First Drug Approved for Ultra-Rare Kidney Disease

The FDA approved iptacopan (Fabhalta) as the first treatment to reduce proteinuria in adults with complement 3 glomerulopathy (C3G), the agency announced Thursday.

“C3G is a debilitating disease often affecting young people, impacting many aspects of their physical and emotional health, and our previous treatment options came with significant challenges,” said pivotal trial investigator Carla Nester, MD, MSA, of the University of Iowa, in a statement from drugmaker Novartis.

“This approval of Fabhalta is historic for the entire C3G community as now, for the first time, we have a therapy that is believed to treat the underlying cause of the disease, providing the potential for a new standard of care for patients,” Nester added.

First approved in 2023 for adults with paroxysmal nocturnal hemoglobinuria, iptacopan since picked up an indication for proteinuria reduction in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression.

Iptacopan is the only oral inhibitor of the alternative complement pathway to selectively target the underlying cause of the C3G, a disease that causes inflammation and damage to the kidney glomeruli, Novartis said. A form of membranoproliferative glomerulonephritis, this ultra-rare disease affects roughly 2 to 3 out of every 1 million people.

Because of damage to kidney glomeruli, people with C3G can experience proteinuria, blood in the urine, low levels of protein in the blood, high blood pressure, fatigue, swelling, and decreased kidney function. Average age of diagnosis is around 23, and within 10 years of diagnosis, about half of C3G patients develop kidney failure requiring lifelong dialysis or kidney transplant.

In the pivotal phase III APPEAR-C3G trial underpinning the approval, iptacopan-treated participants had a 35% reduction from baseline in 24-hour urine protein-to-creatinine ratio (UPCR) compared with placebo at month 6.

After the first 6 months, all 74 trial participants were then treated open-label with iptacopan for an additional 6 months. Those who were initially on treatment maintained proteinuria reduction; those who switched from placebo had a similar magnitude in proteinuria reduction as the original treatment group.

At baseline, all trial participants had a UPCR of at least 1 g/g and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m². During APPEAR-C3G, the most common adverse events (in at least 10% of on-treatment patients) were nasopharyngitis and viral infections.

Prescribing information for iptacopan carries a boxed warning for the increased risk of serious and life-threatening infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b.

Patients should be up-to-date on their vaccination for encapsulated bacteria at least 2 weeks prior to the first dose, but they remain at increased risk for invasive disease caused by encapsulated bacteria even if they develop antibodies following vaccination. Iptacopan is available only through an FDA Risk Evaluation and Mitigation Strategy (REMS) program requiring specific vaccinations.

The drug may increase total cholesterol, LDL cholesterol, and serum triglycerides, so healthcare providers should monitor serum lipid parameters periodically and start cholesterol-lowering medication as indicated.

Iptacopan comes in 200-mg capsules and is taken orally twice daily with or without food.

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