DANICOPAN ADD-ON THERAPY to RAVULIZUMAB or ECULIZUMAB in PATIENTS with PAROXYSMAL NOCTURNAL HEMOGLOBINURIA and CLINICALLY SIGNIFICANT EXTRAVASCULAR HEMOLYSIS STRATIFIED by BONE MARROW FAILURE HISTORY.
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All Authors
Griffin, M.
Kim, J.
Ueda, Y.
De Fontbrune, F.
Brodsky, R.
Vijayran, H.
Tang, Y.
Kulasekararaj, A.
LTHT Author
Griffin, Morag
LTHT Department
Oncology
Haematology
Haematology
Contributor Profession (Non Medical)
Publication Date
2025
Item Type
Conference Abstract
Language
Subject
Subject Headings
Abstract
Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, hematologic disorder characterized by uncontrolled terminal complement activation, intravascular hemolysis, and thrombotic events leading to significant morbidity and mortality.1 In a phase 3 study, danicopan, as an add-on therapy to ravulizumab or eculizumab, demonstrated statistically significant and clinically meaningful improvements in hematologic parameters at week 12 whilst maintaining critical control of terminal complement activity, compared with placebo in patients with PNH and clinically significant extravascular hemolysis (csEVH).2 There is concern that patients with PNH and underlying bone marrow failure (BMF) syndrome may not be able to achieve normalization of hematologic parameters due to impaired erythropoiesis, which may result in persistent anemia despite treatment.AimsTo assess clinical response to danicopan add-on therapy to ravulizumab or eculizumab in patients with PNH and csEVH stratified according to history of BMF using data from the phase 3 ALPHA study (NCT04469465).MethodsALPHA was a randomized, double-blind, placebo-controlled clinical trial in adults aged >= 18 years with PNH and csEVH (hemoglobin [Hb] >= 9.5 g/dL, absolute reticulocyte count [ARC] >= 120 x 109/L). Patients were randomized 2:1 to danicopan or placebo as an add-on therapy to ravulizumab or eculizumab for the first 12 weeks. Following this, all patients switched to danicopan add-on therapy. This post hoc exploratory analysis reports Hb and ARC up to 12 weeks according to history of BMF. BMF was defined as participants with medical history terms in the Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) of "Hematopoietic cytopenias affecting more than one type of blood cell - broad and narrow' and ongoing at study enrollment.ResultsOf 86 patients, 11/57 (19.3%) randomized to danicopan and 7/29 (24.1%) randomized to placebo had a history of BMF. In these patients, mean (standard deviation [SD]) baseline Hb levels were 76.2 (6.7) g/L and 77.9 (9.2) g/L, respectively, and mean ARC was 241.1 (99.5) x 109/L and 196.0 (67.8) x 109/L, respectively. In patients without a history of BMF (danicopan: n = 46; placebo: n = 22), mean (SD) baseline Hb levels were 76.9 (10.1) g/L and 79.3 (10.6) g/L for danicopan and placebo, respectively, and ARC levels were 249.2 (97.7) x 109/L and 231.6 (127.5) x 109/L, respectively. Mean (SD) platelet counts at baseline were 117.9 (55.3) x 109/L and 95.4 (35.0) x 109/L for danicopan and placebo, respectively, in patients with a history of BMF. In patients without a history of BMF, platelet counts were 140.2 (66.9) x 109/L and 140.3 (78.0) x 109/L for danicopan and placebo, respectively. Up to 12 weeks, patients randomized to danicopan showed improvements in Hb levels compared with placebo, regardless of history of BMF (Figure A). Similarly, ARC improved up to week 12 in patients receiving danicopan versus placebo in both patients with and without a history of BMF (Figure B). Summary/ConclusionRegardless of BMF history, danicopan add-on therapy to ravulizumab or eculizumab, showed improvements in hematologic parameters (ARC and Hb levels) up to week 12. These findings demonstrate the benefit of danicopan in addition to C5 inhibitors in a broad range of patients with PNH. Brodsky RA. Blood 2014;124:2804-11. Lee JW. Lancet Haematol 2023;10:e955-65.
Journal
HemaSphere