Improvements in hematologic markers and decreases in fatigue with pegcetacoplan for patients with paroxysmal nocturnal hemoglobinuria and mild or moderate anemia (hemoglobin ≥10 g/dL) who had received eculizumab or were naive to complement inhibitors

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(7), P. e0306407 - e0306407

Published: July 29, 2024

Background Although complement component 5 inhibitors (C5is) eculizumab and ravulizumab improve paroxysmal nocturnal hemoglobinuria (PNH) outcomes, patients may experience persistent anemia. This post hoc analysis investigated whether the 3-targeted therapy pegcetacoplan also improved hematologic outcomes reduced fatigue in with PNH mild/moderate Methods Patients hemoglobin ≥10.0 g/dL at baseline of PADDOCK (N = 6), PRINCE 8), PEGASUS 11) were included. Before receiving pegcetacoplan, C5i-naive; had <10.5 despite stably dosed eculizumab. Hemoglobin concentrations, percentages concentrations ≥12 g/dL, sex-specific normalization assessed after 16 weeks as absolute reticulocyte counts (ARCs) scores normalization. Results From to week 16, mean (SD) increased C5i-naive (PADDOCK: 10.5 [0.4] 12.7 [1.1] g/dL; PRINCE: 11.3 [1.0] 14.0 [1.3] g/dL) those suboptimal responses (PEGASUS: 10.2 [0.2] 12.8 [2.6] g/dL). Percentage 0 60.0% [3 patients]; 25.0% [2 8] 87.5% [7 8]; PEGASUS: 72.7% [8 11]). Sex-specific occurred 40.0% (2 5) (PADDOCK), 62.5% (5 8) (PRINCE), 63.6% (7 (PEGASUS). In all studies, ARCs decreased from above normal ARC increased. Mean Functional Assessment Chronic Illness Therapy–Fatigue below or near normal. Two serious adverse events post-surgery sepsis, breakthrough hemolysis); hemolysis resolved without study discontinuation. Conclusion anemia who treatment initiating switching pegcetacoplan. Trial registration numbers: ( NCT02588833 ), NCT04085601 ; EudraCT, 2018-004220-11), NCT03500549 ).

Language: Английский

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Clinical characteristics and management of paroxysmal nocturnal haemoglobinuria in Latin America: a narrative review

Annals of Hematology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 5, 2024

Language: Английский

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Peptide-based therapeutics targeting genetic disorders

Drug Discovery Today, Journal Year: 2024, Volume and Issue: unknown, P. 104209 - 104209

Published: Oct. 1, 2024

Language: Английский

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Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys

Toxicology and Applied Pharmacology, Journal Year: 2024, Volume and Issue: 495, P. 117191 - 117191

Published: Dec. 7, 2024

CSL040 is a soluble, recombinant fragment of the complement receptor 1 (CR1) extracellular domain that acts as an inhibitor all three pathways system. Systemic toxicity, toxicokinetics (TK), and pharmacodynamics (PD) were assessed in two-week intravenous (IV) bolus studies Han Wistar rats cynomolgus monkeys. Recovery from any effects was evaluated during four-week recovery period. Daily repeat-dose administration for 2 weeks at doses up to 500 mg/kg IV well tolerated monkeys, leading no observed adverse effect level (NOAEL) both species. Safety pharmacology parameters such electrophysiology heart, blood pressure, heart rate, respiratory rate measurements, general toxicological readouts considered unaffected by treatment. Anti-drug antibodies (ADAs) monkeys some highest dose CSL040, but with on pharmacokinetics (PK), supportive adequate exposure levels required safety assessment. All inhibited dose-dependently CSL040. Additionally, cytokine detected vitro using release assay. These non-clinical demonstrated PD activity consistent its mode action, PK properties, profile supporting phase clinical strategy. A small follow-up study comparing PK/PD following subcutaneous (SC) also suggested latter route might be viable alternative administration.

Language: Английский

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PNH and complement gene variants

Blood, Journal Year: 2023, Volume and Issue: 141(15), P. 1780 - 1782

Published: April 13, 2023

Language: Английский

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