225P Initial data from the DELIVER trial of DYNE-251 in males with DMD Mutations amenable to Exon 51 skipping

IF 2.7 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders Pub Date : 2024-10-01 DOI:10.1016/j.nmd.2024.07.076

L. De Waele , C. Campbell , N. Deconinck , K. Flanigan , M. Lorentzos , H. Phan , P. Shieh , C. Mix , S. Ray , D. Wang , W. Farwell , A. Dugar , M. Naylor , M. Guglieri , DELIVER study investigators

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引用次数: 0

Abstract

Duchenne muscular dystrophy (DMD) is caused by absence of functional dystrophin protein. Approved PMO therapies induce exon skipping to restore the DMD mRNA reading frame leading to the production of truncated, functional dystrophin, but their potential is limited by poor muscle delivery. DYNE-251, an investigational therapeutic for DMD, consists of an exon 51-skipping PMO conjugated to a TfR1-targeting Fab to deliver increased levels of PMO to muscles. The safety and efficacy of DYNE-251 in ambulant and non-ambulant males aged 4-16 with DMD mutations amenable to exon 51 skipping are being studied in the Phase 1/2 DELIVER trial (NCT05524883). In the MAD portion of DELIVER, participants are randomized to receive DYNE-251 or placebo Q4W or Q8W for 6 months across 7 PMO dose levels up to 40 mg/kg. For analysis of exon skipping and dystrophin data from the 5 mg/kg cohort, 4 participants received DYNE-251 and 2 received placebo. Safety and tolerability are based on 37 participants enrolled in DELIVER as of the data cut-off date. At 6 months, 5 mg/kg DYNE-251 showed a mean 657 ng/g PMO concentration in muscle and mean absolute exon skipping level of 0.90% (0.80% difference from baseline). Mean absolute dystrophin level, measured by Western blot, increased from 0.60% at baseline to 0.88% of normal at 6 months, and the mean level of dystrophin positive fibers (PDPF) increased from 2.4% at baseline to 22.2% at 6 months. As of the data cut-off date, DYNE-251 demonstrated a favorable safety profile with mostly mild or moderate TEAEs. There was no treatment-emergent anemia or clinically meaningful changes in kidney parameters or electrolytes. Based on these initial data, DYNE-251 had a favorable safety profile and reached levels of dystrophin expression, exon skipping, and PDPF at 6 months that exceeded levels reported at the same time point in prior clinical trials evaluating the standard of care PMO. The data support the continued development of DYNE-251 for DMD.

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225P DELIVER试验的初步数据：DYNE-251治疗男性DMD突变患者。

杜氏肌营养不良症（DMD）是由于缺乏功能性肌营养不良蛋白所致。已获批准的 PMO 疗法可诱导跳过外显子，恢复 DMD mRNA 的阅读框，从而产生截短的功能性肌营养不良蛋白，但其潜力受到肌肉传递不良的限制。DYNE-251是一种用于DMD的试验性疗法，由外显子51跳越PMO与TfR1靶向Fab连接组成，可向肌肉输送更多的PMO。DELIVER 1/2期试验（NCT05524883）正在研究DYNE-251对4-16岁DMD突变适合跳过51号外显子的行动不便和非行动不便男性患者的安全性和疗效。在DELIVER的MAD部分，参与者被随机分配接受DYNE-251或安慰剂Q4W或Q8W，为期6个月，共7个PMO剂量水平，最高为40 mg/kg。在分析5 mg/kg组群的外显子跳越和肌营养不良蛋白数据时，4名参与者接受了DYNE-251治疗，2名参与者接受了安慰剂治疗。安全性和耐受性基于截至数据截止日参加 DELIVER 的 37 名参与者。6个月时，5毫克/千克DYNE-251在肌肉中的平均PMO浓度为657纳克/克，平均绝对外显子跳越水平为0.90%（与基线相比相差0.80%）。用 Western 印迹法测定的肌营养不良蛋白平均绝对水平从基线时的 0.60% 增加到 6 个月时正常值的 0.88%，肌营养不良蛋白阳性纤维（PDPF）的平均水平从基线时的 2.4% 增加到 6 个月时的 22.2%。截至数据截止日，DYNE-251显示出良好的安全性，大多数TEAE为轻度或中度。治疗过程中未出现贫血或肾脏参数或电解质发生有临床意义的变化。根据这些初步数据，DYNE-251 具有良好的安全性，在 6 个月时达到的肌营养不良蛋白表达、外显子跳越和 PDPF 水平超过了之前评估标准治疗 PMO 的临床试验在同一时间点所报告的水平。这些数据支持继续开发 DYNE-251 治疗 DMD。

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来源期刊

Neuromuscular Disorders 医学-临床神经学

CiteScore

4.60

自引率

3.60%

发文量

543

审稿时长

53 days

期刊介绍： This international, multidisciplinary journal covers all aspects of neuromuscular disorders in childhood and adult life (including the muscular dystrophies, spinal muscular atrophies, hereditary neuropathies, congenital myopathies, myasthenias, myotonic syndromes, metabolic myopathies and inflammatory myopathies). The Editors welcome original articles from all areas of the field: • Clinical aspects, such as new clinical entities, case studies of interest, treatment, management and rehabilitation (including biomechanics, orthotic design and surgery). • Basic scientific studies of relevance to the clinical syndromes, including advances in the fields of molecular biology and genetics. • Studies of animal models relevant to the human diseases. The journal is aimed at a wide range of clinicians, pathologists, associated paramedical professionals and clinical and basic scientists with an interest in the study of neuromuscular disorders.