Arrowhead Pharmaceuticals (ARWR) Study Update summary

Unmet needs and current landscape in obesity treatment

• Obesity is a heterogeneous disease with multiple subtypes, and visceral adiposity is a key driver of metabolic complications, especially in type 2 diabetes patients.

• Current pharmacotherapies like GLP-1 agonists (semaglutide, tirzepatide) have improved weight loss outcomes but still leave many patients, particularly those with diabetes, unable to reach optimal targets.

• Only a minority of patients achieve both BMI and waist-to-height ratio targets, highlighting the need for new approaches.

• Combination therapies and novel mechanisms are needed to address the unmet needs in obesity, especially for those with metabolically unhealthy adiposity.

• Reducing visceral fat is crucial for improving cardio-kidney metabolic outcomes.

Study design and rationale

• Phase 1/2a studies evaluated ARO-INHBE and ARO-ALK7 in obese volunteers, with and without type 2 diabetes, including monotherapy and combination with tirzepatide.

• Key endpoints included safety, pharmacokinetics, changes in serum Activin E, body composition, liver fat, and glycemic parameters.

• Both studies fully enrolled single and multiple ascending dose cohorts, with ongoing expansion and planning for Phase 2b.

• Combination with tirzepatide is being assessed due to its established use in diabetes and weight management.

• Phase I/II studies enrolled obese healthy volunteers and obese diabetic patients, with monotherapy and combination arms.

Mechanism of action and genetic validation

• ARO-INHBE targets hepatic INHBE to reduce Activin E, which regulates adipose lipolysis and is linked to insulin resistance and visceral fat accumulation.

• ARO-ALK7 silences ALK7 in adipocytes, a receptor that suppresses lipolysis; genetic variants in ALK7 are associated with lower obesity and diabetes risk.

• Both pathways are genetically validated for their roles in metabolic health and adiposity.

• Both are RNAi-based therapeutics leveraging gene silencing for obesity and metabolic disease.

• Loss-of-function variants in Inhibin E and ALK7 are associated with improved metabolic profiles and reduced visceral fat.