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

Background: Intravenous (IV) anti-C5 monoclonal antibodies (eculizumab [ECU]/ravulizumab [RAV]) are the standard of care (SoC) for treating patients with hemolytic paroxysmal nocturnal hemoglobinuria (PNH). However, up to 60% of patients have clinically meaningful residual anemia with SoC, secondary to C3-mediated extravascular hemolysis. Iptacopan is a first-in-class, oral, selective complement factor B inhibitor that showed promising safety and efficacy in two Phase II trials enrolling anti-C5-treated and -naïve PNH patients. Aim: We report primary efficacy and safety data from the 24-week randomized treatment period of the pivotal, multicenter, Phase III APPLY-PNH trial (NCT04558918; data cut-off: 26 September 2022). Methods: Adult PNH patients with mean hemoglobin (Hb) <10 g/dL on stable SoC therapy (ECU/RAV) for ≥6 months were randomized 8:5 to receive iptacopan monotherapy 200 mg twice daily or to continue their SoC regimen for 24 weeks. Randomization was stratified by prior SoC therapy and red blood cell transfusions (RBCTs) in the preceding 6 months. The two primary endpoints were the proportion of patients with a ≥2 g/dL Hb increase from baseline and the proportion of patients with Hb ≥12 g/dL, each in the absence of RBCTs. Secondary endpoints were transfusion avoidance, changes from baseline in Hb level, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) score, absolute reticulocyte count (ARC) and lactate dehydrogenase (LDH) level, rates of clinical breakthrough hemolysis (BTH) and major adverse vascular events (MAVEs), and safety. A prespecified testing procedure adjusted for multiplicity; 2-sided P values are reported for significant endpoints only. Results: Of 97 patients, 62 and 35 were randomized to iptacopan and SoC, respectively. Baseline disease characteristics were balanced between arms. The mean age was 51 years and 69.1% of patients were female. RBCTs were received by 57.7% of patients in the 6 months before randomization; 64.9% and 35.1% had received prior ECU and RAV, respectively, for a mean duration of 4 years. Both primary endpoints were achieved with iptacopan monotherapy, showing superiority vs. SoC (Table); 51/60 iptacopan-treated vs. 0/35 SoC-treated patients with evaluable/non-missing data had a ≥2 g/dL Hb increase from baseline and 42/60 vs. 0/35, respectively, achieved Hb ≥12 g/dL (both P<0.0001). Iptacopan monotherapy also showed superiority in transfusion avoidance, changes from baseline in Hb level, FACIT-F scores and ARC, and rate of clinical BTH (Table). Adjusted mean Hb change from baseline (95% confidence interval) was +3.59 (3.32, 3.86) g/dL for iptacopan vs. −0.04 (−0.42, 0.35) g/dL for SoC (difference: +3.63 [3.18, 4.08] g/dL); mean Hb levels (standard deviation) at 24 weeks, irrespective of RBCTs, were 12.6 (1.4) vs. 9.2 (1.4) g/dL, respectively (Figure). At 24 weeks, nearly all patients (60/62) in the iptacopan arm remained RBCT free vs. 14/35 in the SoC arm. There were no deaths and no serious encapsulated bacteria infections. One iptacopan-treated patient had a MAVE (transient ischemic attack; considered unrelated to iptacopan; iptacopan treatment is ongoing). Headache (iptacopan: 16.1% vs. SoC: 2.9%) and diarrhea (14.5% vs. 5.7%) were more commonly reported with iptacopan, whereas infections/infestations (38.7% vs. 48.6%) and BTH events (3.2% vs. 17.1%) were more commonly reported with SoC. Two SoC-treated patients had serious adverse events of hemolysis, compared with no iptacopan-treated patients. No patients discontinued iptacopan or SoC because of adverse events. Conclusions: In this Phase III trial in PNH patients with residual anemia on IV anti-C5 SoC therapy, single-agent, oral iptacopan resulted in a significant majority of patients achieving clinically meaningful Hb increases and Hb ≥12 g/dL, via resolution of extravascular hemolysis and maintenance of intravascular hemolysis control. These hematological benefits were associated with transfusion independence in almost all patients and clinically meaningful improvements in patient-reported fatigue. Iptacopan monotherapy was well tolerated with a favorable safety profile. Single-agent iptacopan may represent a practice-changing, oral, outpatient treatment for PNH patients who have an inadequate response to IV anti-C5 SoC therapy, potentially becoming a preferred treatment option for patients with hemolytic PNH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal