Oral splicing modulator branaplam in Huntington's disease: a phase 2 randomized controlled trial.

Branaplam, an orally available HTT messenger RNA splicing modulator, reduces HTT protein levels in vitro and in animal models, and is the first splicing modulator to be evaluated in individuals with HD.

Branaplam是一种口服可用的HTT信使RNA剪接调节剂，已在体外和动物模型中降低HTT蛋白水平，并且是首个在HD患者中进行评估的剪接调节剂。

Here we present the design and results of VIBRANT-HD, a randomized phase 2b study of branaplam in HD, along with preclinical findings in nonhuman primates.

在这里，我们展示了VIBRANT-HD的设计和结果，这是一项针对亨廷顿病(HD)的branaplam随机2b期研究，以及在非人灵长类动物中的临床前发现。

VIBRANT-HD utilized an innovative study design informed by our preclinical data, including targeted safety monitoring measures (for example, neurofilament light chain measurements in blood, nerve conduction studies), and staggered cohorts to capture potential neurotoxic effects early.

VIBRANT-HD采用了一种创新的研究设计，该设计基于我们的临床前数据，包括针对性的安全监测措施（例如血液中的神经丝轻链测量、神经传导研究）以及分阶段的队列，以便早期捕捉潜在的神经毒性效应。

Of the 21 participants in the initial cohort receiving branaplam 56 mg weekly, 18 (85.7%) showed at least one sign or symptom of peripheral neuropathy.

在最初接受每周56毫克branaplam治疗的21名参与者中，有18人（85.7%）表现出至少一种周围神经病变的体征或症状。

This safety signal, along with dose-modeling results triggered the early termination of VIBRANT-HD.

这一安全信号，连同剂量建模结果，触发了VIBRANT-HD的早期终止。

The primary outcome, a decrease in cerebrospinal fluid mutant HTT levels versus placebo, was summarized descriptively, making branaplam the first splicing modulator to lower mutant HTT levels in the cerebrospinal fluid of individuals with HD.

主要结果是与安慰剂相比，脑脊液中突变型HTT水平的降低，这是首次有剪接调节剂在亨廷顿病患者中降低脑脊液中的突变型HTT水平。

Increased neurofilament light chain levels observed in most participants reversed after treatment discontinuation.

大多数参与者观察到的神经丝轻链水平增加，在治疗停止后逆转。

ClinicalTrials.gov identifier: NCT05111249.

临床试验注册号：NCT05111249。