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.

Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Samsung: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Keocyte: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Roeth:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria. Kulasekararaj:Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Samsung: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau. Scheinberg:Pfizer: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy. Ueda:Alexion Pharma: Consultancy, Honoraria, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Speakers Bureau; Chugai Pharma: Consultancy, Research Funding; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de Castro:Apellis Pharmaceuticals: Consultancy, Speakers Bureau; Alexion Pharmacauticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biocryst: Consultancy, Other: DSMB; Novartis: Other: Steering Committee; Regeneron: Other: DSMB; Taiho: Membership on an entity's Board of Directors or advisory committees. Di Bona:Alexion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Institute of Clinical Transfusion Medicine and Immunogenetics Ulm (non- profit organization; subsidiary of University Hospital Ulm and Red Cross Blood Transfusion Service Baden-Württemberg-Hessen): Current Employment; AstraZeneca Alexion Rare Diseases: Honoraria, Research Funding, Speakers Bureau; Sobi (Swedish Orphan Biovitrum GmbH): Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Barcellini:Sanofi: Honoraria, Speakers Bureau; Agios: Honoraria, Research Funding; Alexion: Honoraria; Apellis: Honoraria; Biocryst: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Momenta: Honoraria; Novartis: Consultancy, Honoraria; SOBI: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Tavitian:Pfizer: Other: ASH 2021 (invitation); Servier: Honoraria; Novartis: Other: Symposium. Panse:Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schafhausen:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; AbbVie: Current equity holder in publicly-traded company; Agios Pharmaceuticals: Current equity holder in publicly-traded company; Apellis Pharma: Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company; Raffael Holdings: Current equity holder in publicly-traded company; Seagen: Current equity holder in publicly-traded company; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Merck Serono: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; AOP Orphan: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Mauad:Pfizer: Speakers Bureau. Kerloeguen:Novartis Pharma AG: Current Employment. Levitch:Novartis Pharma AG: Current Employment. Kumar:Novartis Healthcare Pvt. Ltd.: Current Employment, Current equity holder in publicly-traded company. Thorburn:Novartis Pharmaceuticals: Current Employment. Maitra:Novartis Healthcare Pvt. Ltd.: Current Employment, Current equity holder in publicly-traded company. Dahlke:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Risitano:Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Research Funding; Alnylam: Research Funding; Pfizer: Honoraria, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.