Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria | Aplastic Anemia & MDS International Foundation

Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria

Journal Title: 
Haematologica
Primary Author: 
Risitano AM
Author(s): 
Risitano AM, Kulasekararaj AG, Lee JW, Maciejewski JP, Notaro R, Brodsky R, Huang M, Geffner M, Browett P
Original Publication Date: 
Thursday, October 29, 2020

Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.