Summary of participant demographics.

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.

### 背景
ATL1102是一款针对极晚活化抗原4（VLA-4）CD49d α亚基的2’-甲氧基乙基（2’MOE）间隙型反义寡核苷酸，可抑制淋巴细胞表面CD49d的表达，降低淋巴细胞的存活、活化及向炎症部位迁移的能力。杜氏肌营养不良（Duchenne Muscular Dystrophy, DMD）患者的肌肉缺乏肌营养不良蛋白，易受收缩诱导性损伤，该损伤会激活免疫系统，进而加重肌肉损伤。CD49d是DMD的疾病严重程度生物标志物：即使接受糖皮质激素治疗，高表达CD49d的T细胞数量增多仍与更严重、进展更快的肌无力相关。
### 方法
本项2期开放标签试验纳入9名年龄10~18岁的非卧床杜氏肌营养不良男孩，以每周25mg的剂量皮下注射ATL1102，持续24周，评估ATL1102的安全性、有效性及药代动力学特征。试验主要目标为评估ATL1102的安全性与耐受性，次要目标包括：ATL1102对血液淋巴细胞数量的影响、通过上肢功能测试（Performance of Upper Limb test, PUL 2.0）评估的上肢功能变化，以及使用MyoGrip与MyoPinch测量的上肢力量，上述指标均与基线水平进行对比。
### 结果
9名参与者中有8名接受稳定剂量的糖皮质激素治疗。ATL1102整体安全性良好，耐受性佳，未报告严重不良事件，亦无受试者退出试验。最常见的不良事件为注射部位红斑与皮肤色素改变。从基线至给药第8、12、24周，淋巴细胞计数未出现统计学显著变化；但在末次给药后4周（第28周），CD3+CD49d+ T淋巴细胞数量较第24周显著升高（平均变化量0.40×10^9/L，95%置信区间0.05~0.74；p=0.030）。通过PUL2.0、EK2、Myoset握力与捏力测量的肌肉功能强度，以及前臂肌肉的MRI脂肪分数，在整个试验周期内均保持稳定。
### 结论
ATL1102作为一款新型反义药物，开发用于治疗加重杜氏肌营养不良患者肌纤维损伤的炎症，在非卧床杜氏肌营养不良男孩中显示出良好的安全性与耐受性。试验期间评估的多项肌肉疾病进展参数均呈现明显的稳定效果，支持ATL1102用于杜氏肌营养不良治疗的后续开发。
### 试验注册
临床试验注册：澳大利亚新西兰临床试验注册中心编号：ACTRN12618000970246。