Obesity is a chronic metabolic disease, and in recent years, the global prevalence of overweight and obesity has been rapidly increasing, becoming a serious threat to human health. According to the Report on the Nutritional and Chronic Disease Status of Chinese Residents (2020), the overweight and obesity rates among Chinese residents aged 18 and older are 34.3% and 16.4%, respectively. The obesity rates for individuals aged 18–44, 45–59, and 60 and above are 16.4%, 18.3%, and 13.6%, respectively, showing an upward trend. Obesity not only leads to a higher risk of premature death but is also associated with various non-communicable chronic diseases, including type 2 diabetes, stroke, coronary heart disease, hypertension, respiratory diseases, osteoarthritis, and gallstones. Studies suggest that by 2030, the adult overweight and obesity rate in China may reach 65.3%, with medical costs attributed to overweight and obesity potentially amounting to 418 billion RMB, about 21.5% of total national medical expenses. The overweight and obesity rates in China's urban and rural populations, as well as their economic burden, are projected to rise, making obesity prevention and control an urgent priority.
The GLP-1 weight loss drug market has entered an intense phase: on one hand, giants like Eli Lilly and Novo Nordisk are fiercely competing in clinical trials, capacity expansion, and commercialization. On the other hand, Chinese pharmaceutical companies are accelerating research and development to stand out with enhanced drug efficacy and differentiated designs.
However, GLP-1 weight loss drugs have their downsides, such as the controversial "Ozempic Face" caused by semaglutide. In September 2024, Lancet published an article reporting that up to 25%–39% of the weight loss from GLP-1 receptor agonists, such as semaglutide, consists of muscle mass. The loss of muscle mass can lead to significant risks, including reduced immunity, increased risk of infections, and poor blood sugar regulation.
The future of weight loss drugs lies in balancing fat reduction with muscle preservation and even muscle gain, a focus area for many companies. Huachuang Securities notes that increasing muscle mass itself could become a massive market on par with weight loss due to demand for anti-aging solutions targeting muscle atrophy in the elderly, treatments for cancer patients to maintain muscle mass, and consumer interest in body sculpting. Current targets for fat loss and muscle gain include ActRIIA/B, MSTN, THR-β, and SARM.
ActRII (ACVR2A and ACVR2B) are important members of the TGF-β receptor superfamily and play crucial roles in processes such as cell growth, differentiation, and tissue repair. Inhibiting these receptors can promote muscle growth and prevent muscle atrophy, making them attractive targets for treating obesity and related metabolic diseases.
The popularity of ActRII as a target began with Eli Lilly's acquisition of Versanis for nearly $2 billion in July 2023, securing Bimagrumab (an ActRIIA/B monoclonal antibody). In a Phase II trial (NCT03005288), 75 type 2 diabetes patients with a BMI of 28–40 received Bimagrumab or a placebo along with diet and exercise counseling over 48 weeks. Results showed that Bimagrumab-treated patients experienced over 20% fat loss, compared to just 0.5% in the placebo group. Additionally, lean body mass increased by 3.6% in the Bimagrumab group but decreased by 0.8% in the placebo group.
Laekna Pharmaceuticals has developed several ActRII inhibitors: LAE102 (ActRIIA monoclonal antibody) focuses on muscle gain and fat loss, while LAE103 (ActRIIB monoclonal antibody) and LAE123 (ActRIIA/B monoclonal antibody) target muscle atrophy and other indications. In November 2024, Laekna announced a clinical collaboration with Eli Lilly to accelerate the global clinical development of LAE102 for obesity treatment, with Eli Lilly conducting a Phase I study in the U.S. and covering related costs.
THR-β plays a critical role in liver homeostasis through various metabolic actions of thyroid hormones. THR-β agonists have been shown to improve lipid metabolism.
ASC47, developed by Ascletis Pharma, is a liver-targeted, once-monthly injectable selective THR-β small-molecule agonist.
In a preclinical study comparing ASC47 with semaglutide in DIO (diet-induced obesity) mice, the ASC47 group showed a statistically significant fat reduction (-63.5%) compared to semaglutide (-39.6%). The ASC47 group also exhibited a statistically significant muscle mass increase (+5.8%), whereas the semaglutide group experienced a muscle mass decrease (-9.3%).
In a preclinical study comparing ASC47 with tirzepatide in a DIO (diet-induced obesity) mouse model, the ASC47 treatment group showed a statistically significant reduction in overall fat mass (-68.0%), compared to tirzepatide's -50.4%. In the same study, the ASC47 group exhibited a statistically significant increase in total muscle mass (+8.1%), while the tirzepatide group showed a decrease in total muscle mass (-3.8%).
MSTN, a member of the TGF-β family also known as Growth Differentiation Factor 8 (GDF8), negatively regulates muscle growth. Gene mutations or knockout of MSTN lead to significant increases in muscle mass. Inhibiting MSTN has been considered a potential therapeutic strategy for muscle atrophy and sarcopenia. MSTN also relates to metabolic diseases like obesity and diabetes, and regulating MSTN levels can improve patients' metabolic status.
Trevogrumab, an MSTN inhibitor developed by Regeneron, is being investigated in combination with garetosmab (anti-activin A antibody) for obesity treatment in a Phase II trial. In a Phase I study, women receiving Trevogrumab (6mg/kg) and garetosmab (10mg/kg) for 8 weeks showed a 7.7% increase in thigh muscle volume and decreases in total and abdominal fat (-4.6% and -6.7%, respectively).
Following the success of weight loss drugs, the development of drugs to prevent muscle loss has become a new competitive field for pharmaceutical companies. Achieving both weight loss and muscle preservation is a significant challenge. Multiple targets, including ActRIIA/B, MSTN, and THR-β, are closely related to fat loss and muscle gain. Leading players in this field include Laekna Pharmaceuticals and Ascletis Pharma. Beyond drugs, exercise—especially resistance training—remains a simple and effective way to stimulate muscle growth and slow muscle loss.
