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Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria.

Gaya, A; Munir, T; Urbano-Ispizua, A; Griffin, M; Taubel, J; Bush, J; Bhan, I; Borodovsky, A; Wang, Y; Badri, P; et al. Gaya, A; Munir, T; Urbano-Ispizua, A; Griffin, M; Taubel, J; Bush, J; Bhan, I; Borodovsky, A; Wang, Y; Badri, P; Garg, P (2023) Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria. EJHaem, 4 (3). pp. 612-624. ISSN 2688-6146 https://doi.org/10.1002/jha2.748
SGUL Authors: Taubel, Jorg

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Abstract

Complement dysregulation underpins the physiopathology of paroxysmal nocturnal hemoglobinuria (PNH). Cemdisiran, an RNA interference investigational treatment, silences complement component 5 (C5) expression in the liver. Previously reported results showed sustained reduction in C5 levels following cemdisiran monotherapy, with >90% reduction in patients with PNH. This phase 1/2 study evaluated single (Part A, n = 32; 50-900 mg) or multiple (Part B, n = 24; 100-600 mg) ascending doses of cemdisiran or placebo (double-blind, randomized 3:1) in healthy adults, or cemdisiran in patients with PNH who were naive to, or receiving, eculizumab (Part C, n = 6; 200 or 400 mg weekly; open-label). The primary objective was to assess the safety and tolerability of cemdisiran. Other assessments included change in complement activity, lactate dehydrogenase levels, and inhibition of hemolysis following cemdisiran treatment. Cemdisiran was generally well tolerated in this study. Overall, 75%, 89%, and 100% of subjects in Parts A, B, and C, respectively, experienced ≥1 non-serious adverse event (AE). Most events were Grade 1 or 2 in severity and the most common AEs included nasopharyngitis and headache. Cemdisiran elicited robust, sustained reductions in the complement activity in healthy adults and patients with PNH. In Part C, exploratory analyses showed that cemdisiran monotherapy was insufficient to prevent hemolysis in patients with PNH as measured by serum lactate dehydrogenase levels. Cemdisiran and eculizumab combination therapy reduced the dose of eculizumab required to provide adequate control of intravascular hemolysis. These results demonstrate a potential benefit of cemdisiran coadministration in patients who are inadequate responders to eculizumab alone.

Item Type: Article
Additional Information: © 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: cemdisiran, complement C5, paroxysmal nocturnal hemoglobinuria, cemdisiran, complement C5, paroxysmal nocturnal hemoglobinuria
Journal or Publication Title: EJHaem
ISSN: 2688-6146
Language: eng
Dates:
DateEvent
17 August 2023Published
26 June 2023Published Online
15 June 2023Accepted
Publisher License: Creative Commons: Attribution-Noncommercial 4.0
PubMed ID: 37601837
Web of Science ID: WOS:001228421200026
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/116692
Publisher's version: https://doi.org/10.1002/jha2.748

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