Paparella Gabriella, Stragà Cristina, Pesenti Nicola, Dal Molin Valentina, Martorel Gian Antonio, Merotto Vasco, Genova Cristina, Piazza Arianna, Piccoli Giuseppe, Panzeri Elena, Rufini Alessandra, Testi Roberto, Martinuzzi Andrea
Department of Conegliano, Scientific Institute IRCCS E. Medea, 31015 Conegliano, Treviso, Italy.
Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, 20126 Milan, Milan, Italy.
Children (Basel). 2024 Aug 9;11(8):958. doi: 10.3390/children11080958.
A drug repositioning effort supported the possible use of the anti-HIV drug etravirine as a disease-modifying drug for Friedreich ataxia (FRDA). Etravirine increases frataxin protein and corrects the biochemical defects in cells derived from FRDA patients. Because of these findings, and since etravirine displays a favorable safety profile, we conducted a pilot open-label phase 2 clinical trial assessing the safety and potential efficacy of etravirine in FRDA patients.
Thirty-five patients were stratified into three severity groups and randomized to etravirine 200 mg/day or 400 mg/day. They were treated for 4 months. Safety endpoints were the number and type of adverse events and number of dropouts. Efficacy endpoints were represented by changes in peak oxygen uptake and workload as measured by incremental exercise test, SARA score, cardiac measures, measures of QoL and disability. Data were collected 4 months before the start of the treatment (T - 4), at the start (T0), at the end (T4) and 4 months after the termination of the treatment (T + 4).
Etravirine was reasonably tolerated, and adverse events were generally mild. Four months of etravirine treatment did not significantly increase the peak oxygen uptake but was associated with a change in the progression of the SARA score ( value < 0.001), compared to the 4 months pre- and post-treatment. It also significantly increased peak workload ( value = 0.021). No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug.
In this open trial etravirine treatment was safe, reasonably well tolerated and appreciably improved neurological function and exercise performance. Even though a placebo effect cannot be ruled out, these results suggest that etravirine may represent a potential therapeutic agent in FRDA deserving testing in a randomized placebo-controlled clinical trial.
一项药物重新定位研究支持抗艾滋病毒药物依曲韦林可能作为治疗弗里德赖希共济失调（FRDA）的病情改善药物。依曲韦林可增加 frataxin 蛋白并纠正 FRDA 患者来源细胞中的生化缺陷。基于这些发现，且由于依曲韦林显示出良好的安全性，我们开展了一项开放性 2 期临床试验，评估依曲韦林在 FRDA 患者中的安全性和潜在疗效。
35 名患者被分为三个严重程度组，并随机分为每日服用 200 毫克或 400 毫克依曲韦林组。他们接受了 4 个月的治疗。安全性终点指标为不良事件的数量和类型以及退出研究的人数。疗效终点指标由递增运动试验测量的峰值摄氧量和工作量变化、SARA 评分、心脏指标、生活质量和残疾程度测量值来表示。在治疗开始前 4 个月（T - 4）、开始时（T0）、结束时（T4）以及治疗结束后 4 个月（T + 4）收集数据。
依曲韦林耐受性良好，不良事件一般较轻。与治疗前和治疗后的 4 个月相比，4 个月的依曲韦林治疗并未显著增加峰值摄氧量，但与 SARA 评分进展的变化相关（P 值<0.001）。它还显著增加了峰值工作量（P 值 = 0.021）。未观察到心脏指标的变化。健康和生活质量指标在停药时显示恶化。
在这项开放性试验中，依曲韦林治疗是安全的，耐受性较好，并且明显改善了神经功能和运动表现。尽管不能排除安慰剂效应，但这些结果表明依曲韦林可能是 FRDA 的一种潜在治疗药物，值得在随机安慰剂对照临床试验中进行测试。
