A month after axing a Phase II cardiovascular candidate, Arrowhead Pharmaceuticals has placed a bullseye target on the obesity treatment space after it announced the advancement of two RNAi-based candidates to clinic.

The US biotech said it plans to submit clinical trial regulatory applications for the two assets – named ARO-INHBE and ARO-ALK7 – by the end of this year, with the programmes slated to commence in early 2025, as per a 14 August press release.

The news did little to improve shares in the company, which are currently down due to disappointing Q3 earnings, which were released on 8 August.

Arrowhead says preclinical trials have shown the two obesity candidates-in-waiting can reduce body weight and fat mass using a unique mechanism of action that may keep more lean muscle mass compared to currently approved obesity therapies. Clinical trials for weight loss drugs Novo Nordisk’s blockbuster Wegovy (semaglutide) showed a lean muscle mass reduction of around 40%, although there is no current scientific consensus on the limitation.

The two drugs could become the first obesity-focused programmes in Arrowhead’s pipeline, which covers cardiovascular, liver, and pulmonary disease indications, among others.

Arrowhead reckons its therapy modality is “a promising novel mechanism” to treat obesity and associated metabolic diseases. RNAi-based therapies work by mimicking biological machinery to silence genes involved in the pathogenic process, which then affects the production of a specific protein.

ARO-INHBE is designed to reduce the hepatic expression of the INHBE gene and its secreted gene product, Activin E, which stimulates energy expenditure and increases insulin sensitivity. ARO-ALK7 is designed to reduce the adipose expression of activin receptor-like kinase 7 (ALK7), a protein which plays a role in adipocyte function and fat accumulation.

Arrowhead states that loss of function variants is associated with a lower risk of obesity and metabolic diseases, such as type 2 diabetes.

Arrowhead’s chief of discovery and translational medicine James Hamilton said: “When studied as monotherapy and in combination with tirzepatide in diet-induced obesity mouse models, ARO-INHBE and ARO-ALK7 both resulted in suppression of body weight and fat mass and, importantly, preservation of lean mass leading to improved body composition.

“We are in the final stages of preclinical development of ARO-INHBE and ARO-ALK7 and we are eager to engage with regulators by the end of this year to begin clinical studies of these exciting new medicines.”

The biotech shelved its cardiovascular disease asset zodasiran in June 2024, deciding instead to funnel more resources into its parallel candidate plozasiran.

Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.

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