Dana Rizk, MD: “Very Exciting” Pipeline Developments in IgA Nephropathy

Among the most active therapeutic pipelines of any rare disease in recent years is that of IgA nephropathy (IgAN), with the most recent development being the accelerated approval of Novartis’ iptacopan (Fabhalta) for the reduction of proteinuria in adults with primary IgAN.¹

The August 7, 2024, approval made iptacopan the first complement inhibitor to earn US Food and Drug Administration approval for the reduction of proteinuria in primary IgAN and was based on interim data from the phase 3 APPLAUSE-IgAN trial, which demonstrated use of iptacopan was associated with a 38% reduction in proteinuria at 9 months relative to placebo.¹

Mere weeks after this decision, the IgAN community now patiently awaits the potential full approval of sparsentan (Filspari). After earning accelerated approval last year, the non-immunosuppressive dual endothelin / angiotensin receptor agonist is on its way to becoming the second IgAN therapeutic to earn full FDA approval, a feat budesonide (Tarpeyo) achieved in 2023.^2,3

For additional insight into the approval of iptacopan and other pipeline developments in IgAN, the editorial team of HCPLive Nephrology spoke with Dana Rizk, MD, a professor of medicine in the division of nephrology at the University of Alabama at Birmingham.

HCPLive: Can you explain iptacopan’s mechanism of action and why this is thought to be significant in IgAN?

Rizk: Activation of the alternative complement pathway is thought to contribute to the pathogenesis of IgAN. Fabhalta is a first-in-class oral medicine that uniquely targets the alternative pathway of the complement system. As such, it adds to the armamentarium of therapies available to us to treat the disease.

IgAN is known for its variation in presentation, prognosis, and patient response to treatment. Current treatment options do not address all drivers of IgAN pathophysiology, and nephrologists and IgAN patients are eager to have more treatment choices. We need effective, targeted therapies with different mechanisms of action that can help slow or prevent progression to kidney failure.

HCPLive: What were some of the key findings from APPLAUSE-IgAN supporting this accelerated approval?

Rizk: This indication is granted under accelerated approval based on the prespecified interim analysis of the Phase III APPLAUSE-IgAN study measuring reduction in proteinuria at 9 months compared to placebo.

In the interim analysis, Fabhalta achieved a 44% reduction in proteinuria at 9 months relative to baseline, compared with 9% reduction in the placebo arm, demonstrating a clinically meaningful relative reduction of 38% versus placebo (P <.0001). Fabhalta has also had a favorable safety profile and the incidence of treatment-emergent adverse events was balanced between the 2 study arms and were all mild or moderate in intensity.

The Phase III APPLAUSE study is still ongoing evaluating whether Fabhalta slows disease progression as measured by estimated glomerular filtration rate (eGFR) decline over 24 months. The study completion is expected in 2025 and will support the traditional FDA approval of the drug.

HCPLive: Acknowledging that IgAN is difficult to effectively treat, what is the significance of the overall increase in pipeline movement for this disease in recent years? What benefit might different targeted therapies offer over the current standard of care for patients?

Rizk: IgAN is known for its variation in presentation, prognosis, and patient response to treatment, and this heterogeneity contributes to a need for effective, targeted therapies with different mechanisms of action. Fabhalta is currently the first and only FDA-approved complement inhibitor for the reduction of proteinuria in adults with primary IgAN with UPCR ≥1.5 g/g who are at risk of rapid disease progression. Its mechanism of action is fundamentally different from that of other IgAN therapies.

The increase in the number of therapies available to IgAN patients and their treating physicians is very exciting. The current standard of care improves outcomes but does not prevent the lifetime loss of kidney function for a sizable number of patients. We still need more therapies that target different aspects of the disease pathogenesis. As more drugs become available, we will be able to address these unmet needs.

Editors’ Note: Rizk has relevant disclosures with Reata Pharmaceuticals, Travere Therapeutics, Achillion Pharmaceuticals, Pfizer Pharmaceuticals, Calliditas Therapeutics, Otsuka Pharmaceuticals, Chinook Therapeutics, Novartis, George Clinical, and Angion.

References

1. ^{Campbell P. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. HCPLive. August 7, 2024. Accessed September 3, 2024. https://www.hcplive.com/view/iptacopan-receives-accelerated-approval-for-reducing-proteinuria-in-iga-nephropathy}
2. ^{Travere Therapuetics. Travere Therapeutics Announces FDA Accelerated Approval of FILSPARIᵀᴹ (sparsentan), the First and Only Non-immunosuppressive Therapy for the Reduction of Proteinuria in IgA Nephropathy. February 17, 2023. Accessed September 3, 2024. https://ir.travere.com/news-releases/news-release-details/travere-therapeutics-announces-fda-accelerated-approval}
3. ^{Brooks A. FDA Awards Full Approval to Budesonide (Tarpeyo) in Treatment of IgA Nephropathy. HCPLive. December 20, 2023. Accessed September 3, 2024. https://www.hcplive.com/view/fda-awards-full-approval-to-budesonide-tarpeyo-in-treatment-of-iga-nephropathy}