New 100-week data from the ongoing Phase 1/2 study of zigakibart, an investigational anti-APRIL monoclonal antibody, reinforce its potential as a disease-modifying treatment for IgA nephropathy (IgAN). Findings presented at the 62nd ERA Congress demonstrate sustained proteinuria remission, stable kidney function, and a reassuring safety profile in patients with the most common form of glomerular disease worldwide.
Addressing a Critical Unmet Need
IgA nephropathy affects patients globally as the most common form of glomerular disease and a frequent cause of chronic kidney disease. The condition's pathogenesis is marked by inflammation and progressive kidney damage, which can lead to kidney failure. Many patients remain unaware they have the condition until significant kidney damage has occurred, and 50% of IgAN patients will ultimately develop kidney failure.
By targeting the APRIL pathway and reducing production of pathogenic galactose-deficient IgA1 (Gd-IgA1), zigakibart addresses a key driver of disease progression. "Zigakibart is designed to intercept the initiating factor in IgAN pathogenesis, offering a new approach that may halt or significantly delay progression," explained lead investigator Professor Jonathan Barratt.
Robust Clinical Evidence
The ADU-CL-19 trial included 40 adults with biopsy-confirmed IgAN and persistent proteinuria despite stable supportive therapy. Patients received zigakibart every two weeks via intravenous infusion or subcutaneous injection, in addition to maximally tolerated renin–angiotensin system inhibitors (RASi) unless RASi-intolerant, demonstrating efficacy beyond standard care.
At Week 100, proteinuria was reduced by 60% from baseline. Over half of patients (55%) reached proteinuria levels below 500 mg/24h, and 31% achieved levels below 300 mg/24h, indicating deeper remission. Estimated glomerular filtration rate (eGFR) remained stable across subgroups throughout the study period.
"The consistency of eGFR stabilisation over 100 weeks, even across proteinuria response groups, is particularly encouraging," said Prof. Barratt.
Sustained Biochemical Response
Treatment led to sustained reductions in serum immunoglobulins, including a 74% drop in IgA and pathogenic Gd-IgA1, consistent with APRIL pathway inhibition. Earlier 52-week data had shown reductions in IgA, IgM, and IgG of 67%, 78%, and 35%, respectively, demonstrating the treatment's sustained impact on the underlying disease mechanism.
Safety Profile Maintained
Zigakibart was well tolerated throughout the extended study period. Most adverse events were mild or moderate, with no treatment-related serious infections or discontinuations. Infections were the most common adverse events, though the study coincided with a period of high COVID-19 prevalence.
Clinical Significance and Future Directions
This represents the longest duration of eGFR stabilization reported for an anti-APRIL agent in IgAN. "These long-term results build confidence in zigakibart as a potential cornerstone therapy for IgAN," said Prof. Barratt. "We're excited to see how the upcoming Phase 3 trials will further define its role."
The importance of long-term follow-up data cannot be overstated, as Barratt emphasized: "What we need to know is that any response to an anti-APRIL approach is able to be sustained over time because what I think all of the data is showing us is that when you stop these agents, the disease comes back."
The global Phase 3 BEYOND study is now evaluating zigakibart in a broader population, with primary proteinuria endpoints at 40 weeks and long-term kidney function assessment through 104 weeks, potentially establishing this anti-APRIL approach as a new standard of care for IgA nephropathy patients.
