ARTICLE: Phase 2 Study of Danicopan in Paroxysmal Nocturnal Hemoglobinuria Patients with an Inadequate Response to Eculizumab

AUTHORS: Austin Kulesekararaj, Antonio Maria Risitano, Jaroslaw P Maciejewski, Rosario Notaro, Peter J Browett, Jong Wook Lee, Mingjun Huang, Michael Geffner, Robert A Brodsky

JOURNAL: Blood. 2021 Jul 27;blood.2021011388. doi: 10.1182/blood.2021011388. Online ahead of print.


Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral, proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a Phase 2, dose-finding trial, eculizumab-treated, transfusion-dependent PNH patients (n=12) received danicopan 100-200 mg thrice daily in addition to their eculizumab regimen for 24 weeks. Endpoints included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction of blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; one discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean 2.4 g/dL Hgb increase at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared to one transfusion (2 units) in one patient during the 24-week treatment period. Mean FACIT-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to meaningful improvement in Hgb and reduced transfusion requirements in PNH patients who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. Registered at as NCT03472885.

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