Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors
- PMID: 40447351
- DOI: 10.1016/S2352-3026(25)00081-X
Oral iptacopan monotherapy in paroxysmal nocturnal haemoglobinuria: final 48-week results from the open-label, randomised, phase 3 APPLY-PNH trial in anti-C5-treated patients and the open-label, single-arm, phase 3 APPOINT-PNH trial in patients previously untreated with complement inhibitors
Abstract
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.
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Conflict of interest statement
Declaration of interests AG reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Novartis, Roche, and Sobi; support for attending meetings or travel from Alexion (AstraZeneca Rare Disease) and Sobi; and participation in advisory boards for Alexion (AstraZeneca Rare Disease) and Roche. AGK reports consulting fees from Alexion (AstraZeneca Rare Disease), Arrowhead, NovoNordisk, Samsung, and Silence Therapeutics; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Amgen, Celgene/Bristol Myers Squibb, Janssen, Novartis, Pfizer, Ra Pharma/Union Chimique Belge, Roche, and Sobi; support for attending meetings or travel from Alexion (AstraZeneca Rare Disease), Roche, and Sobi; and participation on a data monitoring safety board or advisory board for Agios, Alexion (AstraZeneca Rare Disease), Amgen, Apellis, Biocryst, Celgene/Bristol Myers Squibb, Geron, Janssen, Novartis, Pfizer, Regeneron, Roche, and Sobi. AMR reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Apellis, Kira, Novartis, Omeros, Pfizer, Roche, and Sobi; and support for attending meetings or travel from Novartis and Sobi. AR reports consulting fees from Alexion (AstraZeneca Rare Disease), Apellis, Biocryst, Bioverativ, Kira, Novartis, Roche, and Sanofi; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Apellis, Bioverativ, Novartis, Roche, and Sanofi; and support for attending meetings or travel from Sobi. BHö reports medical writing support for this manuscript; study drug for trial conduction and compensation for expenses in the context of the study (not personally, to their institution); consulting fees from Omeros; honoraria for lectures and advisory boards from Alexion (AstraZeneca Rare Disease), Novartis, Roche, and Sobi; honoraria for advisory boards from Omeros; travel support in the context of said advisory boards; and all honoraria checked for appropriateness by their employer. CF reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Novartis, Pfizer, and Sobi. CMdC reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Apellis, Genentech, Inna Rx, Novartis, and Omeros; and participation on a data safety monitoring board for Regeneron. EB reports payment or honoraria for advisory boards from Alexion (AstraZeneca Rare Disease) and Novartis. E-SY reports support for the present manuscript from Novartis; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and Sysmex. FA reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Agios, Bristol Myers Squibb, Novartis, Pfizer/GBT, and Vertex; support for attending meetings or travel from Bristol Myers Squibb; participation in advisory boards for Bristol Myers Squibb, Novartis, Pfizer/GBT, and Vertex; and other financing of scientific research by Pfizer/GBT. FSdF reports grants/contracts with their institution from Alexion (AstraZeneca Rare Disease), Novartis, and Sobi; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Novartis, and Sobi; support for attending meetings or travel from Novartis; and participation in an advisory board for Samsung. HS reports payment to their institution by Novartis for the conduct of these clinical trials at their site; payment to their institution from Alexion (AstraZeneca Rare Disease) and Novartis for lectures, presentations, speakers' bureaus, manuscript writing, or educational events; support for attending meetings or travel from Alexion (AstraZeneca Rare Disease) and Sanofi; participation in advisory boards for Alexion (AstraZeneca Rare Disease), Amgen, Novartis, Omeros, Roche, Sanofi, and Sobi (payment to institution); and inventor (together with others) of patent application(s) that describe the use of complement inhibitors for therapeutic applications and patent application(s) filed by their institution (University of Ulm). JP reports medical writing support from AMICULUM, funded by Novartis; study-related payments to their institution from Novartis; study-related payments (not related to this manuscript) to their institution from Alexion (AstraZeneca Rare Disease), Apellis, Roche, and Omeros; consulting fees from Apellis/Sobi, Alexion (AstraZeneca Rare Disease), Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Omeros, Pfizer, Roche, and Samsung Bioepis; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Apellis/Sobi, Alexion (AstraZeneca Rare