ALK7

– In preclinical studies ARO-INHBE reduced body weight and fat mass with a novel mechanism of action that may preserve lean muscle mass compared to currently approved obesity therapies PASADENA, CA, USA I September 23, 2024 I Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced that it has filed for regulatory clearance to initiate a Phase 1/2a clinical trial of ARO-INHBE, the company’s investigational RNA interference (RNAi) therapeutic being developed as a potential treatment for obesity. Arrowhead also plans to file for regulatory clearance before the end of 2024 to initiate a clinical trial for its second obesity candidate, ARO-ALK7. “Arrowhead’s two investigational RNAi therapies for the treatment of obesity, ARO-INHBE and ARO-ALK7, are both designed to intervene in the same pathway that signals the body to store fat in adipose tissue. We have generated very promising preclinical data that suggests inhibition of these targets reduces body mass and fat mass but spares lean muscle mass resulting in improved body composition,” said James Hamilton, M.D., Chief of Discovery and Translational Medicine at Arrowhead. “We have designed the initial Phase 1/2 study to evaluate single and multiple doses of ARO-INHBE monotherapy in Part 1 which will enroll patients with obesity, and to evaluate multiple doses of ARO-INHBE in combination with tirzepatide in Part 2 which will enroll diabetic and non-diabetic patients with obesity. We believe new therapeutic strategies with novel mechanisms of action, like ARO-INHBE and ARO-ALK7, have the potential to make a significant impact on the way obesity is treated and we are eager to initiate clinical studies of these important new programs.” ARO-INHBE is designed to reduce the hepatic expression of the INHBE gene and its secreted gene product, Activin E. INHBE is a promising genetically validated target in which loss-of-function INHBE variants in humans are associated with lower risk of obesity and metabolic diseases, such as type 2 diabetes. Activin E acts as a ligand in a pathway that regulates energy homeostasis in adipose tissue​. Intervening in this pathway with investigational ARO-INHBE treatment has the potential to increase lipolysis, and reduce adipose hypertrophy and dysfunction, visceral adiposity, and insulin resistance. An application for approval to initiate the clinical trial was submitted to the New Zealand Medicines and Medical Devices Safety Authority for review by the Standing Committee on Therapeutic Trials. Pending clearance, Arrowhead intends to proceed with AROINHBE-1001, A Phase 1/2a dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-INHBE in up to 78 adult volunteers with obesity. Part 1 of the study is designed to assess single and multiple doses of ARO-INHBE monotherapy, and Part 2 of the study is designed to assess ARO-INHBE in combination with tirzepatide, a subcutaneously administered GLP-1/GIP receptor co-agonist that has been approved in the United States and the European Union for management type 2 diabetes mellitus since 2022 and weight management since 2023/2024 respectively. 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

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.