Danicopan

Risitano A. M, et al, Haematologica, 2021, 106(12), 3188-3197.

This case study explores the clinical application of Danicopan, an oral factor D inhibitor, for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Danicopan's ability to inhibit the complement alternative pathway was assessed in a phase II, open-label, dose-finding trial involving ten previously untreated PNH patients with active hemolysis. Danicopan was administered as monotherapy at doses of 100-200 mg thrice daily for 84 days. The primary endpoint was the change in lactate dehydrogenase (LDH) levels at day 28, complemented by evaluations at day 84 and hemoglobin changes. Safety, pharmacokinetics, pharmacodynamics, and patient-reported fatigue scores were also monitored. Results showed significant inhibition of intravascular hemolysis, evidenced by a reduction in mean LDH levels from 5.7 times the ULN at baseline to 1.8 times ULN at day 28 and 2.2 times ULN at day 84 (P<0.001). Hemoglobin levels increased by 1.1 g/dL and 1.7 g/dL at days 28 and 84, respectively (P<0.005). Importantly, no significant C3 fragment deposition was observed on erythrocytes. The most frequent adverse events included headache and upper respiratory tract infections. This trial underscores Danicopan's experimental potential as a proximal complement inhibitor for PNH.

Kulasekararaj A, et al. Blood, 2025, 145(8), 811-822.

This study explored the long-term efficacy and safety of danicopan, an oral factor D inhibitor, as an add-on therapy to ravulizumab or eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing clinically significant extravascular hemolysis (cs-EVH). In the phase 3 ALPHA trial, 86 participants were randomized to receive either danicopan (150 mg, three times daily) or placebo alongside ravulizumab or eculizumab during the initial 12-week double-blind treatment period (TP1). Patients who initially received placebo were switched to danicopan during the subsequent 12-week open-label period (TP2), and all continued danicopan treatment during a 2-year long-term extension (LTE). Hemoglobin levels, absolute reticulocyte count (ARC), transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scores were evaluated as key endpoints. Danicopan treatment yielded a mean hemoglobin increase of 2.8 g/dL at week 12, sustained up to week 72. Switching from placebo to danicopan also resulted in hemoglobin improvements by week 24. The breakthrough hemolysis rate was 6 events per 100 patient-years, with no new safety concerns. This rigorous clinical assessment underscores the potential of danicopan to sustain hematologic improvements and reduce transfusion requirements in PNH patients with cs-EVH.