Drs Roeth and Kulasekararaj contributed equally as authors.

Background: Iptacopan is the first oral complement inhibitor that acts proximally in the complement system to target factor B in the alternative pathway. Iptacopan has shown efficacy/safety in PNH pts with persistent anemia despite anti-C5 therapy and complement inhibitor-naive pts. In the Phase III APPLY-PNH trial (NCT04558918), iptacopan monotherapy led to clinically meaningful hemoglobin (Hb) increases and normal/near-normal Hb levels in a majority of pts, transfusion avoidance and improved pt-reported fatigue, showing superiority vs C5 inhibitors at Week (Wk) 24.

Aim: We report the final APPLY-PNH data after a 24-wk extension period in which all pts received iptacopan monotherapy (study completion: 6 March 2023).

Methods: Adult PNH pts (mean Hb <10 g/dL, receiving anti-C5 therapy for ≥6 months) were randomized to receive iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks. Pts could then opt to enter an extension period; pts in the iptacopan arm received iptacopan for another 24 wks and pts who had been receiving anti-C5 switched to iptacopan monotherapy.

Results: In the extension period, 95 pts received iptacopan: 61/62 in the iptacopan arm (1 discontinued iptacopan in the randomized period because of pregnancy) and 34/35 in the anti-C5-to-iptacopan arm (1 did not enter the extension period [investigator's decision]). In the iptacopan arm, the improvements at 24 wks were sustained at 48 wks, with maintenance of increased Hb, normal/near-normal mean Hb levels (Figure), improved Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, decreased absolute reticulocyte counts (ARCs) and transfusion avoidance (Table). Pts who switched from anti-C5 to iptacopan had rapid changes in Hb, FACIT-F and ARC, achieving comparable improvements to the iptacopan arm. Mean Hb levels at Wk 48 were 12.2 and 12.1 g/dL in the iptacopan and anti-C5-to-iptacopan arms, respectively (standard deviations 1.6 and 1.4). At Wk 48, the adjusted mean change from baseline in the iptacopan arm was +3.35 g/dL for Hb, +9.80 FACIT-F points and −106.26 × 10 9/L for ARC. In the anti-C5-to-iptacopan arm, the adjusted mean change from baseline at Wk 48 was +3.36 g/dL for Hb, +10.96 FACIT-F points and −107.95 × 10 9/L for ARC (adjusted mean difference in change from baseline at Wk 48 vs Wk 24: +3.02 g/dL, +10.79 points and −102.29 × 10 9/L, respectively). Transfusion avoidance was achieved by 93.5% of pts in the iptacopan arm (Wks 2 to 48) and 94.1% in the anti-C5-to-iptacopan arm (Wks 26 to 48). Mean lactate dehydrogenase levels were generally maintained <1.5 × upper limit of normal in both arms.

In the trial, 6/62 pts in the iptacopan arm had clinical breakthrough hemolysis (BTH). One pt in the anti-C5-to-iptacopan arm had clinical BTH after switching to iptacopan. BTH resolved without changing iptacopan dosing. Three pts had major adverse vascular events (MAVEs; randomized period: 1 serious transient ischemic attack [TIA]; extension period: 1 non-serious TIA, 1 serious portal vein thrombosis [PVT]). The pt with PVT had a history of PVT and discontinued heparin prior to the MAVE. All MAVEs were considered unrelated to iptacopan and resolved without changing iptacopan dosing. After 48 wks in the iptacopan arm, the most frequently reported treatment-emergent adverse events (TEAEs) were COVID-19 (29.0% of pts), headache (19.4%), diarrhea (16.1%) and nasopharyngitis (14.5%). There were no deaths, no serious hemolysis TEAEs on iptacopan, no serious infections caused by N. meningitidis, S. pneumoniae or H. influenzae and no pts discontinued treatment because of TEAEs.

Conclusions: Long-term data from the Phase III APPLY-PNH trial show a durable response to iptacopan monotherapy in anti-C5-treated PNH pts with persistent anemia. Pts who received iptacopan for 48 wks had sustained improvements in multiple hematological and clinical outcomes, including maintenance of increased Hb, mean normal/near-normal Hb levels, transfusion avoidance and decreased pt-reported fatigue; these benefits quickly emerged in the anti-C5-to-iptacopan arm, supporting the benefit of switching from C5 inhibitors to iptacopan monotherapy. The data indicate good control of hemolysis by iptacopan and a similar safety profile at Wk 48 vs Wk 24. Our findings continue to support oral iptacopan monotherapy as a potentially practice-changing treatment for hemolytic PNH.