Disease), Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Omeros, Pfizer, Roche, and Samsung Bioepis; support for attending meetings or travel from Alexion (AstraZeneca Rare Disease) and Sobi; and participation on a data monitoring safety board or advisory board for Apellis/Sobi, Alexion (AstraZeneca Rare Disease), AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Novartis, Omeros, Pfizer, Roche, and Samsung Bioepis. JPM reports consulting fees from Novartis; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Novartis; and participation on a data monitoring safety board for Omeros. JS reports consulting fees from Alexion (AstraZeneca Rare Disease), Novartis, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Amgen, Novartis, Pfizer, and Roche; and support for attending meetings or travel from Alexion (AstraZeneca Rare Disease) and Roche. LPC reports no further disclosures than support from Novartis for the APPOINT-PNH trial and this manuscript. LT reports consulting fees from Novartis; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Novartis; and support for attending meetings or travel from Novartis. MG reports consulting fees from Alexion (AstraZeneca Rare Disease), Amgen, Omeros, Pfizer, and Regeneron; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Amgen, Novartis, Pfizer, and Sobi; and support for attending meetings or travel from Alexion (AstraZeneca Rare Disease) and Amgen. PScha reports speaker honorarium and scientific advisory board participation for Alexion (AstraZeneca Rare Disease), AOP Orphan, Celgene/Bristol Myers Squibb, Incyte, Merck Serono, MSD, Novartis, and GSK; scientific advisory board participation for Blueprint Medicines, Sanofi, Pfizer, and Sobi; speaker honorarium from Roche; support for attending meetings or travel from Alexion (AstraZeneca Rare Disease), AOP Orphan, Celgene/Bristol Myers Squibb, and Novartis; and stock or stock options with AbbVie, Apellis, AstraZeneca, Blueprint Medicines, Bristol Meyers Squibb, Novartis, Omeros, Eli Lilly, and Biontech. PSche reports consulting fees from Biocryst, Novartis, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Novartis, and Pfizer; and participation on a data safety monitoring board or advisory board for Novartis and Pfizer. RJK reports grants/contracts (payment to institution) from Novartis and Sobi; consulting fees from Alexion (AstraZeneca Rare Disease), Florio, Novartis, Omeros, Otsuka, and Sobi; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Novartis, and Sobi; support for attending meetings or travel from Sobi; and participation on a data monitoring safety board or advisory board for Alexion (AstraZeneca Rare Disease), Novartis, and Roche. RN reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Novartis, Roche, and Sobi. RPdL reports grants or contracts from Alexion (AstraZeneca Rare Disease), Novartis, and Pfizer; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Apellis, Novartis, Omeros, Pfizer, Roche, and Sobi; and support for attending meetings or travel from Novartis and Sobi. RT reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease) and Sobi; support for attending meetings or travel from Alexion (AstraZeneca Rare Disease), Novartis, and Sobi; and participation on a data monitoring safety board or advisory board for Alexion (AstraZeneca Rare Disease), Novartis, and Sobi. ST reports support for attending meetings or travel from Amgen and Novartis; and advisory board participation with honoraria for GSK and Novartis. TK reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Chugai, and Novartis. VAQM reports payment or honoraria for speakers' bureaus from Roche; and payment or honoraria for speakers' bureaus and advisory boards from Novartis. VP reports consulting fees (advisory boards and consulting) from Alexion (AstraZeneca Rare Disease) and Novartis. WB reports consulting fees from Novartis. W-HH reports honoraria for lectures from Alexion (AstraZeneca Rare Disease) and Novartis; and support for attending meetings or travel from Alexion (AstraZeneca Rare Disease) and Novartis. YU reports a grant contracted with their institution by Chugai; consulting fees from Alexion (AstraZeneca Rare Disease), Asahi Kasei, Chugai, and Novartis; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Alexion (AstraZeneca Rare Disease), Chugai, Incyte, and Sobi; support for attending meetings or travel from Alexion (AstraZeneca Rare Disease) and Novartis; and participation in advisory boards for Alexion (AstraZeneca Rare Disease), Novartis, and Sobi. AV, CK, MD, PF, RK, SM, SS-Y, TL, and ZW report employment by Novartis and stock held with Novartis. CT, NM, and SL report employment by Novartis. AK, BHa, CY, EDB, HL, JHJ, LM, LWLL, LZ, MU, RF, SG, and SMCL declare no competing interests.
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