Danicopan As Add-on Therapy to Ravulizumab or Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Long-Term Patient-Reported Outcomes from the Phase 3 ALPHA Trial
Authors: Piatek Caroline , Lee Jong Wook , Griffin Morag , Nishimura Jun-Ichi , Patriquin Christopher , Schrezenmeier Hubert , Barcellini Wilma , Shammo Jamile , Gaya Anna , Mahdi Mohammed , Liu Peng , Myren Karl-Johan , Messali Andrew , Sicre de Fontbrune Flore , Panse Jens , Kulasekararaj Austin G. 
Published: December 2024

Background
In patients with paroxysmal nocturnal hemoglobinuria (PNH), the complement C5 inhibitors (C5i) ravulizumab and eculizumab have proven efficacy and safety; ravulizumab provides immediate, complete and sustained inhibition of terminal complement activity, resulting in control of intravascular hemolysis and improved clinical outcomes. Approximately 20% of patients on C5i experience ongoing anemia caused by clinically significant extravascular hemolysis (csEVH). Danicopan is a first-in-class oral factor D inhibitor that targets the alternative pathway of the complement system. In the phase 3 ALPHA trial (NCT04469465), danicopan add-on therapy to ravulizumab or eculizumab demonstrated significant improvements in clinical outcomes in patients with PNH and csEVH.
Objective
To present final long-term patient-reported outcomes (PROs) from the ALPHA trial.
Methods
Patients in this phase 3, randomized, double-blind, placebo-controlled clinical trial were aged ≥ 18 years with a diagnosis of PNH, csEVH (hemoglobin ≤ 9.5 g/dL, absolute reticulocyte count ≥ 120 x 109/L), and ≥ 6 months' treatment with ravulizumab or eculizumab. At week 0, patients were randomized 2:1 to danicopan or placebo add-on therapy for 12 weeks; from week 12, patients in the placebo arm switched to danicopan. From week 24, patients continued to receive danicopan for up to 2 years in a long-term extension (LTE). PROs are reported over time, including Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) and EQ-5D-3L.
Results
In total, 86 patients were randomized to danicopan (n = 57) or placebo (n = 29); of these, 54 and 26 patients, respectively, completed the study up to week 24; and 46 and 24 patients, respectively, completed the LTE. Baseline characteristics were similar between arms.
In patients receiving danicopan, mean (standard deviation [SD]) FACIT-F scores improved from 34.0 (11.3) at baseline to 42.1 (7.7) at week 12, which was close to the general population score of 43.6; improvements were maintained to weeks 24 (40.9 [9.7]) and 72 (40.3 [10.3]). In the placebo-danicopan arm, improvements in FACIT- F were seen at week 24 and maintained to week 72, with a mean (SD) score of 31.7 (11.0) at baseline and 35.4 (10.7), 37.7 (11.5), and 36.7 (11.2) at weeks 12, 24, and 72, respectively. At week 12, change from baseline was significantly greater for danicopan vs placebo in the double-blinded phase (least-squares mean [95% confidence interval]: 8.13 [6.30, 9.96] vs 2.53 [−0.22, 4.91], respectively; p = 0.0004).
EORTC global health status/quality of life (QoL) mean (SD) scores in the danicopan arm improved from 58.3 (20.2) at baseline to 69.9 (18.8), 68.9 (19.4), and 68.3 (17.9) at weeks 12, 24, and 72, respectively, close to the general population norm of 66.1; in the placebo-danicopan arm scores improved from 53.1 (17.9) at baseline to 62.3 (17.0), 64.5 (19.1), and 62.5 (19.3), respectively. Mean (SD) EORTC physical functioning scores in the danicopan arm increased from 73.3 (18.8) at baseline to 85.1 (15.3), 85.9 (14.8), and 83.3 (16.7) at weeks 12, 24, and 72, close to the population norm of 85.1; in the placebo-danicopan arm, scores increased from 64.0 (20.3) at baseline to 66.1 (20.5), 77.0 (21.4), and 74.7 (22.1), respectively. EORTC fatigue subscale scores in the danicopan arm improved from 43.3 (27.2) at baseline to 27.4 (20.3), 25.4 (23.6), and 27.8 (22.2) at weeks 12, 24, and 72, comparable with the general population norm (29.5); in the placebo-danicopan arm scores improved from 49.0 (25.8) at baseline to 47.1 (28.6), 37.5 (27.8), and 44.9 (24.2), respectively.
Mean EQ-5D-3L scores (US Health State Index) were slightly below general population values (0.86-0.96) at baseline in the danicopan (0.84) and placebo arms (0.79) and remained stable with small numerical improvements at weeks 12, 24, and 72 (danicopan: 0.90, 0.91, and 0.87; placebo-danicopan: 0.86, 0.85, and 0.84, respectively).
Conclusions
In patients with PNH and csEVH, long-term danicopan add-on therapy to ravulizumab or eculizumab resulted in sustained improvements in patient-reported fatigue, QoL and physical function for up to 72 weeks, with scores reaching those in the general population. These findings indicate that danicopan add-on therapy is a potential solution for improving QoL in patients with PNH and severe csEVH.