VIDEO: New targets under investigation 'act on different targets across the chain of IgA nephropathy'

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Currently, several phase two and phase three clinical trials are studying the efficacy and safety of anti B cell directed therapies, complement inhibitors, and endothelin receptor antagonists in patients with IgA nephropathy. Complement inhibitors include Fabhalta (iptacopan, Novartis), or iptacopan by its generic name. It's an oral factor B inhibitor of the alternative complement pathway, approved for paroxysmal nocturnal hemoglobinuria. It is currently being studied in the phase three APPLAUSE-IgAN clinical trial to assess its efficacy and safety in treating patients with IgA nephropathy.

An interim analysis showed a clinically and statistically significant reduction of proteinuria for around 38% compared to placebo in patients with IgA nephropathy. IONIS-FB-LRx, which is an antisense oligonucleotide inhibitor of the factor B mRNA, showed in a phase two trial a reduction in proteinuria in patients with IgA nephropathy. Hopefully, this will translate into the phase three study, which is in planning ravulizumab (Ultomiris, Alexion Pharmaceuticals), which is in humanized monoclonal antibody inhibiting complement C5, showed a significant reduction in proteinuria compared with placebo in a phase two study of patients with IgA nephropathy, and the phase three trial is currently recruiting.

Then there are the anti-APRIL, which stands for a proliferation-inducing ligand and anti-BAF, which stands for B-cell activating factor of the TNF family. Zigakibart (BION-1301, Chinook Therapeutics) is a humanized monoclonal antibody that blocks APRIL. APRIL is a soluble factor with elevated blood levels in patient with IgA nephropathy. APRIL promotes IgA class switching, the survival of IgA secreting plasma cells, and the excess prediction of the galactose deficient IgA, which are critical steps in the pathogenesis of IgA nephropathy. Higher APRIL levels correlate with poorer outcomes, including increased proteinuria and decreased GFR. In a phase two study, Zigakibart showed clinically meaningful reduction in proteinuria as early as 12 weeks.

And just this past month, in May, 2024. The FDA granted breakthrough therapy designation to atacicept (Vera Therapeutics) for the treatment of IgAN. Atacicept is a dual APRIL-BAF inhibitor that met the primary endpoint in the phase two trial in patients with IgA nephropathy. This is very encouraging. Hopefully the results will carry to phase three trial. And sibeprenlimab (Visterra), also an anti-APRIL, significantly decreased proteinuria in patients with IgA nephropathy in a phase two study. And finally, in the category of anti-APRIL-BAF is the povetacicept (Alpine Immune Sciences). It's in a phase two demonstrated a greater than 60% reduction in proteinuria at 36 weeks, which is very encouraged. The phase three trial is anticipated to launch in the fall of this year.

And last but not least, they are the atrasentan (Novartis) and zibotentan (AstraZeneca), both selective endothelin receptor A blockers. Atrasentan met its primary efficacy endpoint in the interim analysis of its phase three aligned study, and the community is looking forward to the final efficacy report. And in a phase two study, zibotentan showed a marked reduction in proteinuria on top of the baseline use of dapagliflozin (Farxiga, AstraZeneca). All these feel like a Cambrian explosion of new therapeutics about to land in our clinical repertoire. They all showed an overall greater absolute reduction of proteinuria compared to placebo, between 35% to 45%, and most importantly, they act on different targets across the chain of pathophysiological pathway of IgA nephropathy. Some are oral, some intravenous, and other subcutaneous injectable, allowing flexibility and individualization in treatment selection.