Phase 3 Data Shows Iptacopan Eases Fatigue in C5i-Experienced, -Naïve PNH Patients

Phase 3 data showed iptacopan, a first-in-class, oral, selective complement factor B inhibitor, demonstrated meaningful improvement in fatigue and quality of life among patients with paroxysmal nocturnal hemoglobinuria (PNH).1

The results came from 2 phase 3 trials, APPLY-PNH and APPOINT-PNH, evaluating changes from baseline to day 168 in fatigue and health-related quality of life during treatment with iptacopan. APPLY-PNH was an open-label, randomized, multicenter, phase 3 trial studying iptacopan as a monotherapy in patients with PNH who had persistent anemia despite intravenously administered C5 inhibitor (c5i) therapy either with eculizumab or ravulizumab. APPOINT-PNH was an open-label, multicenter, phase 3 trial evaluating iptacopan monotherapy in C5i-naïve patients with PNH.

“Analysis of MWPC for the FACIT-Fatigue and 4 EORTC QLQ-C30 subscales using patient-centered anchors found that both C5i-experienced patients with persistent anemia and C5i-naive patients experienced meaningful improvements in the symptoms and impacts of PNH during treatment with iptacopan,” wrote investigators, led by Antonio M. Risitano, MD, PhD, from University of Naples Federico II in Italy.

PNH, a rare disease characterized by hemolysis and thrombosis—and often occurs during bone marrow failure—can lead to anemia, fatigue, dyspnea, hemoglobinuria, impaired renal function, abdominal pain, dysphagia, and erectile dysfunction. 80.9% of patients in the International PNH registry reported fatigue.

C5is has been shown to significantly improve symptoms of paroxysmal nocturnal hemoglobinuria: controlling intravascular hemolysis by stabilizing hemoglobin (Hb), reducing thrombosis risk, and improving long-term survival.

Still, many patients treated with C5is experience persistent anemia and fatigue due to extravascular hemolysis or residual intravascular hemolysis. A study in 2023 revealed that a large proportion of patients (70% - 82%) with PNH who were treated with eculizumab did not achieve an optimal clinical response.2 Iptacopan was recently approved to treat adults with PNH, and investigators sought to evaluate the efficacy and safety of iptacopan 200 mg twice daily for patients who were and were C5i-experienced or -naïve.1

Both trials evaluated the proportion of patients who achieved meaningful changes on the FACIT-Fatigue and 4 EORTC QLQ-C30 subscales: physical functioning, role functioning, fatigue, dyspnea. The studies also assessed the correlations between FACIT-Fatigue scores, lactate dehydrogenase, and Hb levels.

APPLY-PNH included 62 participants aged ≥ 18 years with 33 C5i-experienced. Patients were previously treated with a stable regimen of C5i therapy for ≥ 6 months before randomized.

More patients in the iptacopan group reached the meaningful within-patient change (MWPC) threshold for FACIT-Fatigue than in the C5i group (51% vs 11%). Additionally, more patients reached the MWPC threshold on the 4 domains of the EORTC QLQ-C30 in the iptacopan group (39% - 49%) than in the C5i group (9% - 20%). Among C5i-experienced patients, increased Hb levels correlated with improvement in FACIT-Fatigue scores (P < .001).

In APPOINT-PNH (n = 40; aged ≥ 18 years), 56% reached the MWPC threshold on the FACIT-Fatigue, and 41% to 55% reached the MWPC threshold on the EORTC QLQ-C30. Among C5i-naïve patients treated with iptacopan, increased Hb (P < .001) and decreased lactate dehydrogenase (P < .001) were correlated with improved FACIT-Fatigue scores.

The 2 trials revealed C5i-experienced and -naïve patients who received iptacopan demonstrated meaningful improvement in fatigue, health-related quality of life, and disease-related symptoms. These 3 improvements correlated with clinical improvement in hematologic markers of disease control.

“These results, combined with efficacy data from APPLY-PNH and APPOINT-PNH, indicate that iptacopan results in clinically meaningful disease control and meaningful improvements in the fatigue and HRQOL impacts of PNH after 168 days of treatment in C5i-experienced and -naive patients with PNH,” investigators concluded.

References

1. Risitano AM, de Castro C, Han B, Kulasekararaj AG, Maciejewski JP, Scheinberg P, Ueda Y, Vallow S, Bermann G, Dahlke M, Kumar R, Peffault de Latour R. Patient-Reported Improvements in Patients with PNH Treated with Iptacopan from Two Phase 3 Studies. Blood Adv. 2025 Jan 7:bloodadvances.2024014652. doi: 10.1182/bloodadvances.2024014652. Epub ahead of print. PMID: 39774762.
2. Versmold K, Alashkar F, Raiser C, Ofori-Asenso R, Xu T, Liu Y, Katz P, Shang A, Röth A. Long-term outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab in a real-world setting. Eur J Haematol. 2023 Jul;111(1):84-95. doi: 10.1111/ejh.13970. Epub 2023 Apr 2. PMID: 36971028.