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.

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.

Randomized Controlled Trial Evaluating the Use of Zoledronic Acid in Duchenne Muscular Dystrophy.

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. METHODS: Two arm, parallel, randomized controlled trial, set in pediatric hospitals across Australia and New Zealand. Sixty-two (31 per arm) boys with glucocorticoid-dependent DMD between 6 and 16 years were included. Five ZA infusions (0.025 mg/kg at months 0, and 3, and 0.05 mg/kg at months 6, 12, and 18), plus calcium and vitamin D, were compared with calcium and vitamin D alone. The main outcome measures were 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, peripheral quantitative computerized (pQCT) and pain scores. RESULTS: At 12 and 24 months, mean difference in changes of LS BMD 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 than control arms respectively (both P < .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 than control; the evidence for this difference remained at 24 months for radius but not tibia. CONCLUSION: ZA improved BMD in glucocorticoid-dependent DMD boys. Although the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture.

Radiographic features of SARS in paediatric patients: a review of cases in Singapore.

INTRODUCTION: Severe acute respiratory syndrome (SARS) is a newly emerged atypical pneumonia caused by the SARS-associated coronavirus (SARS-CoV). Chest radiographic appearances have been reported as non-specific, ranging from normal to peribronchial thickening and ill-defined airspace shadowing. This study is a retrospective review of chest radiographic findings in children with suspected and probable SARS during the 2003 outbreak in Singapore. MATERIALS AND METHODS: We focused on children admitted to the SARS treatment ward from March 2003 to May 2003. Chest radiographs of children admitted with suspected or probable SARS as well as other febrile illness during this period were retrospectively and independently reviewed by 3 radiologists. The radiographs were randomised and anonymised before interpretation. Subsequently, we identified the radiographs of patients who were categorised as suspected or probable SARS. We present our findings in these patients' radiographs. RESULTS: A total of 67 patients' serial chest radiographs were interpreted. Of these, we subsequently selected those patients with suspected or probable SARS for analysis. The radiographic abnormalities in suspected or probable SARS patients consisted of patchy ground glass opacities or patchy airspace consolidation. The abnormalities had a predominantly lower zone distribution on chest radiographs, followed by mid-zone involvement. There was a slight preponderance of peripheral zone involvement. There was equal distribution of abnormalities in both lungs. All the children with radiographic abnormalities made uneventful recoveries and had normal radiographs on follow-up review. CONCLUSIONS: In children, SARS appears to have a relatively mild and nonspecific pattern of respiratory illness. The radiographic features in children with suspected or probable SARS in our study were comparable to other clusters of paediatric patients during initial presentation. It is difficult to distinguish SARS in children from other viral pneumonias on radiographic features alone. Positive travel history to endemic regions or positive contact history, and laboratory findings of lymphopaenia, leukopaenia and thrombocytopaenia are important clues.