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LONG BEACH, Calif. -- Iptacopan (Fabhalta) was safe and effective for reducing proteinuria in biopsy-confirmed immunoglobulin A nephropathy (IgAN), according to interim findings from the phase III APPLAUSE-IgAN study presented here.

Meeting the first of the two primary endpoints, iptacopan added to supportive care yielded a 38.3% (95% CI 26.0-48.6) reduction in 24-hour urine protein-creatinine ratio (UPCR) at 9 months relative to placebo, Dana Rizk, MD, of University of Alabama at Birmingham, said at the National Kidney Foundation (NKF) Spring Clinical meeting.

There were also reductions in UPCR from first morning void by the second week of treatment. This continued to steadily drop through month 9, ending with a 35.8% (95% CI 22.6-46.7) relative reduction between the arms.

Iptacopan is the first potential treatment for IgAN that specifically targets the alternative complement pathway, Rizk noted during a presentation of the late-breaking findings.

"The alternative complement pathway has been implicated in the pathogenesis of IgAN," NKF President Sylvia Rosas, MD, commented in a statement. "It gives patients hope that a novel therapeutic intervention may lead to slowing progression of chronic kidney disease and avoiding kidney failure."

Rosas, who wasn't involved with the study, underscored the need for more effective, targeted therapies for IgAN patients. It's estimated up to 30% of people with persistent proteinuria will progress to kidney failure within 10 years.

Iptacopan was first approved in December 2023 for the treatment of paroxysmal nocturnal hemoglobinuria. The twice-daily oral treatment acts as a factor B inhibitor of the alternative complement pathway.

"There is at least some school of thought that this is addressing the matter of inflammation," said Rizk, but added that the supporting data suggest the agent works "more broadly in a larger IgAN population, not just the ones we thought of as being highly inflamed and having E lesions and C lesions."

"The main challenge for us is going to be then selecting that patient who then requires this broad immunosuppressive approach," Rizk said in response to a question of where this therapy would fall in the line of treatment.

Recently, there's been a push toward new therapeutics for this rare and progressive condition, also known as Berger's disease. The very first drug specifically indicated to reduce proteinuria in IgAN was budesonide (Tarpeyo), approved in December 2021. Last February, the FDA also granted accelerated approval to sparsentan (Filspari), the first non-immunosuppressive therapy for IgAN.

The interim results presented by Rizk reflected 250 patients who reached month 9 or had discontinued treatment. The study population for the main efficacy analysis included those with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² and UPCR ≥1 g/g based on a 24-hour urine collection at baseline. There was also a smaller group of patients with severe renal impairment (eGFR 20 to <30 mL/min/1.73 m² at baseline) assessed, though this group wasn't included in the main efficacy analyses.

All patients were already on maximally tolerated renin-angiotensin system (RAS) inhibitors for at least 3 months prior to study entry. Those randomized to receive iptacopan were given 200 mg twice daily. The average age was 39.4, around half were Asian, and the average baseline eGFR was 64.1 mL/min/1.73 m². Virtually all participants were on angiotensin converting enzyme inhibitors or angiotensin receptor blockers at baseline and 12.8% were stable on an SGLT2 inhibitor.

Double the proportion of patients on iptacopan achieved a 24-hour UPCR under 1 g/g at month 9 compared with placebo recipients (42.5% vs 21.9%; OR 3.12, 95% CI 1.68-5.79).

No patients in either group had to initiate kidney replacement therapy after the trial started. However, 1.6% and 8% of those on iptacopan and placebo initiated an alternative or rescue medication, respectively.

From baseline to month 9, the proportion of patients with a negative/trace dipstick hematuria on iptacopan more than doubled (19.2% to 46%), while it remained fairly steady with placebo (25% to 32.7%).

"The treatment benefit of iptacopan over placebo [on proteinuria] was consistent across supportive analyses and subgroups that were studied," said Rizk, including sex, geographic region (Asia and non-Asia), all categories of baseline 24-hour UPCR, eGFR, hematuria, and .

A total of 443 patients were included in the safety analysis and adverse events (AEs) were well-balanced between arms, said Rizk, with 63% of patients on iptacopan and 69% of placebo recipients having at least one AE (most were mild or moderate in severity). Serious AEs occurred in 8% and 5%, respectively, and AEs leading to treatment discontinuation occurred in 2.7% of both groups. No deaths were reported in either arm.

Infection rates were generally similar between the treatment and placebo groups -- the most common AE was COVID-19 (14% and 16.7%, respectively).

Rizk pointed out that patients would need to be up-to-date on vaccinations prior to initiating therapy. Iptacopan's of an increased risk for serious infections, especially those caused by encapsulated bacteria. Patients should have complete or updated vaccinations for encapsulated bacteria at least 2 weeks prior to the first dose.

Data for the second of the trial's endpoints -- annualized total eGFR slope over 24 months -- are expected when the study wraps in 2025.

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