Song Ong @SongOngUAB

Song Ong is a professor at the University of Alabama at Birmingham. He is a transplant nephrologist and remains humbled by the fearful and wonderful complexity of the human immune system.

 

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Dana Rizk

Dana Rizk is Tenured Professor in the Division of Nephrology and Associate Dean for Clinical Trials at the University of Alabama at Birmingham Heersink School of Medicine. Her research interest focuses on IgA Nephropathy and she has ~100 peer-reviewed publications in prestigious medical journals including the New England Journal of Medicine.

The remaining competitors, our Left and Right Kidneys:

Team B-cell Modulators

Copyright: Ana Aguirre Perez/ Shutterstock

vs 

Team C3G Treatment

Copyright: Wollertz/ Shutterstock

IgA nephropathy (IgAN) is the most common glomerulonephritis in the world and affects 2.5 per 100,000 adult individuals per year. Once thought of as an indolent disease, we now recognize it is a significant cause of morbidity and mortality with 50% of patients progressing to kidney failure or death in 10-15 years. The search for effective treatments for IgAN had been frustrating and as recently as 2021, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines for IgAN focused mainly on supportive measures with limited options to stem the decline in kidney function. The past 5 years however have witnessed a paradigm shift in our approach to IgAN treatment towards targeting the pathogenesis of the disease itself.  The updated 2025 KDIGO guidelines endorsed budesonide and systemic steroids as disease specific treatments and a recent commentary highlighted B cell targeting  therapies that stop the production of pathogenic forms of IgA as potential future treatments.

Understanding the pathogenesis of IgAN has given us new therapeutic targets. The  widely accepted “four-hit hypothesis” begins with excessive production and elevated serum levels of galactose deficient IgA1 (Gd-IgA1) in genetically susceptible individuals (Hit 1). This in turn triggers autoantibody production to Gd-IgA1 (Hit 2). The subsequent formation of circulating immune complexes (Hit 3) and their deposition in the glomerular mesangium leads to inflammation and kidney injury (Hit4). 

Agents blocking cytokines regulating B cell activity block the first hit by preventing Gd-IgA1 production. B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), are cytokines crucial in the maturation, survival and maintenance of B cells and play an important part in immunoglobulin class switching. Serum levels of BAFF and APRIL are elevated in patients with IgAN and correlate with disease severity. For the first time, we now have agents that can effectively block either one or both cytokines.

Atacicept is a fusion protein that inhibits both APRIL and BAFF.  The ORIGIN phase 2 trial enrolled  116 patients with biopsy-proven IgAN and proteinuria already on maximal renin-angiotensin (RAS) blockade. Participants received weekly subcutaneous atacicept at 25, 75 and 150 mg doses or placebo for 36 weeks followed by an open-label extension of atacicept 150mg weekly for an additional 60 weeks. At 24 weeks proteinuria was reduced by 31% from baseline in the combined 150mg/75 mg Atacicept group, and at 36 weeks this was further reduced to 34% from baseline. Serum Gd-IgA1 levels were reduced by 60% at 36 weeks. Even more exciting, was the geometric mean change in estimated glomerular filtration rate (eGFR)  at 36 weeks of +0.8 ml/min per 1.73m2in the combined 75 and 150 mg treatment groups compared to -4.9 ml/min per 1.73m2 in the placebo arm. An interim analysis (at 36 weeks) from the ORIGIN phase 3 trial using 150 mg subcutaneous weekly dosing showed clinically significant improvements in urine to protein creatinine ratio when compared to placebo(-45.7% vs -6.8%), decreased Gd-IgA1 levels (-68.3% vs -2.9%). Additionally, resolution of hematuria was noted in 81.0% of patients receiving Atacicept vs. 20.7% of those receiving placebo. Adverse events related to infection and infestation were mostly mild to moderate and similar in both arms.   

Sibeprenlimab is a humanized monoclonal antibody that binds and inhibits APRIL. In the phase 2 ENVISION trial,  Sibeprenlimab given as an intravenous infusion of 2mg/kg, 4mg/kg or 8mg/kg every 4 weeks or placebo was given to in patients already on maximal RAAS blockade and demonstrated a dose-dependent  improvement in proteinuria and decreased APRIL and Gd-IgA1 levels.   The mean eGFR change from baseline at month 12 was -2.7, +0.2 and -1.5 ml/min per 1.73 m2 in the three ascending dose arms vs. a loss of 7.4 ml/min per 1.73 m2 in the placebo group. The phase 3 VISIONARY trial compared subcutaneous sibeprenlimab 400mg every 4 weeks to placebo, with dose selection based on the clinical effect of 4mg/kg dosing and modelling showing equivalency with intravenous administration. Results from the interim analysis showed a significant reduction in 24-hour urinary protein-to-creatinine ratio (reduction by 50.2% vs an increase with placebo of 2.1%), and  reduction in levels of APRIL and Gd-IgA1by 95.8% and 67.1%, respectively. Adverse events related to infections and infestations were similar to placebo. Sibeprenlimab has recently been granted accelerated approval by the FDA for treatment of  proteinuria in IgAN and full approval will be contingent on completion of the VISIONARY trial.

Other B-cell modulating agents include zigakibart (anti-APRIL), telitacicept, and povetacicept (inhibiting both circulating BAFF and APRIL). In a  phase 1/ 2 trial, subcutaneous  zigakibart 600 mg given every two weeks in patients with IgAN resulted in a  60% reduction in proteinuria and sustained eGFR stabilization at week 100. Hematuria and levels of IgA and Gd-IgA1 were decreased. Results from stage A of a phase 3 clinical trial of  subcutaneous telitacicept 240 mg weekly for 39 weeks vs placebo in IgAN patients showed significant reduction in proteinuria with a geometric mean ratio of UPCR to baseline of 0.41 and 0.91 in the telitacicept and placebo arms respectively.  Interim 36 week results from the RAINIER trial of povetacicept in IgAN showed a 52.0% reduction in proteinuria , a 77.4% reduction from baseline in serum Gd-IgA1 and  resolution of hematuria in 85.1% of povetacicept treated patients.

With the B- cell modulating  agents, we now have the means to profoundly  alter the course of a disease that as nephrologists, we could do little to stop until now. It is not a stretch to imagine that a combination of B cell therapies with agents that act downstream in the pathogenic cascade that block complement, the renin-angiotensin-aldosterone system, endothelin-A receptor, and sodium-glucose cotransporter-2 are likely to greatly improve outcomes.

The excitement in the scientific and nephrology community surrounding these new treatments has been palpable at recent meetings. The B cell modulating  agents are blazing the way in IgAN and we cannot help but wish that similar progress will be made in other rare glomerular diseases. 

The future is bright and the case for B-cell modulating therapies in IgAN in NephMadness is a slam-dunk.

Copyright: Ana Aguirre Perez/ Shutterstock

– Guest Post written by Song Ong and Dana Rizk

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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