Arrowhead Pharmaceuticals Reports Topline Results from Phase 1/2 ARO-C3 Study in IgA Nephropathy Patients

Arrowhead Pharmaceuticals has reported promising results from Part 2 of its Phase 1/2 clinical trial for ARO-C3, an investigational RNA interference (RNAi) therapeutic. ARO-C3 is designed to reduce the production of complement component 3 (C3) in the liver, potentially offering a new treatment for diseases mediated by the complement system. The topline results were announced by the company in Pasadena, California.

The clinical study focused on patients with IgA nephropathy (IgAN), a condition where the kidneys' ability to filter waste from the blood is compromised due to inflammation. Fourteen patients participated in the trial, receiving subcutaneous doses of 400 mg of ARO-C3 on three separate occasions: Days 1, 29, and 113, with follow-ups continuing until Day 169.

The therapeutic effects of ARO-C3 were significant. The maximum average reduction in C3 levels was 89%, with a sustained mean reduction of over 87% from baseline through week 24. Furthermore, the serum AH50, an alternative pathway hemolytic assay, showed a maximum mean reduction of 85%, maintaining an average reduction of more than 76% over the same period. Additionally, the Wieslab AP test, another marker of alternative pathway activity, indicated a maximum mean reduction of 100% with a sustained reduction greater than 89% from baseline through week 24.

In terms of proteinuria, a condition marked by excessive protein in the urine and indicative of kidney damage, patients experienced a mean reduction of 41% in the spot urine protein-to-creatinine ratio by week 24. Some individuals showed a maximum reduction of 89%.

Safety and tolerability outcomes were also favorable. ARO-C3 was generally well-tolerated among the participants, with no serious or severe treatment-emergent adverse events reported. No adverse events led to the discontinuation of the study or the drug. The most common minor side effects included headaches, cough, and nasopharyngitis, but no infections with encapsulated organisms were observed.

Dr. James Hamilton, the Chief Medical Officer and Head of Research and Development at Arrowhead Pharmaceuticals, emphasized the potential of ARO-C3. He noted that the therapy achieved a robust and consistent reduction in complement activity, which is crucial for managing IgAN. The ability to reduce proteinuria by 41% further underscores the drug's promise in treating renal injury associated with IgAN.

ARO-C3 works by targeting hepatocyte production of C3, aiming to curb the dysregulated activity of the complement system that can lead to tissue injury and disease progression. By silencing C3, ARO-C3 holds potential as a therapeutic approach for complement-mediated renal diseases, modifying the complement cascade's activation.

The AROC3-1001 Phase 1/2a study, listed under NCT05083364, represents a first-in-human, dose-escalating trial. It assesses the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-C3 in both healthy volunteers and patients with complement-mediated renal disease. While Part 1 involved healthy volunteers receiving placebo or ARO-C3 doses, Part 2 engaged adults diagnosed with C3 Glomerulopathy (C3G) and IgA Nephropathy (IgAN), administering three open-label doses of ARO-C3.

Arrowhead Pharmaceuticals continues to develop groundbreaking medicines targeting intractable diseases through RNA interference, a cellular mechanism that suppresses specific gene expressions. By leveraging this natural gene-silencing pathway, Arrowhead's RNAi-based therapies have the potential to induce rapid, profound, and sustained reductions in target gene activity, addressing various genetic diseases. The company remains committed to advancing research and sharing new data from its clinical programs in future scientific forums.