Arrowhead Pharmaceuticals (NASDAQ:ARWR) shared initial interim clinical results from two RNA interference (RNAi) obesity candidates, ARO-INHBE and ARO-ALK7, during a virtual key opinion leader (KOL) event featuring metabolic medicine expert Dr. Carel le Roux and company leadership. Executives emphasized that the data are early, but described the readouts as supportive of the therapeutic hypothesis that targeting the activin E–ALK7 pathway could improve body composition—particularly visceral fat—and potentially complement incretin-based therapies in patients with obesity and type 2 diabetes.
Expert perspective: unmet need in visceral adiposity and diabetes
Dr. le Roux, Chair of Metabolic Medicine at University College Dublin School of Medicine, framed obesity as a heterogeneous condition in which visceral adiposity can drive cardio-kidney-metabolic complications. He highlighted that patients with type 2 diabetes continue to have worse outcomes than those without diabetes and may respond less robustly to existing pharmacotherapies.
Arrowhead’s rationale: inhibiting an adipocyte fat-storage signal
Arrowhead Chief Medical Officer and Head of R&D James Hamilton said the activin E–ALK7 pathway promotes fat storage by slowing lipolysis and stimulating adipocyte hypertrophy. Activin E is encoded by the inhibin E gene in the liver, secreted into the bloodstream, and binds to its receptor ALK7 on adipocytes.
Hamilton cited human genetics observations discussed on the call: loss-of-function variants in inhibin E and ALK7 are associated with improved waist-to-hip ratio adjusted for BMI and reduced risk of atherosclerotic cardiovascular disease and type 2 diabetes, along with favorable changes in measures such as ApoB, hemoglobin A1c, and visceral fat volume. The company’s hypothesis is that silencing either gene could “phenocopy” these favorable traits.
ARO-INHBE: activin E knockdown and early body composition signals
Hamilton reviewed interim results from the ARO-INHBE 1001 trial, which began with single-ascending dose (SAD) and multiple-ascending dose (MAD) cohorts in obese healthy volunteers, and also enrolled combination cohorts pairing tirzepatide with ARO-INHBE in both non-diabetic and diabetic obese participants. He said all cohorts are fully enrolled.
In the monotherapy cohorts, participants had baseline mean body weight over 100 kg and mean BMI above 35, with baseline activin E levels around 450–500 pg/mL. The company reported a dose-response reduction in serum activin E, reaching a mean maximal reduction of 85% at the 400 mg dose, with activity lasting beyond three months after a single dose.
Arrowhead also highlighted changes in body composition associated with ARO-INHBE monotherapy, including:
- About 10% reduction in visceral fat after a single dose
- About 38% relative reduction in liver fat
- About 2% modest increase in lean mass
- Reduction in muscle fatty infiltration
With repeated dosing, Hamilton said visceral fat reductions improved further, reaching placebo-adjusted mean improvements of up to 15.6%.
Combination results in obese diabetics: enhanced weight loss and fat loss vs tirzepatide alone
The event focused heavily on obese patients with type 2 diabetes, described as a population that tends to lose less weight on incretin therapy and may have a more dysregulated activin E pathway. In Arrowhead’s obese diabetic cohorts, baseline mean age was 52, mean weight 103 kg, and mean BMI 36.6. Baseline liver fat measured by MRI-PDFF averaged 17.1%, hemoglobin A1c averaged 7.4, and baseline activin E was higher at roughly 661 pg/mL—which the company said was statistically elevated compared to non-diabetic cohorts.
In these combination cohorts, participants received weekly tirzepatide through week 24, plus ARO-INHBE 200 mg, ARO-INHBE 400 mg, or placebo. Arrowhead reported up to 84% activin E reduction after two doses in the combination groups, with no reduction observed on tirzepatide alone.
Preliminary data in obese diabetics suggested enhanced weight loss when ARO-INHBE was added to tirzepatide. At week 16, mean weight loss was 9.4% in the high-dose combination group compared with 4.8% in the tirzepatide-plus-placebo group. Hamilton said the effect appeared dose-responsive, with a smaller benefit in the lower-dose ARO-INHBE group.
On a week 12 MRI using a 5 mg tirzepatide dose, Arrowhead reported dose-responsive and larger reductions in key fat compartments at the 400 mg ARO-INHBE dose, including:
- 23.2% mean reduction in visceral fat
- 15.4% reduction in total fat
- Up to 76.7% relative reduction in liver fat
Hamilton said these reductions were roughly threefold greater than with tirzepatide alone in the trial and noted the data are preliminary and at an early timepoint. Company leadership also suggested some week 12 combination reductions were “on track” to meet or exceed reductions observed in SURPASS-3 after 52 weeks of tirzepatide in obese diabetics, while stressing the interim nature of the results.
ARO-ALK7: adipocyte-targeted gene silencing proof-of-concept
Hamilton said the ARO-ALK7 program is about two quarters behind ARO-INHBE and uses adipose biopsies to measure ALK7 mRNA knockdown. The obese healthy volunteer cohorts are fully enrolled, and enrollment has begun in combination cohorts.
In single-dose data presented, the 200 mg dose produced mean ALK7 mRNA knockdown of 88%, with a maximum of 96% in an individual, lasting at least 12 weeks. Hamilton and CEO Dr. Chris Anzalone described this as, to their knowledge, the first clinical trial demonstration of siRNA-mediated gene silencing using a platform targeting adipocytes.
The company reported a placebo-adjusted mean visceral fat reduction of 14.1% at the 200 mg dose, measured after eight weeks on MRI.
Safety: Arrowhead said ARO-INHBE was well tolerated as monotherapy and in combination with tirzepatide, with most treatment-emergent adverse events described as mild and no discontinuations attributed to adverse events. Injection site events were characterized as mild and self-limited, and the company said there was no difference in gastrointestinal adverse events between combination therapy and tirzepatide alone. One serious adverse event (a limb abscess) was reported and deemed unrelated to study drug. For ARO-ALK7, preliminary monotherapy safety data were described as similarly favorable, with no serious adverse events reported and no discontinuations.
Next steps: Management said it is planning additions to ongoing studies and moving “as quickly as possible” into phase 2, including combination studies in obese diabetics with tirzepatide and other GLP drugs, and studies evaluating ARO-INHBE and ARO-ALK7 as maintenance therapy after GLP withdrawal. The company also said it intends to initiate monotherapy cohorts in obese diabetic patients and expand follow-up to assess durability out to a year. Executives noted they have not yet discussed a regulatory pathway with FDA or EMA.
About Arrowhead Pharmaceuticals (NASDAQ:ARWR)
Arrowhead Pharmaceuticals, Inc is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of RNA interference (RNAi) therapeutics. Since its founding in 2008, Arrowhead has leveraged its proprietary delivery platform—known internally as the Advanced RNAi Compound (ARC) technology—to silence disease-causing genes in patients suffering from genetically defined diseases. The company’s approach aims to offer durable, targeted treatments across a range of therapeutic areas.
The company’s pipeline includes multiple candidates in various stages of development.
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