FDA Grants Accelerated Approval to Iptacopan For the Reduction of Proteinuria in Adults With IgAN

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The FDA has granted an accelerated approval to iptacopan (Fabhalta; Novartis) for the reduction of proteinuria in adult patients with primary immunoglobulin A nephropathy (IgAN) who are at risk of disease progression. Proteinuria is defined as a urine protein-to-creatine ratio (UPCR) of 1.5 g/g or more. The accelerated approval is based on the pre-specified interim analysis of the phase 3 APPLAUSE-IgAN trial (NCT04578834), and the continued approval of iptacopan may be dependent upon the verification and description of clinical benefit in this study.¹

IgAN is a progressive and rare disease in which the immune system attacks the kidneys and often causes glomerular inflammation and proteinuria. Although approximately 25 per million people worldwide are newly diagnosed with IgAN each year, each person’s disease journey is unique because IgAN progresses differently. Additionally, treatment responses vary from the individual. Despite current standard of care, up to 50% of patients who have IgAN with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis. These patients often require maintenance dialysis with or without kidney transplantation, underscoring the need for additional therapies and treatments.¹

Iptacopan is a prescription medicine that reduces protein in the urine. It is an oral factor B inhibitor of the alternative complement pathway, and was specifically developed for rare diseases such as IgAN, complement 3 glomerulopathy, atypical hemolytic uremic syndrome, immune complex membranoproliferative glomerulonephritis, and lupus nephritis. In December 2023, iptocopan received an FDA approval for the treatment of adults with paroxysmal nocturnal hemoglobinuria.^1-3

"The heterogeneous and progressive nature of IgAN has made it challenging to effectively treat this disease. Thankfully, the treatment landscape is rapidly evolving," said study investigator Dana Rizk, MD, APPLAUSE-IgAN Steering Committee member and professor in the University of Alabama at Birmingham Division of Nephrology, in a news release. "Mounting clinical evidence underscores the pivotal role of complement activation in IgAN. I am thrilled that this advancement is now available to help enable a targeted treatment approach for IgAN patients."¹

The APPLAUSE-IgAN (NCT04578834) trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 study that evaluates the efficacy and safety of the iptacopan in 518 adult patients with primary IgAN. Patients were randomly assigned to receive either twice-daily oral iptacopan (200 mg) or placebo. The main study population included 250 patients with IgAN who had an eGFR≥30 mL/min/1.73 m2 and UPCR ≥1 g/g at baseline, and an additional smaller cohort of patients who had severe renal impairment at baseline (eGFR 20–30 mL/min/1.73 m2) were also enrolled to provide additional information; however, these groups will not contribute to the main efficacy analyses, according to the investigators.^1,4

The 2 primary end points of APPLAUSE-IgAN’s interim and final analysis were proteinuria reduction at 9 months (measured by a 24-hour UPCR) and the annualized total eGFR slope over a 24-month period, respectively. The following secondary end points were also assessed: proportion of participants reaching UPCR less than 1 g/g without corticosteroids, immunosuppressants, or other newly approved drugs, new background therapy, or kidney replacement therapy (KRT); time from randomization to first occurrence of composite kidney failure end point event; and change from baseline to 9 months in the fatigue scale.¹

According to the findings, iptacopan achieved an approximate 44% reduction in proteinuria at 9 months compared to baseline compared with placebo (9% reduction), demonstrating a clinically meaningful and statistically significant 38% reduction compared with placebo. Additionally, the treatment effect on UPCR at 9 months was consistent across all subgroups, regardless of age, sex, race, baseline disease characteristics, and the use of sodium-glucose cotransporter-2 inhibitors. These findings build on previous data presented during a session at the World Congress of Nephrology in Buenos Aires, Argentina, from April 13, 2024, to April 16, 2024.^1,2

Further, iptacopan had a favorable safety profile, consistent with previously reported data. The most common adverse effects reported by those taking iptacopan were upper respiratory tract infection, lipid disorder, and abdominal pain.¹

"Today's approval of [iptacopan] as a first-in-class medicine for IgAN is an important milestone in our journey to evolve rare renal disease care by bringing new treatments to people in urgent need of options," said Victor Bultó, President US, Novartis, in a news release. "We are deeply committed to those living with rare renal diseases and look forward to continued partnership with this community as we further advance our broad portfolio."¹

Editor's Note: Updated on August 8, 2024 at 10:50am.

REFERENCES

1. Novartis. Novartis receives FDA accelerated approval for Fabhalta® (iptacopan), the first and only complement inhibitor for the reduction of proteinuria in primary IgA nephropathy (IgAN). News release. August 8, 2024. Accessed August 8, 2024. https://www.novartis.com/us-en/news/media-releases/novartis-receives-fda-accelerated-approval-fabhalta-iptacopan-first-and-only-complement-inhibitor-reduction-proteinuria-primary-iga-nephropathy-igan

2. McGovern, G. Iptacopan Demonstrates 38.3% Proteinuria Reduction in Patients With IgAN. Pharmacy Times. April 24, 2024. Accessed August 8, 2024. https://www.pharmacytimes.com/view/iptacopan-demonstrates-38-3-proteinuria-reduction-in-patients-with-igan

3. McGovern, G. FDA Approves Iptacopan for the Treatment of Paroxysmal Nocturnal Hemoglobinuria in Adult Patients. Pharmacy Times. December 6, 2023. Accessed August 8, 2024. https://www.pharmacytimes.com/view/fda-approves-iptacopan-for-the-treatment-of-paroxysmal-nocturnal-hemoglobinuria-in-adult-patients

4. Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN). ClinicalTrials.gov identifier: NCT04578834. Updated July 15, 2024. Accessed August 8, 2024. https://clinicaltrials.gov/study/NCT04578834