After Arrowhead Pharmaceuticals cleared out its work on a clinical-stage cardiovascular candidate, the company is filling the blank space with two obesity assets, both set to enter the clinic in early 2025.
The RNA interference (RNAi) company presented two next-gen candidates during an R&D investor event Aug. 14: Dubbed ARO-INHBE and ARO-ALK7, they are designed to treat obesity and metabolic diseases.
In preclinical studies, the candidates have both shown potential reducing body weight and fat mass using a novel mechanism of action that might help preserve lean muscle mass, compared to currently marketed therapies, according to an Arrowhead release. The biotech plans to ask regulatory authorities for green lights to enter human trials for both programs by the end of this year, with the goal of launching clinical studies in obesity early next year.
“It turns out weight loss isn't enough of a value proposition to continue the medication,” Carel le Roux, M.D., Ph.D., a metabolic medicine physician from University College Dublin, said on the R&D day investor call. “You actually have to have health gains and certainly functional gains.”
Referring to long-term use of weight loss medications, the physician explained that some of those gains include maintaining muscle mass. In order to achieve those functional gains alongside weight loss, le Roux suggested targeting new mechanisms, which is what Arrowhead intends to do.
ARO-INHBE is designed to reduce expression of the INHBE gene in the liver, plus INHBE’s secreted gene product, Activin E. Meanwhile, ARO-ALK7 aims to lower the adipose expression of Activin receptor-like kinase 7 (ALK7). Both INHBE and ALK7 are genetically validated targets with loss of function variants being associated with lower risk of obesity and metabolic diseases, such as Type 2 diabetes, according to Arrowhead.
“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,” Arrowhead’s chief of discovery and translational medicine, James Hamilton, M.D., said in the release. “Following the approval and positive clinical impact of new agents for obesity over the last few years, new therapeutic strategies with novel mechanisms of action are emerging that may represent the future in successful treatment and management of patients with obesity and associated diseases.”
The programs are expected to be Arrowhead’s first clinical candidates in obesity, with the company’s current R&D pipeline spread across cardiometabolic, pulmonary, liver, muscular or complement-mediated disease indications.
Earlier this summer, the biotech dropped one of two clinical-stage cardiovascular disease candidates to manage spend. The two cardiometabolic disease assets are plozasiran and zodasiran, RNAi molecules that target APOC3 and ANGPTL3, respectively. Both molecules are designed to improve cardiovascular health by lowering levels of molecules such as triglycerides and lipoproteins that drive disease.
While the biotech took both assets through midphase development, the company decided to bank on plozasiran and let loose zodasiran.
At the time, Vincent Anzalone, Arrowhead’s head of investor relations, said plozasiran generated compelling data in three settings, and funding all those areas could position the company to launch in progressively larger indications and stagger commercial expansion. The company already has one pivotal win under its belt for plozasiran, with plans to enter the market in 2025.
As of June, the business hoped to find a partner for the now-deprioritized zodasiran.