ALK7

PASADENA, CA, USA I August 14, 2024 I Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today presented preclinical data and detailed its plans to advance two next generation RNAi-based candidates, ARO-INHBE and ARO-ALK7, into upcoming clinical studies for the treatment of obesity and metabolic diseases. In preclinical studies to date, these candidates demonstrated the potential to reduce body weight and fat mass with a novel mechanism of action that may lead to improved preservation of lean muscle mass compared to currently approved obesity therapies. Arrowhead plans to submit clinical trial applications with regulatory authorities for both programs by the end of 2024 with the goal of initiating clinical studies in volunteers with obesity in early 2025. “Arrowhead believes that targeting the hepatic expression of the INHBE gene and the production of the Activin E ligand, and the adipose tissue expression of the ALK7 gene and the receptor it encodes, represent promising novel mechanisms to treat obesity and associated metabolic diseases. When studied as mono therapy 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,” said James Hamilton, M.D., Chief of Discovery and Translational Medicine at Arrowhead. “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. 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.” ARO-INHBE is designed to reduce the hepatic expression of the INHBE gene and its secreted gene product, Activin E. ARO-ALK7 is designed to reduce the adipose expression of Activin receptor-like kinase 7 (ALK7). INHBE and ALK7 are both genetically validated targets with loss of function variants being associated with lower risk of obesity and metabolic diseases, such as type 2 diabetes. Both targets are involved in the same pathway that regulates energy homeostasis in adipose tissue​, with Activin E acting as a circulating ligand and ALK7 as a receptor on adipocytes. Intervening in this pathway with ARO-INHBE and ARO-ALK7 is believed to result in increased lipolysis, and reductions in adipose hypertrophy and dysfunction, visceral adiposity, and insulin resistance. To learn more about ARO-INHBE and ARO-ALK7, please join Part IV of Arrowhead’s 2024 Summer Series of R&D Webinars, being held today, August 14, 2024, at 2:00 PM ET. The event will feature Arrowhead management and Carel le Roux, M.D., Ph.D., from University College Dublin. The live event and an archived webcast may be accessed on the Events and Presentations page in the Investors section of the Arrowhead website. About Arrowhead Pharmaceuticals 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. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. For more information, please visit www.arrowheadpharma.com , or follow us on X (formerly Twitter) at @ArrowheadPharma or on LinkedIn . To be added to the Company’s email list and receive news directly, please visit http://ir.arrowheadpharma.com/email-alerts . SOURCE: Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals is joining the hunt for new obesity treatments, betting that its RNA interference expertise can deliver therapies that not only lead to weight loss, but also preserve lean muscle mass. The company plans to have two candidates in clinical development next year, both targeting the same pathway that regulates energy homeostasis in adipose tissue​.James Hamilton, chief of discovery and translational medicine, said “Arrowhead believes that targeting the hepatic expression of the INHBE gene and the production of the Activin E ligand, and the adipose tissue expression of the ALK7 gene and the receptor it encodes, represent promising novel mechanisms to treat obesity and associated metabolic diseases.”The company’s first therapy, dubbed ARO-INHBE, is designed to reduce hepatic expression of the INHBE gene and its secreted gene product, Activin E, while the second candidate, ARO-ALK7, is designed to reduce the adipose expression of ALK7. According to Arrowhead, both INHBE and ALK7 are involved in the pathway that regulates energy homeostasis in adipose tissue​, with Activin E acting as a circulating ligand and ALK7 as a receptor on adipocytes. As such, ARO-INHBE and ARO-ALK7 are expected to lead to increased lipolysis, as well as reductions in adipose hypertrophy and dysfunction, visceral adiposity and insulin resistance.In mouse models of obesity, use of ARO-INHBE and ARO-ALK7 alone, as well as in combination with Eli Lilly’s GLP-1 receptor agonist Mounjaro (tirzepatide), resulted in suppression of body weight and fat mass, as well as preservation of lean mass, Hamilton said. The company suggested that clinical trial applications for both candidates are planned before the end of 2024, with the first studies in volunteers with obesity.Arrowhead’s push into obesity comes shortly after the drugmaker pared back its cardiometabolic pipeline, choosing to focus resources on the development of plozasiran, while seeking a partner for zodasiran. Plozasiran, an RNAi therapeutic designed to reduce the production of apolipoprotein-CIII (ApoC3), is set to advance into a Phase III cardiovascular outcomes trial.

Arrowhead is wading deeper into obesity drug development, with two RNAi-based candidates it said have shown potential in reducing body weight while saving lean muscle mass. 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.