According to a research report, small nucleic acid drugs targeting weight loss indications primarily focus on two targets: INHBE and ALK7. From a corporate development perspective, Arrowhead and Wave are currently making the fastest progress, with both companies' INHBE siRNA molecules expected to report Phase 1 trial data within the next six months. Preclinical rat data shows that Arrowhead's ALK7 siRNA molecule combined with Tirzepatide can further enhance weight loss effects while potentially providing more durable efficacy, enabling longer dosing intervals (such as monthly or quarterly). Additionally, the combination therapy may achieve high-quality weight loss, reducing fat while preserving muscle mass.

**New Trend in Weight Loss Market: Small Nucleic Acid Drugs Poised to Break Through Hundred-Billion-Dollar Market**

Small nucleic acid drugs targeting weight loss indications primarily focus on INHBE (Inhibin subunit beta E) and ALK7 (Activin receptor-like kinase 7) targets. INHBE is mainly expressed in liver cells and acts as an inhibitory factor responsible for encoding and secreting Activin E. This molecule works together with other ligands (such as GDF3, GDF11, ActB, ActE, ActAB, ActC, Nodal) to regulate fat metabolism by binding to ALK7. ALK7 is primarily expressed in adipose tissue and serves as the receptor through which INHBE exerts its effects. When Activin E binds to ALK7, it inhibits lipolysis, leading to decreased non-esterified fatty acid (NEFA) levels. Furthermore, adipocyte hypertrophy and dysfunction are further exacerbated, leading to visceral fat accumulation and increased insulin resistance, all of which provide the biological basis for obesity development.

**Arrowhead, Wave, and Alnylam Accelerating Deployment in Weight Loss Small Nucleic Acid Drug Market**

From a corporate development perspective, Arrowhead and Wave are currently making the fastest progress, with both companies' INHBE siRNA molecules expected to report Phase 1 trial data within the next six months. Although Alnylam's progress is slightly slower, it has the most comprehensive layout, with IND-enabling stage molecules covering INHBE (liver-targeted), ALK7 (adipose-targeted), and GeneD (muscle-targeted).

**Small Nucleic Acid Drugs Combined with GLP-1 Expected to Address Multiple Unmet Clinical Needs**

Preclinical rat data shows that Arrowhead's ALK7 siRNA molecule combined with Tirzepatide can further enhance weight loss effects while potentially providing more durable efficacy, enabling longer dosing intervals (such as monthly or quarterly). Additionally, the combination therapy may achieve high-quality weight loss, reducing fat while preserving muscle mass. Furthermore, human genetic studies indicate that carriers with loss of function (LoF) mutations in INHBE or its receptor ALK7 often exhibit healthier metabolic profiles in the general population, characterized by lower waist-to-hip ratios and less visceral/abdominal fat accumulation, while overall BMI may not be significantly reduced. This suggests that the INHBE/ALK7 pathway plays a crucial role in fat distribution rather than simple weight control. Therefore, inhibiting the INHBE/ALK7 signaling pathway may reduce high-risk abdominal/visceral fat rather than simply achieving weight loss.

**Investment Recommendations**

In the short term, attention should be focused on data readouts from Arrowhead and Wave. Both companies' Phase 1 clinical trials include SAD, MAD, and GLP-1 combination cohorts. Key focus areas should include safety, pharmacokinetics and dosing intervals, biomarker knockdown levels, early efficacy, and changes in other metabolic indicators.

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Beneficiary stocks: Frontier Biotech-U (688221.SH), HENGRUI PHARMA (01276), etc.

**Risk Warnings**

Declining enthusiasm for innovative drug development, clinical development failures, drug safety risks, etc.