Iptacopan may become preferred treatment for hemolytic paroxysmal nocturnal hemoglobinuria
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NEW ORLEANS — Patients with paroxysmal nocturnal hemoglobinuria who received iptacopan vs. standard therapy had clinically meaningful and significant improvement in symptoms, results of the phase 3 APPLY-PNH trial showed.
Data presented at ASH Annual Meeting and Exposition revealed most patients who received iptacopan (Novartis) had resolution of anemia that allowed them to stop receiving regular blood transfusions.
“Single-agent iptacopan may represent a practice-changing ... treatment for patients with [paroxysmal nocturnal hemoglobinuria] who have an inadequate response to IV anti-C5 standard-of-care therapy,” Régis Peffault de Latour, MD, PhD, member of the French Référence Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, said during a press briefing.
“In the end, it may potentially become a preferred treatment option for all patients with hemolytic [paroxysmal nocturnal hemoglobinuria],” he added.
Background
Paroxysmal nocturnal hemoglobinuria is a rare hematologic disorder caused by a somatic alteration in the PIGA gene. Symptoms include intravascular hemolysis, thrombophilia and bone marrow failure.
Current standard-of care treatment with anti-C5 monoclonal antibodies — including eculizumab (Soliris, Alexion Pharmaceuticals) and ravulizumab (Ultomiris, Alexion Pharmaceuticals) — can control hemolysis, reduce thrombosis and extend OS, according to Peffault de Latour. Despite treatment, many patients remain dependent on red blood cell transfusions due to extravascular hemolysis-related residual anemia.
“In a phase 2 study, iptacopan controlled intra- and extravascular hemolysis in 10 patients with a suboptimal response to eculizumab, leading to transfusion independence and [improved] quality of life,” he said. “That was the rationale for our current phase 3 study.”
Methodology
The multicenter, phase 3 APPLY-PNH trial enrolled 97 patients (mean age, 51 years; 69% women) to evaluate the safety and efficacy of iptacopan — a selective complement factor B inhibitor — compared with standard-of-care therapy in adults with hemolytic paroxysmal nocturnal hemoglobinuria.
More than half of patients (57%) required a red blood cell transfusion in the 6 months before study randomization.
In an 8:5 ratio, the investigators randomly assigned adults with a mean hemoglobin level less than 10 g/dL while receiving standard of care therapy for 6 or more months to receive oral iptacopan dosed at 200 mg twice daily (n = 62) or maintain their current standard therapy (n = 35) for a 24-week treatment period. All study participants then entered into a 24-week extension phase and received oral iptacopan dosed at 200 mg twice daily.
The proportion of patients demonstrating a 2 g/dL or greater increase in hemoglobin from baseline and those with hemoglobin levels of 12 g/dL or greater— both without the need for red blood cell transfusions — served as the primary endpoints of the study. Secondary endpoints included transfusion independence, change in baseline hemoglobin levels, Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score, absolute reticulocyte count, lactate dehydrogenase level, clinical breakthrough hemolysis rate, major adverse vascular events and safety.
Data cutoff occurred Sept. 26.
Key findings
The study achieved both of its primary endpoints.
Treatment with iptacopan yielded a 2 g/dL or greater increase in hemoglobin levels for 51 of 60 patients compared with none of those who received standard-of-care therapy (P < .0001). Iptacopan also demonstrated superiority by increasing hemoglobin levels to 12 g/dL or greater in 42 of 60 patients compared with none who received standard-of-care therapy (P < .0001).
Iptacopan produced superior results vs. standard-of-care therapy for transfusion avoidance (96.4% vs 26.1%; difference, 70.3%; 95% CI, 52.6-84.9), changes in baseline hemoglobin levels (adjusted mean difference, 3.63 g/dL; 95% CI, 3.18-4.08), FACIT-F scores (adjusted mean difference, 8.29; 95% CI, 5.28-11.2), absolute reticulocyte count and clinical breakthrough hemolysis rate.
Sixty of 62 patients who received iptacopan remain free from the need for a red blood cell transfusion at 24 weeks compared with 14 of 35 patients in the standard-of-care group.
Safety analysis showed no treatment-related deaths or serious encapsulated bacteria infections during the study.
Investigators noted headache (16.1%) and diarrhea (14.5%) as the most common treatment-related adverse events reported among those who received iptacopan.
No patient in either study arm discontinued treatment due to related adverse events.
Infections (38.7% vs. 48.6%) and breakthrough hemolysis (3.2% vs. 17.1%) occurred more frequently in patients who received standard-of-care therapy.
Clinical implications
Results of the APPLY-PNH study showed iptacopan to be superior to the current standard-of-care treatments for adults with paroxysmal nocturnal hemoglobinuria , Peffault de Latour said.
“Oral iptacopan monotherapy led to a significant majority of patients achieving clinically meaningful hemoglobin increases associated with a higher rate of transfusion independence and reduced patient-reported fatigue compared with standard of care,” he said.
Whether iptacopan should become the standard front-line treatment for all patients with paroxysmal nocturnal hemoglobinuria will depend on results of the ongoing phase 3 APPOINT-PNH trial examining its use in treatment-naive patients, Peffault de Latour added.
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Peffault de Latour R, et al. Abstract LBA-2. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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