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NEW ORLEANS -- The targeted factor B inhibitor iptacopan improved hemoglobin (Hb) levels and led to high rates of freedom from transfusion in patients with paroxysmal nocturnal hemoglobinuria (PNH) and residual anemia despite standard treatment, a randomized trial showed.

The primary analysis showed that 82% of patients treated with iptacopan had at least a 2-g/dL Hb improvement without red blood cell (RBC) transfusions as compared with 2% of patients treated with standard care. Additionally, 68.8% of the iptacopan group achieved Hb levels of at least 12 g/dL without transfusion versus 1.8% of the control group.

The analysis showed that 96.4% of patients in the iptacopan group avoided RBC transfusion during the study versus 26.1% of the control arm, reported Regis Peffault de Latour, MD, PhD, of the Public Assistance Hospitals of Paris, at the 2022 American Society of Hematology annual meeting.

"Single-agent iptacopan may represent a practice-changing oral outpatient treatment for PHN patients who have an inadequate response to intravenous anti-C5 standard-of-care therapy, potentially becoming a preferred treatment option for patients with hemolytic PNH," de Latour said in conclusion.

Following the presentation at a late-breaking abstract session, co-moderator David Garcia, MD, of UW Medicine in Seattle, said many virtual participants wanted to know whether iptacopan should become the first-line standard of care for PNH, but de Latour demurred in his response.

"I think that we should take the data when they are coming through for the moment," he said. "We have a randomized trial that is showing outstanding data in patients who are suboptimal responders to eculizumab [Soliris]. It was publicly released last week that the in treatment-naive patients was positive. We'll see the complete set of data and then afterwards it might also be frontline in patients."

A rare, chronic disorder, PNH is characterized by intravascular hemolysis, thrombophilia, and bone marrow failure. The condition arises from a somatic mutation in PIGA, leading to depletion of complement-regulating proteins and intravascular hemolysis, de Latour noted in his introductory comments. Targeting the terminal complement pathway at C5 with eculizumab and ravulizumab (Ultomiris) controls intravascular hemolysis, reduces thrombosis, and improves survival.

However, as many as two-thirds of patients have clinically important residual anemia, primarily because of extravascular hemolysis. Many of the patients are transfusion dependent. Iptacopan targets the complement system via an alternate pathway, binding the active site of factor B to inhibit C3. In a phase II with suboptimal response to eculizumab, treatment with iptacopan controlled intra- and extravascular hemolysis, resulting in transfusion independence and improved quality of life.

Primary findings from the randomized phase III trial evaluated iptacopan in patients with PNH and residual anemia despite standard-of-care therapy. Patients were randomized 8:5 to iptacopan or continuation of standard of care for 24 weeks. At that point, all patients continued treatment for an additional 24 weeks with iptacopan.

The trial had two primary endpoints: hematologic response, defined as an increase in baseline Hb of ≥2 g/dL and an Hb ≥12 g/dL, both at 24 weeks and in the absence of transfusion. Transfusion avoidance throughout the study was a key secondary endpoint.

The primary analysis showed that 51 of 60 patients in the iptacopan group had Hb increases of ≥2 g/dL from baseline and 42 of 60 had Hb levels ≥12 g/dL at 24 weeks without the need for RBC transfusion. None of the 35 patients in the standard-of-care arm met either endpoint. After prespecified statistical analyses, the results showed statistical superiority for both of the primary endpoints and the secondary endpoint of transfusion avoidance (P<0.0001).

Iptacopan showed superiority (P<0.0001) for reduction in absolute reticulocyte count from baseline (a marker of control for extravascular hemolysis) and in annualized rate of breakthrough hemolysis (2/62 vs 6/35, P=0.0118). Iptacopan and standard therapy achieved similar control of lactate dehydrogenase levels.

Treatment-emergent adverse events (TEAEs) occurred in 82.3% of the iptacopan group and 80.3% of the control arm. Headache (16.1% vs 2.9%), and diarrhea (14.5% vs 6.7%) occurred more often with iptacopan. COVID-19 (26.7% vs 8.1%) and breakthrough hemolysis (17.1% vs 3.2%) occurred more often with standard care. Serious TEAEs occurred more often in the control group (13.4% vs 9.7%). The only major adverse vascular event occurred in the iptacopan arm (transient ischemic attack) but was considered unrelated to the study drug.

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