Context Patients with glucocorticoid dependent Duchenne Muscular Dystrophy (DMD) have increased fracture risk and reduced bone mineral density (BMD), often precipitating mobility loss. Objective To investigate use of Zoledronic acid (ZA) in DMD in improving BMD. Design Two arm, parallel, randomised controlled trial Setting Paediatric hospitals across Australia and New Zealand Patients Sixty-two (31 per arm) boys with glucocorticoid dependent DMD between 6-16 years Intervention(s) Five ZA infusions (0.025mg/kg at months 0,3, 0.05mg/kg at months 6, 12 and 18), plus calcium and vitamin D, compared with calcium and vitamin D alone Main outcome measures Change in lumbar spine (LS) BMD raw and Z-score by dual energy absorptiometry x-ray (DXA) at 12 and 24 months, secondary outcomes assessing mobility, fracture incidence, bone turnover, pQCT and pain scores Results At 12 and 24 months, mean difference in changes of LSBMD Z-score from baseline was 1.2 SD (95% CI: 0.9-1.5), higher by 19.3% (14.6-24.0) and 1.4 SD (0.9-1.9), higher by 26.0% (17.4-34.5) in ZA compared to control arms respectively (both p < 0.001). Five controls developed Genant 3 vertebral fractures, 0 in the ZA arm. Mobility, pain and bone turnover markers were similar between arms at 12 and 24 months Trabecular BMC and vBMD pQCT at radius and tibia were greater at 12 months in the ZA cohort compared to control; difference remaining at 24 months for radius. Conclusion ZA improved BMD in glucocorticoid dependent DMD boys. Whilst the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture.

BackgroundATL1102 is a 2’MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4. ATL1102 inhibits expression of CD49d on lymphocytes, thereby reducing their survival, activation and migration to sites of inflammation. Children with Duchenne muscular dystrophy (DMD) have dystrophin deficient muscles. These are 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.MethodsThis 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. Participants receiving corticosteroid therapy were allowed into the study if on a stable dose for at least 3 months. 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.ResultsATL1102 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 eight (mean change -0.56×109/L 95%CI -1.52, 0.40), week twelve (mean change -0.53×109/L 95%CI -1.65, 0.58) or week twenty-four (mean change -0.28×109/L 95%CI -1.10, 0.55) 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 0.40×109/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.ConclusionATL1102, 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.

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