转甲状腺素蛋白(TTR)相关的淀粉样变性(ATTR)是一种破坏性疾病,会影响包括心脏和周围神经在内的器官组合,如果在平均10年内不治疗,会有致命的结果。Tafamidis,或2-(3,5-二氯-苯基)-苯并恶唑-6-羧酸,以负协同性选择性结合TTR,并在动力学上稳定野生型天然TTR和突变型TTR;因此,tafamidis具有终止由TTR四聚体解离引发的淀粉样蛋白级联的潜力,单体折错,和聚合。第一次tafamidis审判,Fx-005,评估了18个月的tafamidis治疗(每天一次20mg)对疾病进展的影响,以及评估其在TTR-FAPVal30Met患者中的安全性。该试验的次要目的是研究突变的TTR的药效学稳定性。Tafamidis被证明可以有效减少神经病的进展,以及维持1期(无需支持即可行走)Val3OMetTTR-FAP患者的营养状况和生活质量。此外,超过90%的患者实现了TTR稳定。一项扩展研究,进行Fx-006,以确定tafamidis的长期安全性和耐受性,并评估药物对减缓疾病进展的功效。没有发现明显的安全性或耐受性问题。一起来看,两项试验的结果表明,tafamidis的有益作用持续了30个月,因此需要尽早开始治疗.一项扩展的开放标签研究有望获得结果,但已经提供的数据表明,Val30Met患者长期使用tafamidis与多发性神经病的进展减少有关。Tafamidis最初于2011年在欧洲被批准用于商业用途,此后已被批准在日本使用,墨西哥,和阿根廷,它被用作早期TTR-FAP患者的一线治疗选择。在转诊中心应仔细跟踪患者,以确定个体对治疗的反应。在停药的情况下,肝移植和纳入主要旨在抑制TTR产生的新药的临床试验是选择。
Transthyretin (TTR)-related amyloidosis (ATTR) is a devastating disease which affects a combination of organs including the heart and the peripheral nerves, and which has a fatal outcome if not treated within a average of 10 years. Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-type native TTR and mutant TTR; tafamidis therefore has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation. The first tafamidis trial, Fx-005, evaluated the effect of 18 months of tafamidis treatment (20 mg once daily) on disease progression, as well as assessing its safety in TTR-FAP Val30Met patients. The secondary objective of this trial was to study the pharmacodynamic stabilization of mutated TTR. Tafamidis proved effective in reducing the progress of neuropathy, and in maintaining the nutritional status and quality of life of stage 1 (able to walk without support) Val3OMet TTR-FAP patients. Furthermore, TTR stabilization was achieved in more than 90% of patients. An extension study, Fx-006, was conducted to determine the long-term safety and tolerability of tafamidis and to assess the efficacy of the drug on slowing disease progression. No significant safety or tolerability issues were noticed. Taken together, the results from both trials indicated that the beneficial effects of tafamidis were sustained over a 30-month period and that starting treatment early is desirable. Results are expected from an extended open-label study but data that have already been presented show that long-term use of tafamidis in Val30Met patients is associated with reduced progression in polyneuropathy. Tafamidis was initially approved for commercial use in Europe in 2011 and has since been approved for use in Japan, Mexico, and Argentina where it is used as a first-line treatment option for patients with early-stage TTR-FAP. Patients should be carefully followed at referral centers to ascertain the individual response to treatment. In cases of discontinuation, liver transplantation and enrollment in clinical trials of novel drugs aimed mostly toward suppression of TTR production are options.