Oral Iptacopan Monotherapy Leads to Long-Term Improvements in Patient (Pt)-Reported Health-Related Quality of Life (HRQoL) and Investigator-Assessed Signs and Symptoms of Paroxysmal Nocturnal Hemoglobinuria (PNH): 48-Week (Wk) Results from the Phase III APPLY-PNH and APPOINT-PNH Trials

Background: Iptacopan, an oral factor B inhibitor approved as a monotherapy for treatment of adults with PNH, enabled sustained normalization of hemoglobin (Hb) levels, transfusion independence and decreased pt-reported fatigue in PNH pts with persistent anemia despite anti-C5 treatment (APPLY-PNH; NCT04558918) or who were complement inhibitor naïve (APPOINT-PNH; NCT04820530). We report changes in pt-reported HRQoL outcomes and investigator-assessed PNH signs/symptoms with 48 wks of iptacopan monotherapy in APPLY-PNH and APPOINT-PNH.

Methods: In APPLY-PNH, adult PNH pts receiving anti-C5 for ≥6 months with mean Hb <10 g/dL were randomized to receive iptacopan monotherapy 200 mg twice daily (bid) or continue anti-C5 for 24 wks. All pts could then enter a 24-wk extension period (EP) and receive iptacopan monotherapy. In APPOINT-PNH, complement inhibitor-naïve adult PNH pts with mean Hb <10 g/dL received iptacopan monotherapy 200 mg bid for 48 wks (24-wk treatment period and 24-wk EP). Changes in pt-reported HRQoL (assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) and investigator-assessed PNH signs/symptoms (reddish or cola-colored urine/hemoglobinuria, feeling weak or tired, shortness of breath/dyspnea, dysphagia, chest pain, abdominal pain and erectile dysfunction) were exploratory endpoints in both trials.

Results: In APPLY-PNH, 62 and 35 pts were randomized into the iptacopan and anti-C5 arms, respectively, 61 and 34 of whom received iptacopan monotherapy in the EP, respectively. In APPOINT-PNH, 40 pts received iptacopan monotherapy for 48 wks. Pts in the iptacopan arm of APPLY-PNH reported improvements in mean change from baseline (CFBL) to Wk 48 in all functional domains of EORTC QLQ-C30 (mean CFBL [standard deviation (SD)]: cognitive, 9.5 [15.8]; emotional, 11.7 [23.6]; physical, 14.7 [16.4]; role, 14.4 [23.8]; social, 13.2 [30.3]). Mean CFBL in global health status was 16.3 (SD 18.0) at Wk 48 in the iptacopan arm, with pt-reported improvements in dyspnea (mean CFBL: −28.8 [SD 29.5]) and fatigue (mean CFBL: −18.2 [SD 23.5]) observed at Wk 48. Pts who switched from anti-C5 to iptacopan reported improvements comparable with the iptacopan arm in all functional domains, global health status, dyspnea and fatigue at Wk 48 after 24 wks of iptacopan monotherapy. In APPOINT-PNH, improvements in all functional domains, global health status, dyspnea and fatigue were reported by pts at Wk 48.

In APPLY-PNH, 62.9% of pts in the iptacopan arm and 68.6% in the anti-C5 arm had ≥1 PNH sign/symptom at baseline (BL; most common symptoms: feeling weak or tired and dyspnea). In the iptacopan arm, this decreased to 25.8% at Wk 48. In the anti-C5 arm, 57.1% of pts had ≥1 sign/symptom at Wk 24, decreasing to 26.5% at Wk 48 after 24 wks of iptacopan monotherapy. In the iptacopan arm, the proportion of pts not feeling weak or tired was 48.4% at BL and 75.8% at Wk 48. In the anti-C5 arm, the proportion of pts not feeling weak or tired was 31.4% at BL, 45.7% at Wk 24 and 82.4% at Wk 48 after 24 wks of iptacopan monotherapy. In the iptacopan arm, the proportion of pts who did not have dyspnea was 71.0% at BL and 87.1% at Wk 48. At BL, 62.9% of pts in the anti-C5 arm did not have dyspnea; 74.1% did not have dyspnea at Wk 24, which increased to 85.3% at Wk 48 after 24 wks of iptacopan monotherapy. Most pts did not have other signs/symptoms of PNH at BL.

In APPOINT-PNH, the proportion of pts with ≥1 PNH sign/symptom was 97.5% at BL (most common symptom: hemoglobinuria), decreasing to 27.5% at Wk 48. At BL, 22.5% of pts did not have hemoglobinuria, increasing to 95.0% at Wk 48; improvements in all other PNH signs/symptoms were also observed.

Conclusions: Improvements in pt-reported EORTC QLQ-C30 functional domains, global health status and symptom scores, and investigator-assessed PNH signs/symptoms were observed among pts receiving 48 wks of iptacopan monotherapy in APPLY-PNH and APPOINT-PNH. Both pts and investigators reported improvements in debilitating symptoms of PNH, including fatigue and dyspnea, with iptacopan treatment. Pts in APPLY-PNH who switched from anti-C5 to iptacopan experienced improvements in EORTC QLQ-C30 scores and PNH signs/symptoms comparable with those achieved by pts initially randomized to receive iptacopan. These results provide further evidence of the long-term positive impact of iptacopan on HRQoL and common signs/symptoms of PNH.

Risitano:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Apellis: Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Han:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Kulasekararaj:Janssen: Consultancy; Samsung: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Agios: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioCryst: Consultancy, Honoraria, Speakers Bureau; Silence Therapeutics: Honoraria; Apellis: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau. Ueda:Ono: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Nippon Shinyaku: Honoraria; Kaken: Honoraria; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Asahi Kasei: Consultancy; Chugai: Consultancy, Honoraria, Research Funding; Incyte: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Speakers Bureau. Scheinberg:BMS: Consultancy; Janssen: Consultancy; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Alnylam: Research Funding; Astellas: Consultancy; AstraZeneca: Consultancy, Speakers Bureau. de Castro:Novartis: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria. Snellman:Novartis: Current Employment, Current equity holder in publicly-traded company. Somenzi:Novartis: Current Employment. Winnette:Novartis: Current Employment, Current equity holder in private company; BeiGene: Ended employment in the past 24 months; Pfizer: Current equity holder in private company. Maitra:Novartis: Current Employment. Li:Novartis: Current Employment. Dahlke:Novartis: Current Employment, Current equity holder in private company. Peffault De Latour:Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Apellis: Consultancy, Honoraria; Sobi: Consultancy, Speakers Bureau.