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Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3188-3197
Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria
Antonio M. Risitano,1,2 Austin G. Kulasekararaj,3,4 Jong Wook Lee,5 Jaroslaw P. Maciejewski,6 Rosario Notaro,7,8 Robert Brodsky,9 Mingjun Huang,10 Michael Geffner11 and Peter Browett12
1Federico II University of Naples, Naples, Italy; 2AORN Moscati, Avellino, Italy;
3King's College Hospital-NHS Foundation Trust, NIHR/Wellcome King’s Clinical Research Facility, London, UK; 4King’s College London, London, UK; 5Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea; 6Cleveland Clinic, Cleveland, OH, USA; 7Core Research Laboratory, Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Firenze, Italy; 8Azienda Ospedaliera-Universitaria Careggi, Firenze, Italy; 9Johns Hopkins University School of Medicine, Baltimore, MD, USA; 10Achillion, Inc., A Subsidiary of Alexion Pharmaceuticals, Inc., New Haven, CT, USA and Alexion Pharmaceuticals, New Haven CT, USA; 11Achillion Inc., A Subsidiary of Pharmaceuticals, Inc., Blue Bell, PA, USA and 12University of Auckland, Auckland, New Zealand
Presented as an oral presentation at the 24th European Hematology Association Congress, Amsterdam, NL, June 15, 2019. Presented as a poster presentation at the 61st annual meeting of the American Society of Hematology, Orlando, FL, USA December 8, 2019.
ABSTRACT
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the absence of complement regulators CD55 and CD59 on affected erythro- cytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D inhibitor. Therapeutic factor D inhibition was designed to control intravascular hemolysis and prevent C3-mediated extravascular hemolysis. In this open-label, phase II, dose-finding trial, ten untreated PNH patients with hemolysis received danicopan monotherapy (100-200 mg thrice daily). Endpoints included changes in the concentrations of lactate dehydrogenase (LDH) at day 28 (primary endpoint), of LDH at day 84, and of hemoglobin. Safety, pharmacokinet- ics/pharmacodynamics, and patient-reported outcomes were assessed. Ten patients reached the primary endpoint; two later discontinued treat- ment: one because of a serious adverse event (elevated aspartate amino- transferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. Intravascular hemolysis was inhibited, as demonstrated by a mean decrease of LDH (5.7 times upper limit of normal [ULN] at baseline vs. 1.8 times ULN at day 28 and 2.2 times ULN at 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 gly- cosylphosphatidylinositol-deficient erythrocytes. Mean baseline Functional Assessment of Chronic Illness Therapy–Fatigue score, 34, increased by 9 (day 28) and 13 (day 84) points. The most common adverse events were headache and upper respiratory tract infection. These phase II, monotherapy data show that proximal inhibition with danicopan provides clinically meaningful inhibition of intravascular hemolysis and increases hemoglobin concentration in untreated PNH patients, without evidence of C3-mediated extravascular hemolysis. This trial was registered at www.clinicaltrials.gov (#NCT03053102).
Red Cell Biology & its Disorders
Correspondence:
ANTONIO M. RISITANO
amrisita@unina.it
Received: June 3, 2020. Accepted: October 6, 2020. Pre-published: October 29, 2020.
https://doi.org/10.3324/haematol.2020.261826 ©2021 Ferrata Storti Foundation
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