Single-agent iptacopan improved hemoglobin levels and resulted in transfusion independence among patients with hemolytic paroxysmal nocturnal hemoglobinuria (PNH) with an inadequate response to anti-C5 antibodies, according to results of the phase 3 APPLY-PNH study presented at the 2022 ASH Annual Meeting.

Although the anti-C5 antibodies, eculizumab and ravulizumab, are effective therapies for PNH, up to 66% of patients have residual anemia and remain transfusion dependent, Regis Peffault De Latour, MD, PhD, of the University of Paris in France, said when presenting the study. Iptacopan acts earlier in the complement cascade, by binding to Factor B and inhibiting C3 convertase.

The multicenter, phase 3 APPLY-PNH trial included 97 patients with PNH with clinically significant extravascular hemolysis despite standard of care (SOC) treatment with eculizumab or ravulizumab who were randomly assigned 8:5 to receive iptacopan or continue their SOC therapy for 24 weeks. The coprimary endpoints were a 2 g/dL or higher increase in hemoglobin levels from baseline and hemoglobin levels that reached a minimum of 12 g/dL without red blood cell transfusion (RBCT). Secondary endpoints included transfusion avoidance, fatigue, breakthrough hemolysis, and major adverse vascular events (MAVEs).

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At baseline, the mean age was 51 and 69% of patients were female. There were 58% of patients who received an RBCT within the prior 6 months of randomization. The majority of patients were previously treated with eculizumab at 65%, and 35% had received ravulizumab for a mean of 4 years.

Iptacopan met both primary endpoints. Hemoglobin levels rose by at least 2 g/dL among an observed 85% of patients treated with iptacopan compared with 0 treated with the SOC. The population estimate was 82.3% and 2.0% in the iptacopan and SOC arms, respectively, with a difference of 80.3% (P <.0001).

Furthermore, an observed 70% of patients in the iptacopan arm achieved a hemoglobin level of at least 12 g/dL compared with 0 in the SOC arm. The population estimate was 68.8% with iptacopan and 1.8% with SOC, resulting in a difference of 67.0% (P <.0001).

There were an observed 96.8% of patients in the iptacopan arm who were RBST-free at 24 weeks compared with 40% in the SOC arm. The population estimate was 96.4% and 26.1% in the iptacopan and SOC arms, respectively, resulting in a difference of 70.3% (P <.0001).

Other secondary endpoints that were also improved with iptacopan treatment included including fatigue scores, breakthrough hemolysis, and absolute reticulocyte count (all P <.0001). The change in lactate dehydrogenase from baseline was similar between the 2 treatment groups.

The annualized rate of clinical breakthrough hemolysis was 0.07% with iptacopan compared with 0.67% with SOC (rate ratio, 0.10; 95% CI, 0.02-0.61; P =.0118).

The rate of MAVEs was similar between the treatment arms, with one patient in the iptacopan group who experienced a MAVE of transient ischemic attack that was considered unrelated to treatment.

The rate of treatment-emergent adverse events (AEs) was similar between the groups. The most common AEs in the iptacopan arm were headache and diarrhea. Serious treatment-emergent AEs were more common with the SOC at 14.3% compared with 9.7% with iptacopan.

Dr De Latour concluded that “overall, single-agent iptacopan may represent a practice change for patients’ treatment for PNH who are suboptimal responders to eculizumab.” He added that “it will become possibly a preferred option for all patients with PNH in the near future.”

Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.


Da Latour RP, Roeth A, Kulasekararaj A, et al. Oral monotherapy with iptacopan, a proximal complement inhibitor of factor B, has superior efficacy to intravenous terminal complement inhibition with standard of care eculizumab or ravulizumab and favorable safety in patients with paroxysmal nocturnal hemoglobinuria and residual anemia: results from the randomized, active-comparator-controlled, open-label, multicenter, phase III APPLY-PNH study. Presented at ASH 2022. December 10-13, 2022. Abstract LBA-2.