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Danicopan, an oral factor D inhibitor for PNH
Introduction
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by chronic intravascu- lar hemolysis, severe thrombophilia, and bone marrow failure.1 PNH is due to somatic mutations of the phos- phatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene in hematopoietic stem cells that impair biosynthesis of glycosylphosphatidylinositol (GPI) anchors and surface expression of GPI-linked proteins.2-4 While bone marrow failure is secondary to T-cell-mediat- ed immune attack that spares PIGA-mutated hematopoi- etic stem cells,5,6 both hemolysis and thromboembolism are complement-mediated. GPI-deficient erythrocytes (and platelets) lack GPI-linked complement regulators CD557 and CD598 and are exquisitely vulnerable to com- plement activation, which occurs continuously and spon- taneously due to “C3 tick-over”9 and acutely with specific triggers. PNH treatment was revolutionized by introduc- tion of the terminal complement C5 inhibitor eculizumab, which has proven effective in addressing intravascular hemolysis10,11 and thromboembolism,12 with a significant impact on long-term survival.13,14 Recently, a new long-act- ing C5 inhibitor dosed every 8 weeks, ravulizumab, has demonstrated non-inferiority to eculizumab in controlling intravascular hemolysis.15,16 Although the significant bene- fits of C5 inhibition in the treatment of PNH patients have been clearly demonstrated, the hematologic benefit may be hampered by the emergence of C3-mediated extravas- cular hemolysis from early phases of complement activa- tion,17,18 which C5 inhibition cannot address.19-21 Thus, alternative strategies of complement inhibition are required to improve PNH treatment, and agents are in development to address this and other unmet patients’ needs, including improved convenience.22
The complement cascade has three activating pathways (alternative, classical, and lectin-mannose) that merge at the key complement component C3; from this level (which is amplified by alternative pathway [AP] proteins), the effector pathway starts, with generation of anaphyla- toxins and the membrane attack complex (MAC).23 Novel strategies of therapeutic complement inhibition in devel- opment aim to intercept the complement cascade upstream of C5, some targeting upstream at pathway-spe- cific initiating events.22 During AP initiation, the serine protease complement factor D cleaves factor B, leading to AP C3 convertase generation. Danicopan (ACH-4471, ACH-044471, ALXN2040) is a first-in-class, oral, small- molecule factor D inhibitor that prevents new AP C3 con- vertase formation.24 Consequently, proximal inhibition at the level of factor D blocks AP-initiated upstream events and up to 80% of classical or lectin pathway-initiated downstream events via amplification-loop inhibition.25 In vitro, danicopan inhibited both AP-mediated hemolysis and C3 fragment deposition on red blood cells from PNH patients.24 Phase I data from healthy human volunteers in single and multiple ascending-dose trials showed that dan- icopan was generally well tolerated and could achieve inhibition of AP complement activity.26 This work identi- fied danicopan 200 mg thrice daily (tid) as a safe and effec- tive dose/regimen.26 For PNH, targeting factor D inhibition with a small molecule represents a potentially important treatment advancement because proximal AP inhibition may disable both terminal complement activation (inhibiting MAC–mediated intravascular hemolysis) and C3 fragment opsonization (preventing extravascular
hemolysis), with additional convenience of oral adminis- tration.
We investigated the factor D inhibitor danicopan as sin- gle-agent treatment for untreated PNH, aiming to control intravascular hemolysis while preventing C3-mediated extravascular hemolysis.
Methods
Study design
This international, open-label, single-arm, dose-finding, phase II study investigated danicopan in patients with hemolytic PNH not receiving complement inhibitor treatment. This trial was approved by regulatory agencies/local ethics committees and con- ducted according to International Conference on Harmonisation and Good Clinical Practice Standards. Achillion, Inc., a subsidiary of Alexion Pharmaceuticals, Inc., designed and sponsored the study, with advice from the investigators. All participants provid- ed written informed consent. The trial is registered at www.clinical- trials.gov as #NCT03053102.
Patients
This study was conducted from March 2017 to November 2018 and involved adults with untreated PNH. To be enrolled, patients had to have hemoglobin <12 g/dL (and adequate reticulocytosis according to the investigator), GPI-deficient granulocytes or type III erythrocyte clone size ≥10%, lactate dehydrogenase (LDH) ≥1.5 times upper limit of normal (ULN), platelet counts ≥50x109/L, and willingness to be vaccinated for N. meningitidis, H. influenzae, and S. pneumoniae. Investigators used their clinical judgement to assess whether patients had enough bone marrow capacity to derive potential benefit by comparing the level of pre-entry hemo- globin to the absolute reticulocyte count. None of the subjects was receiving eculizumab, because of lack of availability and/or the patients’ willingness.
Treatment
Patients received oral danicopan at a starting dose of 100 mg or 150 mg tid. The starting dose was based on phase I data showing that danicopan doses of 200 to 600 mg reached peak plasma levels within 1 to 2 h and were well-tolerated, and that 200 mg tid was effective on PNH red blood cells.22,26 Dose escalations were per- mitted based on hemolysis control, assessed by LDH, per investi- gator assessment in stepwise increments up to 200 mg tid. Dose escalation criteria for the first 28 days were specified in the study protocol with potential dose escalation points occurring at days 7 and 14 (Online Supplementary Appendix). Dose escalation was per- mitted thereafter and was done in consultation between the inves- tigator and sponsor based on the hemoglobin response; absolute reticulocyte count, LDH, and indirect bilirubin were reviewed to evaluate evidence for possible additional clinical benefit from dose escalation. Because this study was the first treatment experience with danicopan in PNH patients, dose escalations were approached cautiously, especially when moving to the higher doses in the study (from 150 to 175 mg and 175 to 200 mg) or if alanine aminotransferase levels had fluctuated relative to the base- line value. Patients were instructed to take their medication approximately every 8 h. On study center days, when blood for laboratory tests was drawn, the morning dose was to be adminis- tered in the study center by the site personnel following safety and pharmacokinetic assessments. Additionally, patients were instructed to take each dose with food, including prior to intensive sampling for pharmacokinetic studies on days 1, 13, and 28. The planned duration of treatment was 84 days; patients completing
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