Small nucleic acid drugs are revealing potential targets in the weight loss field, such as INHBE and ALK7. Compared to GLP-1 drugs, small nucleic acid therapies are set to shift the paradigm from simply "suppressing appetite" to "precisely regulating lipid metabolism," offering long-acting weight loss effects and potentially ushering in a new era of superior, healthier weight management. While pipelines of leading overseas companies are in early clinical stages, domestic firms have rapidly deployed small nucleic acid weight loss pipelines, actively catching up in terms of targets, delivery platforms, and indications, which is expected to accelerate the release of the potential value of small nucleic acids in areas like healthy weight loss and fatty liver disease.
Overweight and obesity can trigger serious health issues. GLP-1 drugs, with their significant weight loss effects, are rapidly gaining market share and are expected to become the top-selling global drug by 2025. However, the flip side of their "appetite suppression" mechanism includes challenges such as weight rebound after discontinuation, loss of lean body mass, and gastrointestinal intolerance, leading to low usage rates and poor adherence. Consequently, the global weight loss market still harbors substantial unmet needs.
Unlike GLP-1 drugs, small nucleic acid therapies can regulate fat metabolism at the genetic level, demonstrating potential to break through the bottlenecks of current weight loss treatments. Recently, Wave Life Sciences and Arrowhead Pharmaceuticals disclosed early clinical data for siRNA targeting INHBE and ALK7, respectively, successfully providing proof-of-concept for the INHBE target and siRNA delivery to adipose tissue. Preliminary data indicate that siRNA can achieve long-term fat reduction while preserving muscle mass, with even better efficacy when combined with low-dose tirzepatide, potentially heralding a new epoch for healthy weight loss.
INHBE: Possesses differentiated clinical value with strong drug development certainty. The activin E encoded by INHBE can bind to the ALK7 receptor in adipose tissue, inhibiting lipolysis. Therefore, siRNA therapies targeting INHBE and ALK7 can activate fat breakdown by reducing the expression levels of the ligand and receptor in this signaling pathway, achieving weight loss and lowering the risk of related metabolic diseases. Recent early clinical data for WVE-007 and ARO-INHBE show: 1) INHBE siRNA is safe and tolerable, demonstrating long-acting fat reduction and muscle preservation as a monotherapy; when combined with tirzepatide, it achieved double the weight loss, triple the fat loss, and triple the reduction in visceral/liver fat; 2) Compared to GLP-1 drugs, its uniqueness lies in selectively reducing adipose tissue (particularly visceral fat) while maintaining muscle mass, thus offering a rarer, healthier differentiated clinical value. Furthermore, since INHBE is primarily expressed in the liver, the GalNAc delivery system it employs has already been validated by multiple approved drugs like Inclisiran, giving INHBE siRNA strong certainty in clinical development regarding longevity and safety.
ALK7: Potentially superior fat reduction effects, with adipose delivery becoming a key competitive factor. ALK7 is mainly distributed in adipocytes, so ALK7 siRNA requires a fat tissue-targeted delivery system. Early clinical data for ARO-ALK7-1001 show: 1) A breakthrough has been achieved in adipose-targeted delivery. From 10-200mg, ARO-ALK7 achieved a dose-dependent reduction in ALK7 mRNA. At the 200 mg dose, an average 88% and a maximum individual 96% knockdown efficiency of ALK7 mRNA was observed just 4 weeks after a single dose, sustained for up to 12 weeks; 2) ALK7 may be superior to INHBE in the speed and extent of visceral fat reduction. After a single 200mg dose and placebo adjustment, visceral fat was reduced by 14.1% at week 8, whereas INHBE siRNA with similar or lower baseline levels showed data not exceeding 10% at both 12 and 16 weeks.
Investment advice and relevant investment targets: Hengrui Pharmaceuticals, Innovent Biologics, CSPC Pharmaceutical Group, Salubris, Sino Biopharmaceutical, Sunshine Guojian Pharmaceutical; Other small nucleic acid targets: Youcare Pharmaceutical, Frontier Biotechnologies, Fuyuan Pharmaceutical, HitGen, Hotgen Biotech, Bebetter Medicine, Ribo Life Science. Risks: If subsequent clinical data for small nucleic acid drugs in weight loss fall short of expectations, it could adversely impact the commercial value of these pipelines; if innovative drugs targeting other mechanisms demonstrate superior clinical data or faster progress, they could challenge the clinical and commercial value of small nucleic acid weight loss pipelines.
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