Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, LC, Italy.
Department of Neurosciences, Santobono-Pausilipon Children's Hospital, Naples, NA, Italy.
Drug Des Devel Ther. 2024 Nov 6;18:5023-5040. doi: 10.2147/DDDT.S383133. eCollection 2024.
Trofinetide is a first-in-class pharmacological treatment proposed for patients with Rett Syndrome. It is a long half-life derivative of glycine-proline-glutamate, the tripeptide normally excided from Insulin-like Growth Factor 1 upon degradation. Due to containing glutamate and glycine in its structure, trofinetide is thought to act through NMDA receptor modulation, thus providing a normalization of neuronal activity and survival. Trofinetide was tested in a series of short and long-term trials, showing good efficacy at improving scores on the Clinical Global Impression-Improvement scale and Rett Syndrome Behavior Questionnaire, with specific effect only on some subscales, ie General Mood subscale and Repetitive Face Movement subscale. No effects were documented on other subscales or on epilepsy, heart and bone -related symptoms. The main adverse effects of trofinetide, severe enough to determine discontinuation, include diarrhea, vomiting, and consequent weight loss. These may be scarcely avoidable, given the need to assume a very large amount of trofinetide per day. Other inherent limitations of use possibly regard the limited duration of drug supplies, as one bottle may last three days only, depending on weight, and the relatively high cost per bottle. Trofinetide has no direct competitors: single symptoms of the Rett Syndrome, for instance, seizures or aggressive behaviors, are currently treated with drugs that have been developed for patients without the Rett Syndrome. This leads to suboptimal efficacy and increased risk of adverse effects. The place in therapy of trofinetide is yet to be determined, based on the results of clinical trials, on its practical usability, and on the windows of opportunity for intervention. Moreover, trofinetide may be curative if given early enough during brain development, or merely symptomatic if given to young adults, and no data exist on this aspect. The place in therapy of trofinetide will require reassessment after competing treatments enter the market.
曲非奈肽是一种首创的用于治疗雷特综合征的药物。它是甘氨酸-脯氨酸-谷氨酸的长半衰期衍生物，该三肽通常在胰岛素样生长因子 1 降解时被切除。由于其结构中含有谷氨酸和甘氨酸，曲非奈肽被认为通过 NMDA 受体调节起作用，从而提供神经元活动和存活的正常化。曲非奈肽在一系列短期和长期试验中进行了测试，显示在改善临床总体印象-改善量表和雷特综合征行为问卷评分方面有良好的疗效，仅对某些子量表有特定效果，即一般情绪子量表和重复面部运动子量表。在其他子量表或癫痫、心脏和骨骼相关症状方面没有记录到效果。曲非奈肽的主要不良反应严重到足以导致停药，包括腹泻、呕吐和随之而来的体重减轻。鉴于每天需要服用大量的曲非奈肽，这些不良反应可能难以避免。使用的其他固有限制可能涉及药物供应的有限持续时间，因为一瓶药可能仅根据体重持续三天，而且每瓶药的成本相对较高。曲非奈肽没有直接的竞争对手：例如雷特综合征的单一症状，如癫痫发作或攻击性行为，目前使用的药物是为没有雷特综合征的患者开发的。这导致疗效不佳和不良反应风险增加。根据临床试验结果、实际可用性以及干预的机会窗口，曲非奈肽在治疗中的地位尚待确定。此外，如果在大脑发育早期给予曲非奈肽，它可能具有治愈作用，如果给予年轻成年人，则可能只是对症治疗，而这方面没有数据。在竞争治疗药物进入市场后，曲非奈肽在治疗中的地位将需要重新评估。
