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The FDA approved iptacopan (Fabhalta) as the first oral monotherapy for adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare but potentially fatal disorder affecting red blood cells (RBCs), Novartis .

A factor B inhibitor, iptacopan controls RBC destruction (hemolysis) by inhibiting the immune system's alternative complement pathway. Currently available anti-C5 therapies require infusions and may not control PNH symptoms. Many patients have persistent anemia associated with anti-C5 treatment and require blood transfusions.

"An efficacious oral treatment with a demonstrated safety profile could be practice changing for physicians and help relieve burdens experienced by people with PNH," said Vinod Pullarkat, MD, of City of Hope in Duarte, California, in a company statement. "In clinical studies, iptacopan was superior to anti-C5s in hemoglobin improvement in the absence of RBC transfusion and transfusion avoidance rate and also effective in complement inhibitor-naive individuals, by providing clinically meaningful hemoglobin-level increases without the need for blood transfusions."

Driven by a genetic mutation, PNH occurs in . Premature breakdown of red cells can cause symptoms that include fatigue, weakness, pallor, dyspnea, and tachycardia. Affected individuals might also have an increased risk of infection because of PNH-associated leukopenia. PNH increases a person's risk of developing certain types of leukemia.

Principal support for the approval came from the phase III APPLY-PNH trial involving patients with residual anemia despite prior anti-C5 treatment. Additional support came from the single-arm phase III in patients with no prior exposure to C5 inhibitors.

Results at 24 weeks showed that 82.3% of patients with prior anti-C5 therapy had a sustained hemoglobin increase ≥2 g/dL from baseline versus 0% in those who continued C5 inhibition (P<0.0001). Three-fourths of patients with no prior anti-C5 treatment achieved the same outcome.

Two-thirds of C5-treated patients maintained a hemoglobin level ≥12 g/dL without RBC infusions versus 0% of the patients who continued anti-C5 therapy (P<0.0001). Transfusion-avoidance rates were 95.2% with iptacopan versus 45.7% with continued anti-C5 treatment (P<0.0001).

In the APPLY-PNH trial, the most commonly reported (≥10%) adverse events (AEs) with iptacopan and anti-C5 agents were headache (19% vs 3%), nasopharyngitis (16% vs 17%), diarrhea (15% vs 6%), abdominal pain (15% vs 3%), bacterial infection (11% vs 11%), nausea (10% vs 3%), and viral infection (10% vs 31%). In the APPOINT-PNH trial, the most commonly reported AEs with iptacopan were headache (28%), viral infection (18%), nasopharyngitis (15%), and rash (10%).

Correction: This story has been updated to include the correct transfusion-avoidance rates in patients who continued anti-C5 treatment.

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