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The FDA granted accelerated approval to iptacopan (Fabhalta) for primary immunoglobulin A (IgA) nephropathy, a rare progressive disease where the immune system attacks the kidneys, late on Wednesday.

A first-in-class complement inhibitor, iptacopan acts as a factor B inhibitor of the immune system's alternative complement pathway and is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid progression, generally defined as a urine protein-to-creatinine ratio (UPCR) of 1.5 g/g or above.

"Despite current standard of care, up to 50% of IgAN [IgA nephropathy] patients with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis," the company said in its announcement. "These patients often require maintenance dialysis and/or kidney transplantation."

Approval of iptacopan was underpinned by the APPLAUSE-IgAN study, which met the first of its primary endpoints in an interim analysis. When added to supportive care, treatment with iptacopan significantly reduced 24-hour UPCR compared with placebo at 9 months (44% vs 9%, respectively, P<0.0001).

It has not been established whether the drug can slow kidney decline, however, and continued approval of iptacopan may be contingent upon further demonstration of clinical benefit. A final analysis of the phase III study, expected next year, will measure the second primary endpoint: annualized total estimated glomerular filtration rate (eGFR) slope over 24 months.

"The heterogeneous and progressive nature of IgA nephropathy has made it challenging to effectively treat this disease. Thankfully, the treatment landscape is rapidly evolving," said investigator Dana Rizk, MD, of the University of Alabama at Birmingham, in a statement. "Mounting clinical evidence underscores the pivotal role of complement activation in IgA nephropathy. I am thrilled that this advancement is now available to help enable a targeted treatment approach for IgAN patients."

This marks the third drug indicated for IgA nephropathy following the 2021 approval of the corticosteroid budesonide (Tarpeyo) and the 2023 approval of sparsentan (Filspari), an endothelin and angiotensin II receptor antagonist.

In APPLAUSE-IgAN, iptacopan's treatment effect on UPCR was consistent across all subgroups. All patients in the trial were already on a stable dose of maximally tolerated renin-angiotensin system inhibitor therapy with or without a stable dose of an SGLT2 inhibitor.

The most common adverse events with iptacopan in the study included upper respiratory tract infections (9%), lipid disorder (6%), and abdominal pain (6%).

Iptacopan comes in 200-mg capsules taken twice daily with or without food, according to . It's not recommended for patients with severe hepatic impairment and is contraindicated in those with a hypersensitivity to iptacopan and in those with unresolved serious infections caused by encapsulated bacteria.

It also carries a boxed warning about increased risk of infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b that could be serious and life-threatening.

Patients should complete or update their vaccination for encapsulated bacteria at least 2 weeks prior to the first dose of iptacopan unless the risks of delaying iptacopan outweigh the risk of developing a serious infection. However, patients are still at increased risk for invasive disease caused by encapsulated bacteria even if they develop antibodies following vaccination.

Iptacopan was first approved in late 2023 for the treatment of paroxysmal nocturnal hemoglobinuria. The drug is also in development for other diseases, including C3 glomerulopathy, atypical hemolytic uremic syndrome, immune complex membranoproliferative glomerulonephritis, and lupus nephritis.

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