Arrowhead Pharmaceuticals (ARWR) Status Update summary

Obesity disease landscape and unmet need

• Obesity is a complex, heterogeneous disease with significant metabolic, cardiovascular, and diabetes risks, requiring diverse and chronic treatment approaches beyond lifestyle and surgery.

• Effective anti-obesity medications have emerged, but long-term benefit requires continued treatment, and discontinuation rates remain high.

• Current therapies often reduce both fat and muscle mass, and adverse events, particularly gastrointestinal, are common.

• There is a need for novel treatments that address disease subtypes, maintain lean mass, and improve body composition.

Mechanism of action and scientific rationale

• ARO-INHBE silences the INHBE gene in hepatocytes, reducing Activin E secretion and downstream ALK7 signaling, while ARO-ALK7 targets ALK7 in adipocytes; both are genetically validated targets linked to lower obesity and diabetes risk.

• Intervening in the Activin E/ALK7 pathway may increase lipolysis, reduce adipose hypertrophy, visceral adiposity, and insulin resistance.

Arrowhead's obesity pipeline and TRiM platform

• Arrowhead is advancing ARO-INHBE and ARO-ALK7, leveraging the TRiM platform for potent, durable, and selective siRNA delivery to adipose tissue, achieving up to 99% target knockdown in preclinical models.

• Preclinical data show both candidates reduce fat mass, preserve lean mass, improve glycemic control, and enhance lipid mobilization without increasing liver steatosis.

• Combination of ALK7 siRNA with tirzepatide in mice further improves weight loss and body composition.

• Preclinical safety studies show no significant adverse effects and high tissue selectivity in rodents and non-human primates.