Introduction: Despite achieving a ‘good response’ with anti-C5 therapy (defined as hemoglobin [Hb] levels 10 to <12 g/dL), some patients with paroxysmal nocturnal hemoglobinuria (PNH) remain anemic and continue to experience symptoms due to extravascular hemolysis. Iptacopan, the first oral selective factor B inhibitor, demonstrated superior efficacy vs anti-C5 therapy (eculizumab/ravulizumab) in patients with PNH and Hb <10 g/dL on anti-C5 in APPLY-PNH (NCT04558918). APPULSE-PNH (NCT05630001) was a Phase 3b trial evaluating iptacopan in patients with Hb ≥10 g/dL who had received anti-C5 therapy. The study met its primary and key secondary objectives: noninferiority and superiority in Hb change from baseline (BL) after switching to iptacopan. Here, we present subgroup analyses in patients with BL Hb 10 to <12 g/dL.

Methods: In APPULSE-PNH,adult patients with PNH and mean Hb ≥10 g/dL on stable anti-C5 therapy for ≥6 months, who had not received red blood cell (RBC) transfusions for 6 months, were switched to oral iptacopan monotherapy 200 mg twice daily for 24 weeks. The primary endpoint was change from BL in Hb, tested hierarchically for noninferiority (primary objective) and superiority (key secondary objective) compared with anti-C5 therapy using predefined thresholds (lower bound of 95% confidence interval [CI] greater than –1 and 0 g/dL, respectively). All endpoints reported as adjusted mean change from BL, or ratio vs BL, used the mean of four visits between Days 126 and 168, except Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) and Treatment Satisfaction Questionnaire for Medication – 9 items (TSQM-9), which used Day 168 only. Exploratory subgroup analyses of BL Hb levels 10 to <12 g/dL were performed for the primary and key secondary endpoints.

Results: Of the52 patients enrolled in APPULSE-PNH, 32 (61.5%) had BL Hb 10 to <12 g/dL. In this subgroup of patients, mean age was 47.0 years; 43.8% were female and mean (standard deviation [SD]) time since diagnosis was 9.4 (6.8) years; 93.8% switched from ravulizumab and 6.3% from eculizumab. The mean (SD) duration of anti-C5 treatment was 3.0 (2.2) years. Mean (SD) BL Hb and lactate dehydrogenase (LDH) were 11.1 (0.5) g/dL and 236.6 (75.5) U/L, respectively. Overall adjusted mean (95% CI) change from BL in Hb was +2.0 g/dL (1.7, 2.3; P<0.0001 for both noninferiority and superiority). In patients with BL Hb 10 to <12 g/dL, adjusted mean (95% CI) change from BL in Hb was +2.4 (2.0, 2.7) g/dL. The lower bound of the 95% CI exceeded thresholds for noninferiority and superiority. No patients required RBC transfusions between Days 1 and 168. Adjusted mean (95% CI) change from BL in absolute reticulocyte count (ARC) was −101.9 109/L (−107.9, −95.9) in these patients. Geometric adjusted mean ratio (95% CI) of LDH vs BL was 1.0 (0.9, 1.1) in patients with Hb 10 to <12 g/dL. FACIT-Fatigue improved by +6.4 (95% CI: 3.2, 9.5). TSQM-9 scores for effectiveness, convenience, and global satisfaction improved by +11.1 (95% CI: 0.7, 21.6), +25.1 (16.4, 33.9), and +20.6 (12.3, 28.8) in patients with 10 to <12 g/dL, respectively.

In the overall population of APPULSE-PNH (N=52), the most frequently occurring treatment-emergent adverse events were headache (17.3% of patients), diarrhea, nausea, and nasopharyngitis (11.5% each). No patients experienced clinical breakthrough hemolysis, major adverse vascular events, treatment-related serious adverse events, or died.Conclusions: In APPULSE-PNH, switching from anti-C5 to oral iptacopan monotherapy led to clinically meaningful increases in Hb in patients with PNH and Hb ≥10 g/dL. Results in patients with BL Hb 10 to <12 g/dL were consistent with the overall study findings. Iptacopan was well tolerated. These results support iptacopan as a potentially practice-changing, outpatient treatment option for patients with PNH with BL Hb 10 to <12 g/dL.

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2025
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