Arrowhead Pharmaceuticals has reported early-stage trial results showing that its RNAi therapeutic ARO-INHBE, when combined with Eli Lilly’s tirzepatide, doubled the weight loss achieved by tirzepatide alone in patients with type 2 diabetes. According to a company press release, four patients who received both drugs experienced a 9.4% reduction in weight at week 16, compared to a 4.8% reduction among five patients who received only tirzepatide.
The study also found that ARO-INHBE tripled reductions in visceral fat, total fat, and liver fat compared to tirzepatide alone. These findings were based on data from three patients. When tested without tirzepatide, ARO-INHBE reduced visceral fat by 9.9%, liver fat by 38%, and increased total lean tissue by 3.6%. The placebo-adjusted mean visceral fat reduction was 15.6% at week 24.
Arrowhead stated that these interim results provide proof of concept for inhibiting the Activin E pathway as a way to improve body composition and enhance weight loss over tirzepatide alone in people with type 2 diabetes.
“Truist Securities, reflecting on the results’ implications for Lilly in a Tuesday morning note, called the weight loss achieved by Arrowhead’s drug ‘substantial’ and ‘meaningful.’ The firm said that interest in weight loss quality has waned recently as the market looks to the launch of oral options from Lilly and Novo Nordisk. But Arrowhead’s results could reignite that conversation. Key opinion leaders in metabolic disease remain concerned about the long-term impact of weight loss without more targeted therapies,” according to Truist.
Other companies developing therapies focused on improving body composition during weight loss include Scholar Rock (apitegromab), Eli Lilly (bimagrumab), and Wave Life Sciences (WVE-007).
Regarding safety, Arrowhead reported that treatment-emergent adverse events were mild and did not lead to discontinuations. There was one case of limb abscess considered unrelated to treatment; gastrointestinal side effects were similar between groups; no clinically significant changes were observed in liver enzymes or other laboratory measures.
Arrowhead also shared initial data for another candidate, ARO-ALK7, which demonstrated gene target silencing—reducing adipose ALK7 mRNA by 88% at week eight—and led to a placebo-adjusted reduction of visceral fat by 14.1%. This therapy was well tolerated according to Arrowhead.
CEO Chris Anzalone previously told BioSpace he is particularly optimistic about ARO-ALK7 because it targets the ACVR1C gene involved in obesity-related metabolic complications.
Both programs are being developed internally at Arrowhead rather than through external partnerships seen elsewhere in the industry.
The Phase I/IIa trials for both ARO-INHBE and ARO-ALK7 are ongoing with further updates expected later this year.
In November 2025, Arrowhead received its first FDA approval for plozasiran (Redemplo) for familial chylomicronemia syndrome.
Truist noted that these new results could benefit Eli Lilly as it awaits regulatory decisions on its oral obesity drug orforglipron; if approved as soon as March, orforglipron would not directly compete with Arrowhead’s injectable option but could be used alongside it depending on patient needs.
