FDA Approves First oral Treatment for rare Glomerulopathy

The US Food and Drug Administration (FDA) has approved iptacopan (Fabhalta) as the first treatment to reduce proteinuria in adults with complement 3 glomerulopathy (C3G). This rare kidney disease, which often affects young individuals, previously had limited treatment options. The approval marks a significant advancement in managing C3G, offering patients a targeted oral therapy for the first time.

Fabhalta is an oral capsule, taken twice daily. 

FDA first approved Fabhalta in 2023 for the treatment of adults with paroxysmal nocturnal hemoglobinuria. It is also approved under accelerated approval for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression.

Disease or Condition

C3G is a rare disease that causes inflammation and damage to the kidney glomeruli, which are responsible for filtering blood and producing urine. In C3G, the complement system (proteins in the blood that play a critical role in the immune system) becomes abnormally activated. Complement products can become lodged in the glomeruli causing them to become leaky and harming their ability to filter blood. Waste products and toxins then build up in the blood, which decreases the kidneys’ ability to balance salts and minerals, decreases urine production, and causes continued kidney damage.

Common symptoms of C3G include blood in the urine, protein in the urine (proteinuria), low levels of protein in the blood, high blood pressure, fatigue, swelling, and decreased kidney function. Approximately half the people affected with C3G develop kidney failure within 10 years of diagnosis.

It is estimated that C3G affects 2 to 3 out of every 1 million people.

Effectiveness

The efficacy and safety of Fabhalta were evaluated in a randomized, double-blind, placebo-controlled study in 74 adults with biopsy confirmed C3G who had a urine protein-to-creatinine ratio (UPCR) ≥1 gram/gram and an estimated glomerular filtration rate (eGFR) ≥ (eGFR) ≥30 mL/min/1.73 m2 (NCT04817618). Patients were randomized to receive either Fabhalta or placebo for 6 months, followed by a 6-month open-label treatment period in which all patients received Fabhalta.

The primary efficacy endpoint assessed the percent change in proteinuria (UPCR sampled from a 24-hour urine collection) after 6 months of treatment. At 6 months, there was a 35% reduction from baseline in 24-hour UPCR in the Fabhalta group compared to placebo.

Following the initial 6-month treatment period, all patients were treated with Fabhalta for an additional 6 months. In patients initially randomized to Fabhalta, the reduction in 24-hour UPCR seen at 6 months was maintained at 12 months. In patients who switched from placebo to Fabhalta, the magnitude of the reduction in 24-hour UPCR from 6 to 12 months was similar to the reduction seen in patients initially randomized to Fabhalta.

Safety Information

Fabhalta increases the risk of serious and life-threatening infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. Patients should complete or update vaccination for encapsulated bacteria at least 2 weeks before the first dose of Fabhalta, unless the risks of delaying treatment outweigh the risks of developing a serious infection. Health care providers should monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected.

Fabhalta may increase total cholesterol, LDL-cholesterol, and serum triglycerides. Health care providers should monitor patients’ serum lipid parameters periodically during treatment with Fabhalta and initiate cholesterol-lowering medication, if indicated.

Fabhalta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

The most common adverse reactions (reported in at least 10% of patients) to Fabhalta were nasopharyngitis (common cold) and viral infections.

Fabhalta received Priority Review, Breakthrough Therapy, and Orphan Drug designations for the treatment of adults with C3G to reduce proteinuria.