Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic disease characterized by complement-mediated intravascular hemolysis. Although C5 inhibitors (C5i) secure effective control of intravascular hemolysis (IVH), a variable degree of consequent extravascular hemolysis (EVH) might be responsible for persistent anemia. Danicopan (ALXN2040) is an oral proximal complement inhibitor of alternative pathway factor D, conceived to control both EVH and IVH.

Aims and methods: We report the Italian collaborative real-world evidence on danicopan added to a C5i in patients with PNH. Fourteen Italian centres have accessed the Alexion® early access program (EAP) from September 2023 to date. Overall, 15 patients received danicopan under the Alexion® EAP from January 2024 to May 2025. Patients currently treated with danicopan+C5i were identified and anonymized. Data collection included patient age and gender, PNH characteristics, PNH response to treatments, clinically significant adverse events, breakthrough hemolysis (BTH) episodes, transfusion support, anticoagulant/antithrombotic therapy, and laboratory data at different time points (before C5i, before danicopan start, after 1 month (M), 2M, 3M, and 6M of danicopan).

Results: to date, data from 10 of the treated patients are available (4 females, median age 41.5ys, range 22-49, and 6 males, median age 58ys, range 33-86). Patients mainly suffered from classical PNH (80%), followed by PNH/aplastic anemia (PNH/AA, 20%). Median laboratory tests at the beginning of the C5i were as follows: hemoglobin level (Hgb) 8.9 g/dl (range, 7.0-9.8), reticulocytes (Ret) count 180*10^6/L (range, 20-341), LDH value 5 x upper limit of normality (ULN) (range, 1.5-28). At the time of enrolment in the danicopan EAP, 3 patients were receiving eculizumab (median duration 193 months, range 25-210), and 7 ravulizumab (median duration 25 months, range 10-59). None of the patients were receiving concomitant immunosuppressive therapy (IST). Antithrombotic prophylaxis was reported in 4 patients (2 warfarin and 2 low molecular weight heparin (LMWH)). No thrombotic events were reported, while 70% of patients had received at least one red blood cell (RBC) transfusion (median number per patient 4, range 1-6). Four patients experienced at least one BTH (median Hgb 6.7 g/dl), managed with RBC transfusion in all cases, and an extra dose of C5i in 2 cases. One BTH required hospitalization. The main reason to add danicopan was persistent anemia due to EVH (n=6) followed by inadequate response (n=4). Before adding danicopan, laboratory values were as follows: median Hgb level 8.9 g/dl (range 6.9-10.8), median Ret count 187*10^6/L (range 12-248), median LDH value 1.1 xULN (range 0.8-2.1). The percentage of patients who achieved a response from good to complete was 60% after 1M of danicopan+C5i treatment (n=10), 77.8% at 2M (n=9), 100% at 3M (n=8), and 83.3% at 6M (n=6). Considering laboratory values, median Hgb value gradually increased: 10.5 g/dl (range 7.4-13.2) at 1M (+1.6 g/dl from baseline, p=0.03), 10.7 g/dl (range 7.9-12.9) at 2M (+1.8 g/dl from baseline, p=0.04), 11.5 g/dl (range 10.2-12.8) at 3M (+2.6 g/dl, p=0.001), and 12.3 g/dl (range 8.9-13.8) at 6M (+3.4 g/dl, p=0.009). As expected, the percentage of PNH RBCs increased during treatment, from a median value of 79% (range 1-99) to 97% (range 66-100) (p=0.05). Median LDH value was 1xULN (range 0.6-1.1) at 1M, 1xULN (range 0.7-1.4) at 2M, 0.9xULN (range 0.8-2.7) at 3M, and 1.1xULN (range 0.8-1.8) at 6M. Median Ret count was 140*10^9/L (range 12-229) at 1M, 136*10^6/L (range 19-190) at 2M, 102*10^6/L (range 11-195) at 3M, and 165*10^6/L (range 110-204) at 6M. No statistical difference in LDH and Ret count was found between baseline and different time points. To date, the median duration of danicopan+C5i was 8.5 months (range 1-18). None of the patients received concomitant IST. Three patients received antithrombotic therapy (1 warfarin and 2 LMWH). None of the patients experienced thrombosis. The total number of RBC transfusions recorded in the cohort was 3, each corresponding to an episode of BTH. A total of 3 BTH were reported in two patients (20%) (median Hgb 7.9 g/dl). Not clinically relevant side effects were reported in two patients (20%): mild abdominal pain and diarrhea.

In conclusion, danicopan added to C5i appeared to be a promising combination therapy for patients with PNH and residual EVH.

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2025
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