Fabhalta is approved for the treatment of IgAN patients who are at risk of rapid disease progression, which is indicated by a urine protein-to-creatinine ratio of at least 1.5 g/g.
The FDA on Thursday signed off on the use of Novartis’ complement inhibitor Fabhalta (iptacopan) to lower proteinuria in patients with primary IgA nephropathy, marking the first regulatory win for a complement inhibitor in this indication.
Fabhalta is a first-in-class complement blocker that had been previously approved for paroxysmal nocturnal hemoglobinuria, a rare blood disease.
Thursday’s approval expands Fabhalta’s label to cover patients with IgA nephropathy (IgAN) who are at risk of “rapid disease progression,” according to Novartis. In general, this criterion refers to patients with a urine protein-to-creatinine ratio of at least 1.5 g/g. IgAN is a rare and progressive kidney disorder where the immune system attacks the kidneys, often leading to bloody and foamy urine and eventually kidney failure and other complications.
Fabhalta’s IgAN approval was granted under the FDA’s accelerated pathway, under which Novartis needs to run a confirmatory Phase III study to validate the drug’s efficacy in this indication.
The FDA’s decision was supported by data from the Phase III APPLAUSE-IgAN study, a randomized, double-blinded, parallel-group and placebo-controlled trial with around 470 patients enrolled. Twice-daily, participants were given 200-mg oral doses of Fabhalta on top of supportive care, which consisted of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.
Novartis announced in October 2023 that Fabhalta cleared APPLAUSE-IgAN but did not provide specific data at the time. In Thursday’s announcement, the company revealed that Fabhalta cut proteinuria by 44% through nine months of follow-up, while placebo comparators only saw a 9% reduction in proteinuria. This effect was “clinically meaningful and statistically significant,” Novartis said, with a p-value of less than 0.0001.
APPLAUSE-IgAN also found Fabhalta to be safe in this indication, with no new signals of concern. The most common adverse effects were respiratory tract infection, lipid disorder and abdominal pain. Fabhalta’s label carries a boxed warning for serious infections caused by encapsulated bacteria, such as Streptococcus pneumoniae and Neisseria meningitidis.
APPLAUSE-IgAN is ongoing and will continue to evaluate Fabhalta’s effect on slowing the decline of kidney function in patients, as quantified by estimated glomerular filtration rate. Results from this analysis, which Novartis expects to come in 2025, will support Fabhalta’s traditional approval.
Beyond Fabhalta, Novartis is also working on two other late-stage IgAN assets—the oral endothelin A receptor blocker atrasentan, and the subcutaneous anti-APRIL monoclonal antibody zigakibart.
Atrasentan aced the Phase III ALIGN trial, eliciting a 36.1% drop in proteinuria at 36 weeks, compared with placebo. Novartis submitted a regulatory application for the drug candidate in the second quarter of 2024, while zigakibart entered Phase III development in July 2023.