Risitano:Novartis: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Research Funding. Kulasekararaj:Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achillion: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst: Consultancy; Samsung: Consultancy. Roeth:Apellis Apellis Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria. Scheinberg:BioCryst: Consultancy, Research Funding; Novartis: Consultancy, Other: Scientific presentations, Research Funding, Speakers Bureau; Alexion: Consultancy, Other: Scientific presentations/speaker; Pfizer: Consultancy, Other: Speaker, Research Funding; F. Hoffmann-La Roche Ltd,: Consultancy, Other: Scientific presentations, Research Funding; Amgen: Consultancy, Other: Scientific presentations/speaker; AstraZeneca: Consultancy, Other: Scientific presentations/speaker, Research Funding; Janssen: Consultancy, Other: Scientific presentations/speaker; AbbVie: Consultancy, Other: Speaker; Alnylam: Research Funding; BMS: Other: Speaker; Viracta: Research Funding. Ueda:Asahi Kase: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Consultancy, Honoraria. de Castro:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Honoraria; Apellis: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Omeros: Honoraria; Regeneron: Honoraria. Di Bona:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Griffin:Amgen: Membership on an entity's Board of Directors or advisory committees; Biocryst: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Consultancy; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: educational grant support . Schrezenmeier:Roche: Other: honoraria (to University of Ulm) ; Apellis: Other: honoraria (to University of Ulm) ; Sobi: Honoraria, Other: travel support, Research Funding; Novartis: Honoraria, Other: travel support, Research Funding; Alexion, AstraZeneca Rare Disease: Honoraria, Other: travel support, Research Funding; Sanofi: Other: honoraria (to University of Ulm). Barcellini:Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Panse:Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy; Sanofi Ltd: Consultancy; BMS: Consultancy; Apellis Pharmaceuticals, Inc.: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd,: Membership on an entity's Board of Directors or advisory committees, Other: Third party writing assistance by Akshaya Srinivasan, PhD, of MediTech Media Ltd and funded by F. Hoffmann-La Roche Ltd, , Speakers Bureau; SOBI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Samsung Bioepis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schafhausen:Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Merck Serono: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; BMS/Celgene: Consultancy, Honoraria, Other: Travel and accomodation support; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; AOP Orphan: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support. Tavitian:Servier: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: Webinar; Novartis: Membership on an entity's Board of Directors or advisory committees. Gaya:SOBI: Honoraria, Other: Lectures, educational activities; Novartis: Honoraria, Other: Lectures, educational activities; Alexion: Honoraria, Other: Lectures, educational activities; Roche: Honoraria, Other: Lectures, educational activities. Huang:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kitawaki:Novartis: Other: lecture. Kutlar:GBT/Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma/Novo-Nordisk, Akira Bio: Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Vertex: Other: Event adjudication committee (EAC) Chair. Maciejewski:Regeneron: Consultancy, Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Omeros: Consultancy. Notaro:SAMSUNG BIOEPIS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pullarkat:Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Schubert:Alexion: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Terriou:Sobi: Honoraria; Alexion: Honoraria; Eusapharma: Consultancy. Sicre De Fontbrune:Alexion, AstraZeneca Rare Disease: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Samsung: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Alashkar:Agios: Speakers Bureau; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Gandhi:Novartis: Honoraria, 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; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau. Kumar:Novartis: Current Employment, Current equity holder in publicly-traded company. Thorburn:Novartis: Current Employment. Maitra:Novartis: Current Employment, Current equity holder in publicly-traded company. Solar-Yohay:Novartis: Current Employment, Current equity holder in publicly-traded company. Lawniczek:Novartis: Current Employment, Current equity holder in publicly-traded company. Dahlke:Novartis Pharma AG: Current Employment. Peffault De Latour:Alexion Pharma France: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Keocyte: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Samsung: Consultancy, Honoraria; Roche: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

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2023
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