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<0.001). Mean baseline hemoglobin, 9.8 g/dL, increased by 1.1 (day 28) and 1.7 (day 84) g/dL (both p<0.005). No significant C3 fragment deposition occurred on GPI-deficient erythrocytes. Mean baseline Functional Assessment of Chronic Illness Therapy–Fatigue score, 34, increased by 9 (day 28) and 13 (day 84) points. Most common adverse events were headache and upper respiratory tract infection. This phase 2, monotherapy data shows proximal inhibition with danicopan provides clinically meaningful IVH inhibition and hemoglobin improvement in untreated PNH patients, without evidence of C3- mediated EVH. Registered at www.clinicaltrials.gov (#NCT03053102).
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