APPULSE-PNH: ORAL IPTACOPAN MONOTHERAPY DEMONSTRATES CLINICALLY MEANINGFUL HEMOGLOBIN (HB) INCREASES IN PATIENTS (PTS) WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) AND HB >=10 G/DL ON ANTI-C5 THERAPY.

Kulasekararaj, A.; De Fontbrune, F.S.; Valls, A.G.; Weitz, I.; Kuter, D.; Araten, D.J.; Patel, B.J.; Singh, A.; Jang, J.H.; Kelly, R.J.; Di Bona, E.; Loschi, M.; Pullarkat, V.; Schubert, J.; Vannucchi, A.; Yenerel, M.N.; De Latour, R.P.; Mahajan, N.; Monaco, L.; Ding, T.; Lawniczek, T.; Ferber, P.; Dahlke, M.; Risitano, A.M.

APPULSE-PNH: ORAL IPTACOPAN MONOTHERAPY DEMONSTRATES CLINICALLY MEANINGFUL HEMOGLOBIN (HB) INCREASES IN PATIENTS (PTS) WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) AND HB >=10 G/DL ON ANTI-C5 THERAPY.

All Authors

Kulasekararaj, A.

De Fontbrune, F.S.

Valls, A.G.

Weitz, I.

Kuter, D.

Araten, D.J.

Patel, B.J.

Singh, A.

Jang, J.H.

Kelly, R.J.

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LTHT Author

Kelly, Richard

LTHT Department

Oncology
Haematology

Publication Date

2025

Item Type

Conference Abstract

Abstract

Background Many pts with PNH on anti-C5 remain anemic. Iptacopan, the first oral selective factor B inhibitor, had superior efficacy vs anti-C5 (eculizumab/ravulizumab) in pts with PNH and Hb <10 g/dL on anti-C5 in APPLY-PNH (NCT04558918). Aims We report primary efficacy and safety data from the single-arm, open-label, multicenter, Phase IIIb APPULSE-PNH trial (NCT05630001) in pts with PNH and Hb >=10 g/dL in response to anti-C5 who switched to iptacopan. Methods Adult pts with PNH and mean Hb >=10 g/dL on stable anti-C5 for >=6 months who had not received red blood cell transfusions (RBCTs) for 6 months were switched to iptacopan monotherapy 200 mg bid for 24 weeks. Primary endpoint was change from (DELTA) baseline (BL) in Hb, which was tested hierarchically for noninferiority (primary objective) and superiority (key secondary objective) of iptacopan vs prior anti-C5 using predefined thresholds (lower bound of 95% confidence interval [CI] >-1 and >0 g/dL, respectively). All endpoints reported as adjusted mean DELTABL or ratio vs BL use the mean of four visits between Day 126 and 168, except Functional Assessment of Chronic Illness Therapy - Fatigue (FACITFatigue) and Treatment Satisfaction Questionnaire for Medication - 9 items (TSQM-9), which use Day 168 only. Results Fifty-two pts were enrolled: mean age was 46.0 years; 38.5% were female; mean time since diagnosis was 10.8 years (standard deviation [SD] 7.5); 88.5% switched from ravulizumab and 11.5% from eculizumab. BL mean (SD) Hb and lactate dehydrogenase (LDH) were 11.87 g/dL (1.32) and 226.8 U/L (69.05), respectively; 38.5% of pts had BL Hb >=12 g/dL. Adjusted mean (95% CI) DELTABL in Hb was +2.01 g/dL (1.74, 2.29) and statistically significant (P<0.0001 for both noninferiority and superiority); subgroup results for BL Hb <12/>=12 g/dL were +2.37 (2.01, 2.74) and +1.44 (1.04, 1.84) g/dL, respectively. Mean Hb at 24 weeks was 13.88 g/dL (SD 1.27; Figure). No pts required RBCTs between Day 1 and 168. Proportion of pts with Hb >=12 g/dL between Day 126 and 168 was 92.7% (95% CI 84.6, 98.1). Adjusted mean DELTABL in absolute reticulocyte count (ARC) was -89.19 x 109/L (95% CI -95.47, -82.92). Mean ARC at 24 weeks was 60.40 x 109/L (SD 22.36; Figure). Geometric adjusted mean ratio of LDH vs BL was 0.99 (95% CI 0.93, 1.04). Adjusted mean (95% CI) DELTABL in FACIT-Fatigue was +4.29 (1.74, 6.85) and in TSQM-9 effectiveness, convenience and global satisfaction was +12.54 (5.58, 19.49), +23.86 (17.62, 30.10) and +18.53 (12.87, 24.19), respectively. One pt discontinued iptacopan because of a treatment-emergent adverse event (TEAE) of non-serious palpitations suspected to be related to iptacopan. Two pts had serious TEAEs (bacterial pneumonia; pyrexia with traumatic subdural hematoma); none were reported as related to iptacopan. Headache (17.3% of pts), diarrhea, nausea and nasopharyngitis (11.5% each) were the most frequent TEAEs and the infections system organ class had the most pts with TEAEs (42.3%). No pts had clinical breakthrough hemolysis, major adverse vascular events or died. Summary/Conclusion APPULSE-PNH met its primary and key secondary objectives. Oral iptacopan monotherapy led to clinically meaningful increases in Hb, Hb normalization in almost all pts, transfusion avoidance in all pts and reductions in ARC. Pts also reported improvements in fatigue and treatment satisfaction. Iptacopan was well tolerated with no new safety findings. Iptacopan is a potentially practice-changing treatment that may become a preferred outpatient option for pts with PNH.