221P DYNE-101 用于 1 型肌营养不良症（DM1）成人患者的初步试验数据

IF 2.7 4区医学 Q2 CLINICAL NEUROLOGY

Neuromuscular Disorders Pub Date : 2024-10-01 DOI:10.1016/j.nmd.2024.07.072

D. Wolf , J. Lilleker , G. Bassez , J. Diaz-Manera , J. Kools , M. Pane , R. Roxburgh , B. Schoser , C. Turner , C. Mix , S. Ray , B. Han , W. Farwell , V. Sansone

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引用次数: 0

摘要

DM1是一种剪接病，由DMPK RNA中的CUG重复序列扩增引起，会导致多系统临床表现。DYNE-101 是一种用于治疗 DM1 的试验性疗法，由 TfR1 结合 Fab 与针对突变核 DMPK RNA 设计的 ASO 连接组成，以纠正剪接。DYNE-101对成人（18-49岁）的安全性和疗效正在1/2期ACHIEVE试验（NCT05481879）中进行研究。在本次分析中，ACHIEVE 的 MAD 部分中，1.8 mg/kg（近似 ASO）剂量队列中的 16 名参与者拥有随访 6 个月（6M）的疗效数据，3.4 mg/kg 剂量队列中的 16 名参与者拥有随访 3M 的活检数据。参与者被随机分配接受DYNE-101（6人）或安慰剂（4人）Q4W治疗，或接受两剂DYNE-101治疗，然后在MAD期间的剩余时间接受安慰剂治疗（6人）。安全性和耐受性基于截至数据截止日参加ACHIEVE的45名参与者。在3M时，1.8和3.4 mg/kg DYNE-101分别显示出平均10.0 ng/g和21.5 ng/g ASO浓度、平均25%和40%的DMPK基因敲除率以及平均13%和19%的剪接校正基线。6M时，1.8 mg/kg DYNE-101显示平均16%的DMPK基因敲除，CASI较基线变化+7%，肌张力改善3.8秒，MDHI（患者报告结果）改善。3/5的可评估参与者在3M时进行了剪接校正，并持续到6M。在 3.4 毫克/千克的组群中，5/5 的可评估参与者在 3 毫秒时出现了拼接校正。截至数据截止日，DYNE-101的安全性状况良好，大多数TEAE为轻度或中度，肝肾参数或治疗引起的贫血没有发生有临床意义的变化。DYNE-101 的初步数据显示，ASO 的剂量依赖性递送、DMPK 基因敲除和剪接校正具有持久效果。在测试的最低剂量下，肌张力也得到了改善。这些数据支持继续开发用于治疗 DM1 的 DYNE-101。

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221P Initial data from the achieve trial of DYNE-101 in adults with myotonic dystrophy type 1 (DM1)

DM1 is a spliceopathy caused by expansion of CUG repeats in the DMPK RNA that leads to multisystem clinical manifestations. DYNE-101, an investigational therapeutic for treatment of DM1, consists of a TfR1-binding Fab conjugated to an ASO designed against mutant nuclear DMPK RNA to correct splicing. The safety and efficacy of DYNE-101 in adults (18-49 years old) are being investigated in the Phase1/2 ACHIEVE trial (NCT05481879). For this analysis, 16 participants had efficacy data through 6 months (6M) of follow-up in the 1.8 mg/kg (approximate ASO) dose cohort and 16 participants had biopsy data through 3M of follow-up in the 3.4 mg/kg dose cohort of the MAD portion of ACHIEVE. Participants were randomized to receive DYNE-101 (n=6) or placebo (n=4) Q4W, or two doses of DYNE-101 followed by placebo for the remainder of the MAD period (n=6). Safety and tolerability are based on 45 participants enrolled in ACHIEVE as of the data cut-off date. At 3M, 1.8 and 3.4 mg/kg DYNE-101 showed mean 10.0 ng/g and 21.5 ng/g ASO concentration, mean 25% and 40% DMPK knockdown, and mean 13% and 19% splicing correction from baseline, respectively. At 6M, 1.8 mg/kg DYNE-101 showed mean 16% DMPK knockdown, +7% CASI change from baseline, 3.8-second improvement in myotonia, and improvement in MDHI, a patient-reported outcome. 3/5 evaluable participants had splicing correction at 3M, persisting through 6M. In the 3.4 mg/kg cohort, 5/5 evaluable participants had splicing correction at 3M. DYNE-101 had a favorable safety profile as of the data cut-off date, with mostly mild or moderate TEAEs and no clinically meaningful changes in kidney and liver parameters or treatment-emergent anemia. The initial data with DYNE-101 demonstrated dose-dependent ASO delivery, DMPK knockdown, and splicing correction with durable effect. Improvement in myotonia was also observed at the lowest dose tested. The data support the continued development of DYNE-101 for the treatment of DM1.

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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.