Arrowhead Pharmaceuticals has announced promising topline results from Part 2 of its Phase 1/2 clinical study evaluating ARO-C3 in patients with IgA nephropathy (IgAN). The investigational RNA interference (RNAi) therapeutic, designed to reduce liver production of complement component 3 (C3), demonstrated potent inhibition of the alternative complement pathway and improvements in proteinuria, a key marker of kidney function.
The study enrolled 14 patients with IgAN who received subcutaneous doses of ARO-C3 (400 mg) on Days 1, 29, and 113, with follow-up through Day 169. The results revealed substantial pharmacodynamic effects and clinical benefits.
Significant Reduction in Complement Activity
ARO-C3 achieved remarkable suppression of complement activity, with a maximum mean reduction in C3 of 89% and sustained reduction greater than 87% from baseline through week 24. The drug also demonstrated maximum mean reductions of 85% in serum AH50 (alternative pathway hemolytic assay) and 100% in Wieslab AP (alternative pathway), with sustained reductions of greater than 76% and 89%, respectively.
"ARO-C3 has shown potent and consistent results in normal healthy volunteers and now in patients with IgA nephropathy, including up to 89% mean reduction of complement component 3, which led to reductions of 85% in AH50 and 100% in Wieslab AP, both markers of alternative pathway complement activity," said James Hamilton, M.D., MBA, Chief Medical Officer and Head of R&D at Arrowhead.
Dr. Hamilton emphasized that "such durable and near complete inhibition of the alternative complement pathway achieved with infrequent subcutaneous dose administration may be advantageous" for patients requiring long-term treatment.
Improvements in Kidney Function Markers
Perhaps most encouraging for patients with IgAN was the effect on proteinuria, a surrogate marker of renal injury. The study reported a mean reduction in spot urine protein-to-creatinine ratio (UPCR) of 41% by week 24, with one patient experiencing a maximum individual reduction of 89% from baseline.
Proteinuria reduction is particularly significant in IgAN, as persistent protein in the urine indicates ongoing kidney damage and is associated with disease progression. The substantial reductions observed suggest ARO-C3 may help preserve kidney function in these patients.
Favorable Safety Profile
ARO-C3 was generally well-tolerated in the IgAN patient population. The study reported no serious or severe treatment-emergent adverse events (TEAEs), and no TEAEs led to study or study drug discontinuation. The only adverse events reported in more than one subject were headache, cough, and nasopharyngitis.
Importantly, no infections with encapsulated organisms were observed—a potential concern when targeting the complement system, which plays a role in immune defense against certain bacteria.
Convenient Dosing Schedule
The pharmacodynamic data demonstrated a duration of effect that supports once every three months or less frequent subcutaneous dosing in later-stage studies. This infrequent dosing schedule could offer significant advantages for patient convenience and adherence compared to more frequently administered therapies.
About IgA Nephropathy and Complement-Mediated Renal Diseases
IgA nephropathy is the most common form of glomerulonephritis worldwide. The disease occurs when immunoglobulin A (IgA) deposits build up in the kidneys, causing inflammation and damage to the glomeruli, the kidney's filtering units. Over time, this can lead to kidney failure in up to 30% of patients.
The complement system, particularly the alternative pathway, has been implicated in the pathogenesis of IgAN and other complement-mediated renal diseases. By silencing C3, ARO-C3 aims to modulate activation of the complement cascade and potentially slow or halt disease progression.
Future Development Plans
Arrowhead plans to present additional results from the Phase 1/2 clinical study at a medical meeting in 2025. The company has not yet announced specific plans for Phase 2b or Phase 3 studies, but the positive results from this trial suggest ARO-C3 may advance to later-stage clinical development for IgAN and potentially other complement-mediated renal diseases.
The AROC3-1001 study (NCT05083364) is also evaluating ARO-C3 in patients with C3 Glomerulopathy (C3G), another complement-mediated kidney disease, though results from this cohort were not included in the current announcement.
RNAi Therapeutic Approach
ARO-C3 leverages RNA interference, a natural cellular mechanism that inhibits the expression of specific genes. By targeting the gene responsible for C3 production in the liver, ARO-C3 reduces the amount of C3 protein in circulation, thereby dampening complement activation throughout the body.
This approach differs from other complement-targeting therapies that typically inhibit specific complement proteins after they've been produced. The RNAi approach may offer advantages in terms of potency, duration of effect, and convenient dosing.
As Arrowhead continues to develop ARO-C3, the therapy could potentially address a significant unmet need for patients with IgAN and other complement-mediated renal diseases who currently have limited treatment options.
