Budimirovic Dejan B, Dominick Kelli C, Gabis Lidia V, Adams Maxwell, Adera Mathews, Huang Linda, Ventola Pamela, Tartaglia Nicole R, Berry-Kravis Elizabeth
Department of Psychiatry, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, United States.
Department of Psychiatry and Behavioral Sciences-Child Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, United States.
Front Pharmacol. 2021 Oct 8;12:757825. doi: 10.3389/fphar.2021.757825. eCollection 2021.
Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200-trinucleotide repeat expansion in the 5' untranslated region of the fragile X mental retardation 1 () gene. Individuals with FXS can present with a range of neurobehavioral impairments including, but not limited to: cognitive, language, and adaptive deficits; ASD; anxiety; social withdrawal and avoidance; and aggression. Decreased expression of the γ-aminobutyric acid type A (GABA) receptor subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a -subunit-selective, extrasynaptic GABA receptor agonist that enhances GABAergic tonic inhibition, providing the rationale for assessment of OV101 as a potential targeted treatment of FXS. No drug is approved in the United States for the treatment of FXS. This 12-weeks, randomized (1:1:1), double-blind, parallel-group, phase 2a study was designed to assess the safety, tolerability, efficacy, and optimal daily dose of OV101 5 mg [once (QD), twice (BID), or three-times daily (TID)] when administered for 12 weeks to adolescent and adult men with FXS. Safety was the primary study objective, with key assessments including treatment-emergent adverse events (TEAEs), treatment-related adverse events leading to study discontinuation, and serious adverse events (SAEs). The secondary study objective was to evaluate the effect of OV101 on a variety of problem behaviors. A total of 23 participants with FXS (13 adolescents, 10 adults) with moderate-to-severe neurobehavioral phenotypes (Full Scale Intelligence Quotient, 41.5 ± 3.29; ASD, 82.6%) were randomized to OV101 5 mg QD ( = 8), 5 mg BID ( = 8), or 5 mg TID ( = 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection ( = 4), headache ( = 3), diarrhea ( = 2), and irritability ( = 2). No SAEs were reported. Improvements from baseline to end-of-treatment were observed on several efficacy endpoints, and 60% of participants were identified as treatment responders based on Clinical Global Impressions-Improvement. Overall, OV101 was safe and well tolerated. Efficacy results demonstrate an initial signal for OV101 in individuals with FXS. These results need to be confirmed in a larger, randomized, placebo-controlled study with optimal outcomes and in the most appropriate age group. www.ClinicalTrials.gov, identifier: NCT03697161.
脆性X综合征（FXS）是智力障碍和自闭症谱系障碍（ASD）最常见的单基因病因，由脆性X智力低下1（FMR1）基因5'非翻译区超过200个三核苷酸重复序列扩增所致。患有FXS的个体可出现一系列神经行为障碍，包括但不限于：认知、语言和适应性缺陷；ASD；焦虑；社交退缩和回避；以及攻击行为。γ-氨基丁酸A型（GABA）受体亚基表达降低和GABA能紧张性抑制不足可能与FXS的症状有关。加波沙朵（OV101）是一种亚基选择性、突触外GABA受体激动剂，可增强GABA能紧张性抑制，为评估OV101作为FXS潜在靶向治疗药物提供了理论依据。在美国，尚无药物被批准用于治疗FXS。这项为期12周的随机（1:1:1）、双盲、平行组2a期研究旨在评估FXS青少年和成年男性服用12周的5毫克OV101[每日一次（QD）、每日两次（BID）或每日三次（TID）]的安全性、耐受性、疗效和最佳日剂量。安全性是主要研究目标，关键评估包括治疗中出现的不良事件（TEAE）、导致研究停药的治疗相关不良事件以及严重不良事件（SAE）。次要研究目标是评估OV101对各种问题行为的影响。共有23名患有中度至重度神经行为表型（全量表智商，41.5±3.29；ASD，82.6%）的FXS参与者（13名青少年，10名成年人）被随机分为5毫克OV101 QD组（n = 8）、5毫克BID组（n = 8）或5毫克TID组（n = 7），为期12周。所有3种治疗方案中OV101的耐受性均良好。最常见的TEAE为上呼吸道感染（n = 4）、头痛（n = 3）、腹泻（n = 2）和易怒（n = 2）。未报告SAE。在几个疗效终点观察到从基线到治疗结束的改善，并且根据临床总体印象改善情况，60%的参与者被确定为治疗反应者。总体而言，OV101安全且耐受性良好。疗效结果表明OV101在FXS个体中初步显示出治疗信号。这些结果需要在一项更大规模、随机、安慰剂对照且具有最佳结果的研究以及最合适的年龄组中得到证实。ClinicalTrials.gov网站，标识符：NCT03697161。
