Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.
Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.
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DOI：
10.1161/circulationaha.113.008285
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发表时间：
2014-07-01
期刊：
影响因子：
37.8
通讯作者：
Progeria Clinical Trials Collaborative
中科院分区：
文献类型：
--
作者：
Gordon LB;Massaro J;D'Agostino RB Sr;Campbell SE;Brazier J;Brown WT;Kleinman ME;Kieran MW;Progeria Clinical Trials Collaborative
Hutchinson-Gilford早衰综合征是一种极罕见的节段性过早衰老疾病，可导致心脏病发作或中风导致早期死亡。目前还没有批准的治疗方法，但从2007年开始，最近的几项单臂临床试验已经给予了蛋白质法尼基化的抑制剂，旨在降低致病蛋白质早老蛋白的毒性。没有研究评估治疗是否影响患者的生存。该分析所需的关键要素是稳健的自然生存史，并与足够大的患者人群进行比较，这些患者人群已接受足够长时间的疾病靶向药物治疗。我们对迄今为止最大的未经治疗的Hutchinson-Gilford早衰综合征队列进行了生存Kaplan-Meier生存分析。平均生存期为14.6年。比较治疗组与年龄和性别匹配的未治疗组的生存率，风险比为0.13（95%CI 0.04-0.37; P<0.001），自治疗开始后中位随访时间为5.3年。未接受治疗的受试者中有21/43例死亡，而接受治疗的受试者中有5/43例死亡。治疗使平均生存期延长了1.6年。这项研究提供了一个强大的未经治疗的疾病生存谱，可以用于现在和未来的比较，以评估HGPS治疗后生存的变化。目前的比较估计增加生存与蛋白法尼基化抑制剂提供了第一个证据的治疗影响这种致命性疾病的生存。标识符：NCT 00425607、NCT 00879034和NCT 00916747。
Hutchinson-Gilford progeria syndrome is an ultra-rare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single arm clinical trials have administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study has assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. We generated survival Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age-and-gender-matched untreated cohorts, hazard ratio was 0.13 (95% CI 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21/43 deaths in untreated versus 5/43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. This study provides a robust untreated disease survival profile, which can be utilized for comparisons now and in the future to assess changes in survival with treatments for HGPS. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. www.clinicaltrials.gov. Indentifiers: NCT00425607, NCT00879034 and NCT00916747.