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Clinical Trial
. 2025 Apr 22;9(8):1816-1826.
doi: 10.1182/bloodadvances.2024014652.

Patient-reported improvements in paroxysmal nocturnal hemoglobinuria treated with iptacopan from 2 phase 3 studies

Antonio M Risitano  1   2 , Carlos de Castro  3 , Bing Han  4 , Austin Kulasekararaj  5   6   7 , Jaroslaw P Maciejewski  8 , Phillip Scheinberg  9 , Yasutaka Ueda  10 , Susan Vallow  11 , Georgina Bermann  12 , Marion Dahlke  12 , Rakesh Kumar  13 , Régis Peffault de Latour  14   15
Affiliations
Clinical Trial

Patient-reported improvements in paroxysmal nocturnal hemoglobinuria treated with iptacopan from 2 phase 3 studies

Antonio M Risitano et al. Blood Adv. .

Abstract

Iptacopan, a first-in-class, oral, selective complement factor B inhibitor, demonstrated efficacy and safety as monotherapy in C5 inhibitor (C5i)-experienced (APPLY-PNH; NCT04558918) and C5i-naive (APPOINT-PNH; NCT04820530) patients with paroxysmal nocturnal hemoglobinuria (PNH). In the APPLY-PNH and APPOINT-PNH trials, changes in fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]) and health-related quality of life (HRQOL; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) from baseline to day 168 were evaluated. The proportion of patients achieving meaningful within-patient change (MWPC) on the FACIT-Fatigue and 4 EORTC QLQ-C30 subscales was evaluated using anchor-based thresholds, and correlations between FACIT-Fatigue scores, lactate dehydrogenase (LDH), and hemoglobin (Hb) levels were assessed. In APPLY-PNH (iptacopan, n = 62; C5i, n = 33), more patients in the iptacopan versus the C5i group reached the MWPC threshold for FACIT-Fatigue (51% vs 11%). More patients achieved MWPC on EORTC QLQ-C30 subscales in the iptacopan group (39%-49%) versus the C5i group (9%-20%). In APPOINT-PNH (N = 40), 56% achieved MWPC on the FACIT-Fatigue, and the proportion of patients who achieved MWPC on the EORTC QLQ-C30 ranged from 41% to 55%. In C5i-experienced patients, increased Hb levels correlated with improvement in FACIT-Fatigue scores (R = 0.48); in C5i-naive patients, increased Hb (R = 0.42) and decreased LDH (R = -0.53) (all P < .001) correlated with improved FACIT-Fatigue scores. C5i-experienced and -naive patients receiving iptacopan exhibited meaningful improvement in fatigue, HRQOL, and disease-related symptoms, which correlated with clinical improvement in hematologic markers of disease control.

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Conflict of interest statement

