FDA Approves Iptacopan for the Treatment of Paroxysmal Nocturnal Hemoglobinuria in Adult Patients


During clinical trials, individuals treated with iptacopan had increased hemoglobin levels and did not need to receive blood transfusions.

The FDA has approved iptacopan (Fabhalta; Novartis) for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH), making it the first oral monotherapy to be approved for the treatment of PNH. In the APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530) clinical trials, most patients treated with iptacopan had increased hemoglobin and did not receive blood transfusions.

Iptacopan is an oral, Factor B inhibitor of the alternative complement pathway and is indicated for the treatment of adults with PNH. It is currently in development for a range of complement-mediated diseases, such as immunoglobulin A nephropathy, C3 glomerulopathy, immune complex membranoproliferative glomerulonephritis, and atypical hemolytic uremic syndrome.

The randomized, multinational, multicenter, active-comparator controlled, open-label phase 3 APPLY-PNH trial evaluated the efficacy and safety of twice-daily, oral iptacopan monotherapy for the treatment of PNH. A total of 97 patients with residual anemia were randomly assigned to receive twice daily, oral iptacopan monotherapy or continue on the same regimen of intravenous anti-C5 therapies (US-approved and non-US-approved eculizumab and ravulizumab). Compared to patients who remained on anti-C5 therapies, patients who switched to iptacopan experienced noticeable increases in hemoglobin levels (0% vs 82.3% and 0% vs 67.7%, respectively), both in the absence of red blood cell transfusions.

The multination, multicenter, open-label, uncontrolled single-arm phase 3 study APPOINT-PNH evaluated the efficacy and safety of twice-daily oral iptacopan monotherapy in adult patients with PNH who are naïve to complement inhibitor therapy, including anti-C5 therapies (eculizumab or ravulizumab). A total of 40 patients were enrolled in the trial.

“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, MRCP, clinical professor, department of hematology and hematopoietic cell transplantation, City of Hope, in a press release. “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-naïve individuals, by providing clinically meaningful hemoglobin-level increases without the need for blood transfusions.”

Individuals with PNH have an acquired mutation making red blood cells susceptible to premature destruction by the complement system, and is characterized by hemolysis, bone marrow failure, and thrombosis in various combinations and levels of severity. Up to 88% of patients on anti-C5 treatments may have persistent anemia, with over 33% of those patients requiring blood transfusions at least once per year. Further, these C5 inhibitor treatments may leave PNH symptoms uncontrolled.

The most common reported adverse effects (AEs) with iptacopan and anti-C5s in the APPLY-PNH trial 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%); 2 patients (3%) who received iptacopan reported they experienced serious AEs. The most common reported AEs in the APPOINT-PNH trial were headache (28%), viral infection (18%), nasopharyngitis (15%), and rash (10%), with 2 patients (5%) who received iptacopan reporting they experienced serious AEs.

“The US approval of [iptacopan] is an extraordinary moment for people living with PNH, their loved ones and the healthcare providers who care for them,” said Victor Bultó, president of Novartis, in the press release. “This new, effective oral medicine may mean that patients can reset their expectations of living with PNH, a chronic and life-altering blood disease…we are exploring the potential of [iptacopan] in other complement-mediated diseases—with an ultimate goal to drive meaningful change for patients.”


Novartis. Novartis receives FDA approval for Fabhalta® (iptacopan), offering superior hemoglobin improvement in the absence of transfusions as the first oral monotherapy for adults with PNH.News release. December 6, 2023. Accessed December 6, 2023. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-fabhalta-iptacopan-offering-superior-hemoglobin-improvement-absence-transfusions-first-oral-monotherapy-adults-pnh

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