Arrowhead Pharmaceuticals has initiated dosing in the first subjects of a Phase 1/2a clinical trial evaluating ARO-ALK7, an investigational RNA interference (RNAi) therapeutic being developed as a potential treatment for obesity. The milestone represents the first RNAi therapeutic to enter clinical studies targeting a gene expressed in adipose tissue, highlighting Arrowhead's leadership in delivering siRNA to multiple tissues throughout the body using its proprietary Targeted RNAi Molecule (TRiM™) platform.
Novel Mechanism Targets Fat Storage Pathway
ARO-ALK7 is designed to silence adipocyte expression of the ACVR1C gene to reduce production of Activin receptor-like kinase 7 (ALK7), which acts as a receptor in a pathway that regulates energy homeostasis in adipose tissue. The therapeutic intervenes in a known pathway that signals the body to store fat in adipose tissue.
"Arrowhead's two clinical stage RNAi-based obesity programs, ARO-ALK7 and ARO-INHBE, intervene in a known pathway that signals the body to store fat in adipose tissue," said James Hamilton, M.D., Chief Medical Officer and Head of R&D. "Both programs have strong genetic validation and promising results in preclinical studies, which suggest that silencing the respective genes may lead to reduced body weight and potentially preserve lean muscle mass resulting in improved body composition."
Strong Genetic Validation and Preclinical Results
In large genetic datasets, reduced ACVR1C expression has been associated with healthier adipose distribution and reduced risk of obesity-related metabolic complications. Preclinical animal studies demonstrated that ALK7 silencing in adipose tissue led to reduced body weight and fat mass with preservation of lean muscle. Treatment with investigational ARO-ALK7 has the potential to reduce visceral adiposity and improve lipid and glycemic parameters.
Phase 1/2a Study Design
The AROALK7-1001 study (NCT06937203) is a first-in-human dose-escalating study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-ALK7 in up to 90 adult volunteers with obesity. The study is structured in two parts: Part 1 will assess single and multiple doses of ARO-ALK7 monotherapy in otherwise healthy obese subjects, while Part 2 will evaluate ARO-ALK7 in combination with tirzepatide.
The study is expected to progress rapidly to investigate combinations of ARO-ALK7 with tirzepatide in obese patients with and without type 2 diabetes. Tirzepatide is a subcutaneously administered GLP-1/GIP receptor co-agonist that has been approved in the United States and the European Union for management of type 2 diabetes mellitus since 2022 and weight management since 2023/2024 respectively.
"This ongoing Phase 1/2a clinical study will evaluate single and multiple ascending doses of ARO-ALK7 as monotherapy in otherwise healthy obese volunteers as well as multiple doses in obese patients with or without type 2 diabetes in combination with incretin therapy," Hamilton explained.
Advancing RNAi Technology Platform
Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein.
