RA.
Phase Ib Trial Shows Weight Reduction
Interim results from the Phase Ib MAD study revealed a 6.3% mean body weight reduction after 28 days in the first cohort, which received doses ranging from 2mg to 20mg. The second cohort, receiving doses between 2mg and 40mg, experienced a 4.3% mean body weight reduction from baseline over the same period. Ascletis expects to release data from the third cohort, which is being dosed up to 60mg, later this year.
"We are excited that these interim results from our Phase Ib MAD study demonstrated potential best-in-class characteristics to treat patients with obesity," said Jinzi Jason Wu, founder of Ascletis.
Safety and Tolerability
In the Phase Ia SAD study, ASC30 was generally well-tolerated. Adverse events (AEs) were primarily mild (grade 1) or moderate (grade 2) and mostly gastrointestinal (GI)-related, including constipation, diarrhea, vomiting, and nausea. No serious adverse events (SAEs) or grade 3 or higher AEs were reported. Liver enzyme levels, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), remained within normal ranges.
Potential Best-in-Class Characteristics
ASC30 is designed as a GLP-1R biased small molecule agonist without β-arrestin recruitment, potentially allowing for both once-daily oral and once-monthly subcutaneous injection dosing options. Ascletis reports that ASC30 has two- to three-fold better in vitro potency against GLP-1R compared to orforglipron. Animal model data also suggest the possibility of up to once-weekly oral dosing with a new tablet formulation that is stable at room temperature and has a relative oral bioavailability of 99%.
Obesity: A Growing Global Concern
The World Health Organization (WHO) estimates that approximately 16% of adults over 18 years were living with obesity in 2022, with the global prevalence more than doubling between 1990 and 2022. The Centers for Disease Control and Prevention (CDC) reported a 40.3% obesity prevalence among adults in the United States between August 2021 and August 2023.
Ascletis anticipates sharing topline results from the Phase Ib MAD trial, including weight loss, safety, and PK data, by the end of March 2025. These results will further clarify ASC30's potential in the competitive landscape of obesity treatments, which includes established injectable GLP-1RAs like Novo Nordisk’s semaglutide (Wegovy) and Eli Lilly’s tirzepatide (Zepbound).
