Lancet Haematol. 2025 Jun;pii: S2352-3026(25)00081-X. [Epub ahead of print]12(6): e414-e430
Antonio M Risitano,
Austin G Kulasekararaj,
Phillip Scheinberg,
Alexander Röth,
Bing Han,
Jaroslaw P Maciejewski,
Yasutaka Ueda,
Carlos M de Castro,
Eros Di Bona,
Rong Fu,
Li Zhang,
Morag Griffin,
Saskia M C Langemeijer,
Jens Panse,
Hubert Schrezenmeier,
Wilma Barcellini,
Vitor A Q Mauad,
Philippe Schafhausen,
Suzanne Tavitian,
Eloise Beggiato,
Lee Ping Chew,
Anna Gaya,
Wei-Han Huang,
Jun Ho Jang,
Toshio Kitawaki,
Abdullah Kutlar,
Rosario Notaro,
Vinod Pullarkat,
Jörg Schubert,
Louis Terriou,
Michihiro Uchiyama,
Lily Wong Lee Lee,
Eng-Soo Yap,
Camilla Frieri,
Luana Marano,
Flore Sicre de Fontbrune,
Shreyans Gandhi,
Roochi Trikha,
Ferras Alashkar,
Chen Yang,
Hui Liu,
Richard J Kelly,
Britta Höchsmann,
Tomasz Lawniczek,
Navin Mahajan,
Susan Solar-Yohay,
Cécile Kerloëguen,
Philippe Ferber,
Rakesh Kumar,
Zhixin Wang,
Christine Thorburn,
Samopriyo Maitra,
Shujie Li,
Aurelie Verles,
Marion Dahlke,
Régis Peffault de Latour.
BACKGROUND: The factor B inhibitor iptacopan improved 24-week outcomes in adult patients with paroxysmal nocturnal haemoglobinuria in the phase 3 APPLY-PNH and APPOINT-PNH trials; the trial extension periods assessed clinical activity and safety up to 48 weeks. Here, we report the final 48-week data from APPLY-PNH and APPOINT-PNH.
METHODS: In both APPLY-PNH and APPOINT-PNH trials, patients were aged 18 years or older, with paroxysmal nocturnal haemoglobinuria (red and white blood cell population sizes ≥10%) and without laboratory evidence of bone marrow failure. In APPLY-PNH (an open-label, randomised, phase 3 trial conducted in 39 centres [38 hospitals, one outpatient research clinic] from 12 countries or regions), patients with haemoglobin concentration lower than 10 g/dL on anti-C5 treatment (stable eculizumab or ravulizumab regimen for ≥6 months) were randomly assigned (8:5) via interactive response technology to either receive oral iptacopan 200 mg twice daily (iptacopan group) or to continue their individual intravenous eculizumab or ravulizumab regimen for 24 weeks (anti-C5 group). Randomisation was stratified by type of anti-C5 and receipt of red blood cell (RBC) transfusions in the preceding 6 months. In APPOINT-PNH (an open-label, single-arm, phase 3 trial conducted in 12 hospitals from eight countries), complement inhibitor-naive patients with paroxysmal nocturnal haemoglobinuria and with haemoglobin concentration lower than 10 g/dL and lactate dehydrogenase (LDH) concentration higher than 1·5 times the upper limit of normal received iptacopan 200 mg twice daily for 24 weeks. Both trials had 24-week extension periods in which all patients received iptacopan monotherapy. Primary endpoints were the proportion of patients with an increase from baseline in haemoglobin concentration of 2 g/dL or higher (APPLY-PNH and APPOINT-PNH) and haemoglobin concentration 12 g/dL or higher (APPLY-PNH) between weeks 18 and 24, all in the absence of RBC transfusions between weeks 2 and 24; results for these primary endpoints have been reported previously. We report final activity and safety data at the completion of both trials (week 48). Prespecified endpoints at week 48 included percentage of patients with a haemoglobin increase from baseline of 2 g/dL or higher or haemoglobin 12 g/dL or higher (including post-transfusion data). Efficacy data were analysed per the intention-to-treat principle, and safety was analysed according to the treatment that patients received. APPLY-PNH and APPOINT-PNH are registered with ClinicalTrials.gov, NCT04558918 and NCT04820530, respectively.
FINDINGS: In APPLY-PNH, between Jan 25, 2021, and April 8, 2022, 62 patients (43 [69%] female, 19 [31%] male; 48 [77%] White, 12 [19%] Asian, two [3%] Black) were randomly assigned to the iptacopan group and 35 patients (24 [69%] female, 11 [31%] male; 26 [74%] White, seven [20%] Asian, two [6%] Black) to the anti-C5 group; 61 (98%) and 34 (97%), respectively, entered the extension period. At trial completion (March 6, 2023), the median duration of iptacopan treatment was 337 days (IQR 168-338). In APPOINT-PNH, 40 patients were enrolled between July 19, 2021, and May 17, 2022, and received iptacopan (17 [43%] female, 23 [58%] male; 12 [30%] White, 27 [68%] Asian, one [3%] Black); all entered the extension period. At trial completion (April 18, 2023), the median duration of iptacopan treatment was 337 days (IQR 337-344). At week 48, irrespective of RBC transfusions, the number of patients who had an increase in haemoglobin concentration of 2 g/dL or higher was 51 (86%) of 59 in the APPLY-PNH iptacopan group, 21 (72%) of 29 in the APPLY-PNH anti-C5-to-iptacopan group, and 38 (97%) of 39 in APPOINT-PNH. The number of patients who had haemoglobin concentration of 12 g/dL or higher at week 48 was 40 (68%) of 59 in the APPLY-PNH iptacopan group, 17 (59%) of 29 in the APPLY-PNH anti-C5-to-iptacopan group, and 31 (79%) of 39 in APPOINT-PNH. There were no treatment discontinuations because of treatment-emergent adverse events or deaths. Across the 48-week trials, clinical breakthrough haemolysis occurred in seven (7%) of 96 iptacopan-treated patients in APPLY-PNH (including both groups) and two (5%) of 40 in APPOINT-PNH, but it was generally mild or moderate with no iptacopan discontinuation. Three major adverse vascular events occurred in APPLY-PNH by trial completion; all were considered unrelated to iptacopan. The most common treatment-emergent adverse event was COVID-19 in APPLY-PNH (iptacopan: 18/62 patients [29%]; anti-C5-to-iptacopan: 8/34 [24%]) and headache in APPOINT-PNH (12/40 [30%]). Severe and serious treatment-emergent adverse events were experienced by six (10%) and nine (15%) of 62 patients in the APPLY-PNH iptacopan group, respectively; in APPOINT-PNH, these were experienced by four (10%) and eight (20%) of 40 patients, respectively. The most common serious treatment-emergent adverse event was COVID-19, occurring in one (2%) of 62 patients in the APPLY-PNH iptacopan group and two (5%) of 40 patients in APPOINT-PNH. No severe treatment-emergent adverse events occurred in more than one patient.
INTERPRETATION: Long-term data indicate durable haemolysis control with iptacopan in paroxysmal nocturnal haemoglobinuria, maintained normal or near-normal haemoglobin, and no new safety concerns. We believe that these data support iptacopan as a potential therapy option, suggesting that we are in a new treatment era for paroxysmal nocturnal haemoglobinuria.
FUNDING: Novartis.