A phase 2 open-label study of the safety and efficacy of weekly dosing of ATL1102 in patients with non-ambulatory Duchenne muscular dystrophy and pharmacology in mdx mice.

Autor: Woodcock IR; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.; The Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Tachas G; Antisense Therapeutics Ltd, Melbourne, Australia., Desem N; Antisense Therapeutics Ltd, Melbourne, Australia., Houweling PJ; The Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Kean M; Department of Medical Imaging, The Royal Children's Hospital, Melbourne, Australia., Emmanuel J; Department of Medical Imaging, The Royal Children's Hospital, Melbourne, Australia., Kennedy R; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.; The Murdoch Children's Research Institute, Melbourne, Australia.; Department of Physiotherapy, University of Melbourne, Melbourne, Australia., Carroll K; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.; The Murdoch Children's Research Institute, Melbourne, Australia., de Valle K; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.; The Murdoch Children's Research Institute, Melbourne, Australia.; Department of Physiotherapy, University of Melbourne, Melbourne, Australia., Adams J; The Murdoch Children's Research Institute, Melbourne, Australia., Lamandé SR; The Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Coles C; The Murdoch Children's Research Institute, Melbourne, Australia., Tiong C; The Murdoch Children's Research Institute, Melbourne, Australia., Burton M; The Murdoch Children's Research Institute, Melbourne, Australia., Villano D; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia., Button P; McCloud Consulting Group, Sydney, Australia., Hogrel JY; Institut de Myologie, GH Pitié-Salpêtrière, Paris, France., Catling-Seyffer S; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.; The Murdoch Children's Research Institute, Melbourne, Australia., Ryan MM; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.; The Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Delatycki MB; Victorian Clinical Genetics Service, Melbourne, Australia.; Murdoch Children's Research Institute, Bruce Lefroy Centre for Genetic Health Research, Melbourne, Australia., Yiu EM; Department of Neurology, The Royal Children's Hospital, Melbourne, Australia.; The Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Jan 25; Vol. 19 (1), pp. e0294847. Date of Electronic Publication: 2024 Jan 25 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0294847
Abstrakt: Background: ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment.
Methods: This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline.
Results: Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period.
Conclusion: ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD.
Trial Registration: Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246.
Competing Interests: The ATL1102 in DMD clinical trial was funded in its entirety by the commercial sponsor Antisense Therapeutics Ltd. Antisense Therapeutics Ltd is a publicly traded company, listed on the Australian ASX. At the time of the trial, authors Ms Desem and Dr Tachas were employees of the sponsor and so received payment for services from the sponsor as employees. Ms. Desem and Dr Tachas hold an equity interest in the sponsor. Dr Tachas and Ms Desem along with other sponsor employees and sub-contracted specialists were involved in the study design and data analysis. Ms Desem has since left the company and no longer is employed by the sponsor. Authors Dr Woodcock and Dr Ryan were at the time of the trial employees of the Royal Children’s Hospital and Murdoch Children’s Research Institute and are not affiliated with the sponsor in any way and have not received any direct personal payment or honoraria from the sponsors, nor do they or their family members hold a financial interest or stock in the sponsor company. Dr Woodcock is still an employee of the above institutions, but Dr Ryan has since left the employment to take up public office as a Member of the Australian Parliament. Dr Woodcock and Dr Ryan were involved in the trial design as unpaid consultants. Dr Woodcock has received honoraria for work performed including educational activities and attendance at advisory board meetings from pharmaceutical companies Biogen, Novartis, Roche and Avidity and an educational travel bursary to attend an international conference in 2016 from Biogen. Dr Woodcock has received grants for research work from FSHD Global Research Foundation, FSHD Society and Fulcrum Therapeutics. Dr Woodcock has been principal investigator on a number of industry-sponsored clinical trials. None of these disclosures affected the work Dr Woodcock performed on this clinical trial. Dr Ryan has received honoraria for work performed including educational activities and attendance at advisory board meetings from pharmaceutical companies Biogen, Novartis, Roche. Dr Ryan has been principal investigator on a number of industry-sponsored clinical trials. None of these disclosures affected the work Dr Ryan performed on this clinical trial. Dr Yiu has received advisory board honoraria from Biogen and Roche, and has received research support from Biogen, Roche, Pfizer and PTC therapeutics unrelated to the content of this manuscript. Dr Yiu has been principal investigator on a number of industry-sponsored clinical trials. None of these disclosures affected the work Dr Yiu performed on this clinical trial. Prof. Delatycki has received grant awards from NHMRC and is principal investigator in industry sponsored clinical trials including trials sponsored by Rearta and PTC. As this was a clinical trial, publication was always planned from trial inception. No employees of the sponsor were involved in the data collection, although Ms Desem did liaise closely with the MCRI/RCH site staff and Clinical Trial Organisation throughout the trial. As the study statistician, author Dr Button was paid a consultancy fee for his services from the trial sponsor commercial company Antisense Therapeutics Ltd. Authors Dr Houweling, Dr Coles and Dr Tiong were recipients of a grant to perform the MDX studies. This grant was paid by the sponsor Antisense Therapeutics Ltd. None of the other authors received any payment from the sponsor to conduct this study. All other authors had input into writing or revising this manuscript. The authors confirm that the involvement of employees of the sponsor Antisense Therapeutics Ltd in the trial design, data analysis and decision to publish this data does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2024 Woodcock et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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