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

PLoS One. 2024 Jan 25;19(1):e0294847. doi: 10.1371/journal.pone.0294847. eCollection 2024.

Abstract

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.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adrenal Cortex Hormones / adverse effects
  • Adrenal Cortex Hormones / metabolism
  • Animals
  • Australia
  • Child
  • Humans
  • Inflammation / metabolism
  • Male
  • Mice
  • Mice, Inbred mdx
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophy, Duchenne* / complications
  • Muscular Dystrophy, Duchenne* / drug therapy
  • Muscular Dystrophy, Duchenne* / genetics

Substances

  • Adrenal Cortex Hormones

Grants and funding

The ATL1102 in DMD clinical trial was funded in its entirety by the sponsor Antisense Therapeutics Ltd. Authors Ms Desem and Dr Tachas are 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. 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. Dr Woodcock and Dr Ryan were involved in the trial design as unpaid consultants. 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. Author Dr Button was paid for services as the study statistician. 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.