Conflict-of-interest disclosure: A.M.R. reports research support from Alexion, Novartis, Alnylam, and Ra Pharma; consultancy from Amyndas; speakers fees from Alexion, Novartis, Pfizer, and Sobi; and membership on an entity’s board of directors or advisory committees of Alexion, Apellis, Novartis, F. Hoffmann-La Roche, Achillion, and Samsung. C.d.C. reports consulting fees from Alexion and Apellis; honoraria from BioCryst, Omeros, and Regeneron; speakers fees from Alexion, Apellis, and Novartis; and membership on an entity’s board of directors or advisory committees of Novartis. A.K. reports research support from Novartis and Bristol Myers Squibb; consulting fees from Alexion, Novartis, Amgen, Agios, Pfizer, Samsung, Celgene, F. Hoffmann-La Roche, and Sobi; honoraria from Alexion, Novartis, Pfizer, Amgen, Samsung, Celgene, F. Hoffmann-La Roche, Bristol Myers Squibb, Sobi, and Silence Therapeutics; and speakers fees from Alexion, Novartis, Amgen, Pfizer, Celgene, F. Hoffmann-La Roche, Sobi, and Ra Pharma. J.P.M. reports consulting fees from Regeneron and Omeros; honoraria from Novartis and Regeneron; speakers fees from Novartis; and membership on an entity’s board of directors or advisory committees of Alexion. P.S. reports research support from Alnylam, BioCryst, Novartis, Pfizer, and F. Hoffmann-La Roche; consulting fees from Alexion, AstraZeneca, BioCryst, Janssen, Novartis, Pfizer, and F. Hoffmann-La Roche; and speakers fees from Alexion, AstraZeneca, Bristol Myers Squibb, Janssen, Novartis, Pfizer, F. Hoffmann-La Roche, and Novartis. Y.U. reports research support from Chugai; consulting fees from Alexion, Asahi Kase, Chugai, Janssen, Novartis, Ono, Sanofi, and Sobi; honoraria from Alexion, Chugai, Kaken, Nippon Shinyaku, Sobi, Incyte, and Sanofi; speakers fees from Alexion, Novartis, and Sanofi; and membership on an entity’s board of directors or advisory committees of Alexion, Janssen, Novartis, and Sanofi. S.V. is an employee of Novartis Services Incorporated and holds shares and/or stock options in the company. G.B. was an employee of Novartis Pharma AG. M.D. is an employee of Novartis Pharma AG and holds shares and/or stock options in the company. R.K. is an employee of Novartis Healthcare Private Limited and holds shares and/or stock options in the company. R.P.d.L. reports research support from Alexion, Pfizer, Novartis, Jazz, and Amgen; consulting fees from Alexion, Pfizer, Novartis, Sobi, Roche, Samsung, Keocyt, Merck Sharp & Dohme, Gilead, Jazz, and Amgen; and honoraria from Alexion, Pfizer, Novartis, Sobi, Roche, Samsung, Keocyt, Merck Sharp & Dohme, Gilead, Jazz, and Amgen. B.H. declares no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Summary of fatigue. (A) FACIT-Fatigue responder analysis in C5i-experienced patients from the 168-day randomized treatment period in APPLY-PNH. (B) Cumulative distribution of changes from baseline in FACIT-Fatigue scores by treatment and visit in APPLY-PNH. (C) FACIT-Fatigue responder analysis in C5i-naive patients from the 168-day randomized treatment period in APPOINT-PNH. bid, twice daily. C5i, C5 inhibitor; eCDF, empirical Cumulative Distribution Function; FACIT-Fatigue, Functional Assessment of Chronic Illness-Fatigue; RBC, red blood cell. a Proportions are mean of days 126, 140, 154, and 168, including RBC transfusion. b An eCDF represents the proportion of observations that fall below each unique value in a dataset. The red line represents the 9-point MWPC threshold for the FACIT-Fatigue. Higher FACIT-Fatigue scores represent less fatigue. P values are from the Mann-Whitney test that compares proportions with FACIT-Fatigue improvements of ≥ 9 points.
Figure 2.
Figure 2.
Summary of health-related quality of life. EORTC QLQ-C30 MWPC responder analysis from the 168-day randomized treatment period in (A) APPLY-PNH and (B) APPOINT-PNH. bid, twice daily. C5i, C5 inhibitor; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; PGIS, Patient Global Impression of Severity. a Proportions are mean of days 126, 140, 154, and 168, including transfusions. b Thresholds were derived on the medians of changes from baseline for patients who improved on PGIS merged categories corresponding to improvement and based on item 29 from the EORTC QLQ-C30 as supporting anchor.
Figure 3.
Figure 3.
Overview of hematologic markers and correlations with fatigue. (A) Least squares mean change from baseline in Hb level, LDH, and FACIT-Fatigue score during the 168-day core treatment period of APPLY-PNHa,b. (B) Correlation of Hb, LDH, and FACIT-Fatigue at day 168 of APPLY-PNH. (C) Least squares mean change from baseline in Hb level, LDH, and FACIT-Fatigue scores during the 168-day core treatment period of APPOINT-PNHa,b. (D) Correlation of Hb, LDH, and FACIT-Fatigue at baseline and day 168 of APPOINT-PNH. Bas, baseline; bid, twice daily; C5i, C5 inhibitor; FACIT-Fatigue, Function Assessment of Chronic Illness–Fatigue; Hb, hemoglobin; LDH, lactate dehydrogenase; RBC, red blood cell; ULN, upper limit of normal. a Change from baseline in Hb level does not include data within 30 days of RBC transfusion. Change from baseline in FACIT-Fatigue score and LDH includes data from patients who received RBC transfusion. b Error bars represent 95% confidence intervals.
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