Arrowhead's RNAi Kidney Disease Candidate Shows Promise in Early-Stage Trial

Arrowhead Pharmaceuticals has reported encouraging results from a phase 1/2a study of its investigational RNA interference (RNAi) therapy for kidney disease. The candidate, ARO-C3, demonstrated a favorable safety profile and promising pharmacodynamic effects in patients with IgA nephropathy (IgAN), also known as Berger's disease.

Safety and Tolerability

The open-label, two-part trial enrolled both healthy adult participants and adults with complement-mediated renal disease. In the cohort of 14 IgAN patients, ARO-C3 was generally well-tolerated through day 169 of the study. No severe treatment-emergent adverse events (TEAEs) were reported, with headache, cough, and cold symptoms being the only TEAEs observed in more than one participant.

Pharmacodynamic Effects

Patients received 400 mg subcutaneous doses of ARO-C3 on days 1, 29, and 113. The therapy, designed to reduce liver production of complement component 3 (C3), showed significant pharmacodynamic effects:

• A greater-than-87% mean sustained reduction in C3 through week 24
• An 85% maximum mean reduction in serum alternative pathway hemolytic assay (AH50)
• A 100% maximum mean reduction in Wieslab AP (alternative pathway)

These results indicate potent inhibition of the alternative complement pathway, which may be advantageous in treating complement-mediated kidney diseases.

Clinical Implications

Dr. James Hamilton, Arrowhead's chief medical officer and R&D head, highlighted the potential benefits of ARO-C3's durable and near-complete inhibition of the alternative complement pathway achieved with infrequent subcutaneous dosing. Additionally, the study observed a 41% reduction in spot urine protein-to-creatinine ratio, a surrogate marker of renal injury in IgAN, suggesting potential therapeutic efficacy.

ARO-C3 is one of Arrowhead's earliest-stage clinical candidates and one of two assets designed to target complement-mediated diseases. The company plans to present additional results from this study at a medical meeting later this year, which may provide further insights into the therapy's potential in treating kidney diseases.