Arrowhead Pharmaceuticals Shares Preclinical Data on ARO-ALK7 for Obesity Treatment

Arrowhead Pharmaceuticals, Inc., a company listed on NASDAQ under the ticker ARWR, has unveiled promising preclinical findings for its investigational RNA interference (RNAi) therapeutic, ARO-ALK7. This new therapeutic is being developed as a potential treatment targeting Activin receptor-like kinase 7 (ALK7) to combat obesity. The results were showcased in a poster presentation at the Keystone Symposia on Obesity and Adipose Tissue, held from February 23-26, 2025, in Banff, Canada.

ARO-ALK7 is the pioneering RNAi-based therapy aimed at a gene specifically expressed in adipose tissue. This development underscores Arrowhead’s innovative approach in delivering small interfering RNA (siRNA) across various tissues and cells using their proprietary TRiM™ platform. The company has cleared regulatory hurdles to commence a Phase 1/2a clinical trial of ARO-ALK7 in New Zealand, with plans to begin patient dosing in the second quarter of 2025.

Dr. James Hamilton, the Chief Medical Officer and Head of R&D at Arrowhead, highlighted the role of ALK7 as a promising target for obesity treatments based on human genetic studies. Variants of ALK7 that cause a loss of function have been linked to improved body composition and a reduced risk of type 2 diabetes and cardiovascular issues. Current treatments for obesity, primarily incretin-based therapies, face challenges such as significant lean mass loss, gastrointestinal issues at higher doses, and disproportionate fat mass gain after stopping the therapy.

In preclinical trials involving rodents and non-human primates, ARO-ALK7 showed significant and lasting reductions in ALK7 mRNA expression in adipose tissue. In diet-induced obese mouse models, the silencing of ALK7 led to improved body composition, including a roughly 50% reduction in fat mass while preserving lean mass. Additionally, when combined with tirzepatide, a co-agonist for GLP-1/GIP receptors, the therapeutic effect was enhanced compared to using tirzepatide alone. Mice experienced further reductions in body weight and fat mass, while maintaining lean mass, an improvement over the effects seen with tirzepatide monotherapy. The fat loss observed in mice was attributed to increased energy expenditure and lipolysis, without changes in food intake, suggesting that the treatment promoted fat metabolism rather than simply reducing caloric intake.

Preclinical results indicated that single subcutaneous doses of ARO-ALK7 in non-human primates resulted in significant and sustained reductions in ALK7 mRNA in abdominal fat. Doses of 0.3 mg/kg achieved approximately 80% knockdown of ALK7 mRNA, while 1.5 mg/kg doses resulted in around 91% knockdown, with a 75% knockdown still observable after 12 weeks.

In toxicology studies, ARO-ALK7 was generally well-tolerated with no significant adverse effects or dose-limiting findings in Han Wistar rats.

ARO-ALK7 aims to reduce the expression of the ACVR1C gene in adipocytes, thereby decreasing the production of ALK7. This reduction is expected to positively affect energy homeostasis in adipose tissue, offering potential benefits for obesity-related metabolic conditions. The upcoming AROALK7-1001 Phase 1/2a clinical study will assess the safety, tolerability, and effects of ARO-ALK7 in up to 90 adult volunteers with obesity, both as a monotherapy and in combination with tirzepatide.

Arrowhead Pharmaceuticals is focused on developing treatments for challenging diseases by silencing the genes responsible for them. Their approach leverages RNA interference to achieve significant and lasting reductions in target gene expression, offering a novel pathway to potential new therapies.