Efficacy and Safety of Pegcetacoplan in PNH Patients with Extra-Vascular Hemolysis Under Anti-C5: The Real-Life Experience of the National French Reference Center

Introduction: Pegcetacoplan (PEG), the first proximal C3 inhibitor controls intravascular hemolysis without inducing extravascular hemolysis (EVH). PEG was shown to be superior to eculizumab in improving change in hemoglobin level in patients with persistent anemia du to EVH in patients under anti-C5 in a randomized control trial (PEGASUS trial). PEG is now approved in France for the treatment of adult patient who remain anemic after at least 3 months of anti-C5 treatment. Here we report the real-life experience of the French national reference center.

Methods: clinical and biological data of all consecutive's patients who received PEG outside a clinical trial and who have agreed to have their data recorded in the French national center database were analyzed.

Results: From June 2022 to July 2024, 39 patients were included. Twenty-six (66.7%) were female and median age at diagnosis of PNH was 36.4 years (IQR [24.8; 61.3]). Thirteen patients (33.3%) had previously received an immunosuppressive therapy for associated aplastic anemia and 7 (17.9%) of them had experienced a thrombotic event. The median time from anti-C5 start to PEG initiation was 39.6 months (IQR [20.25 ;65.43] (6.689 ;198.1). Twelve patients (30.8%) were receiving ravulizumab and 27 (69.2%) eculizumab. Median hemoglobin level, reticulocytes counts and bilirubin level during the 6 months preceding PEG were 8.8 g/dL (IQR [8.25 ;9.475]), 183.3 x 10⁹/L (IQR [142.4 ;253]), 21 mmol/L, (IQR, [15.9 ;46]), respectively. Twenty-nine patients (74.4%) required a median of 8 red blood cell pack transfusions during the 12 months (IQR [5; 21]) preceding PEG initiation. The median duration of PEG treatment was 16.7 months (from 104 days to 5.3 years) and the median follow-up (FU) after PEG initiation was 17.7 months (from 97 days to 5.3 years). PEG was stopped during FU in 8 patients (20.5%) for the following reason: allogeneic transplant in 2 patients (aplastic anemia and acute myeloblastic leukemia (AML)), persisting hemolysis and infection in 2 patients, severe hemolysis with thrombosis in 1 patient, severe adverse events in 1 patient (idiopathic interstitial pneumonia) and death after the diagnosis of AML in the last one. Among the 36 patients with at least 6 months of PEG exposure, 21 (58%) had at least an improvement of hemoglobin level of 2 g/dL and 20 (56%) achieved a hemoglobin level above 12 g/dL. Among the 27 patients with at least 12 months of PEG, 18 (67%) had at least an improvement of hemoglobin level of 2 g/dL and 17 (63%) achieved a hemoglobin level above 12 g/dL. At last FU under PEG, after censoring the 3 patients who had developed AML or aplastic anemia, median hemoglobin level, reticulocytes count and bilirubin level were 11.1 g/dL (IQR [9.8; 11.85]), 87 x 10⁹/L (IQR [69; 122]), 12.6 mmol/L, (IQR, [9 ;16]). Under PEG, 1 patient experienced a thrombotic event, a Budd-Chiari syndrome in the context of severe hemolysis crisis and severe multiple bacterial infections. Thirteen patients experienced 1 to 3 acute hemolytic events (n=20, median 1 per patient, IQR [1; 2]) with hospitalization required to manage 6 events. An increase in the frequency of injections to 3 per week was performed for half of the hemolytic events, while in 4 others an injection of eculizumab was done (6 events were managed without modification of anti-complement therapy). Only 1 patient required a red blood cell transfusion. An infection was identified as the triggering factor in 12 out of 20 cases. Nine patients required 3 injections per week at last FU. Overall 12 patients required 22 unscheduled hospitalizations during PEG treatment period: the main reasons were hemolysis in 6/22, infections in 6, heart failure not related to PEG in 3 and fever in 2. Eighteen patients experienced 29 infections (from 1 to 5 infections per patient). Two death were reported during FU which were not considered related to PEG (related to an adenocarcinoma and an AML). Two patients experienced clonal evolution to AML at 7 and 19 months after PEG start.

Conclusion: in this real-life analysis, after 12 months of PEG exposure 63% of our patients with significant HEV hemolysis obtained a hemoglobin level over 12g/dL. Discontinuation of PEG due to side effects or insufficient efficacy was observed in 4 patients among 39 (10%) and 29% required an increase of injection's frequency at last FU. Acute hemolysis events were observed in a third of them, requiring a hospitalization one in 4 times. There was no death related to PEG.

Sicre de Fontbrune:Sobi: Honoraria, Research Funding; Alexion, AstraZeneca Rare Disease: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Samsung: Honoraria, Research Funding. Forcade:Novartis: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; GSK: Speakers Bureau; Novartis: Consultancy; Sanofi: Other: Travel support, Speakers Bureau; Gilead: Other: Travel support, Speakers Bureau; Astellas: Research Funding; Maat Pharma: Consultancy; Alexion: Other: Travel support, Speakers Bureau; Sobi: Speakers Bureau. Terriou:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Alexion Pharma: Consultancy, Honoraria. Alcazer:Sobi: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria. Peffault de Latour:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.