New England Journal of Medicine (NEJM)发布了Vertex的ORKAMBITM(lumacaftor/ivacaftor)联合用药治疗囊性纤维化的二期试验结果。这一1108病人参与的试验显示lumacaftor和ivacaftor联合用药能显著提高病人的生存质量，可望延长病人生命预期。

囊性纤维化为一种罕见的遗传性疾病，在北美，欧洲和澳洲有约75000患者。囊性纤维化通常由基因突变引起细胞膜上囊性纤维化跨膜传导调节蛋白(cysticfibrosis transmembrane conductance regulatory protein, CFTR)缺陷或缺失所致。这一蛋白缺陷或缺失导致盐和水跨膜流动障碍，异常粘厚的粘液在肺脏堆积，引起慢性感染和进行性肺损伤。通常这种疾病只能对症处理，包括稀释粘液便于咳出，预防和治疗感染等举措。但效果不佳，病人的预期寿命在34到47岁间，平均死亡年龄（中位数）只有20多。

CFTR突变类型较多，现在发现的有超过1900种，最常见为F508del形式。F508del蛋白不能在细胞内正常加工运输，从而导致细胞膜上这一蛋白数量现状降低或缺失。该项试验针对年龄12岁及以上F508del的囊性纤维化病人，采用lumacaftor和ivacaftor的联合应用。Lumacaftor和ivacaftor都是直接针对致病机制的药物，前者针对蛋白处理和运输缺陷，后者加强细胞表面CFTR蛋白的功能。这一研究发现经24周的联合用药，能改善患者肺功能，因药物对肠道粘液也其作用，治疗过程患者体重也得到改善。

这一研究结果令人兴奋，有望成为治疗囊性纤维化的基本治疗举措。

Cystic fibrosis is a rare,life-threatening genetic disease affecting approximately 75,000 people in NorthAmerica, Europe and Australia.

http://www.nejm.org/doi/full/10.1056/NEJMoa1409547

BACKGROUND

Cystic fibrosis is a life-limitingdisease that is caused by defective or deficient cystic fibrosis transmembraneconductance regulator (CFTR) protein activity. Phe508del is the most commonCFTR mutation.

METHODS

We conducted two phase 3, randomized,double-blind, placebo-controlled studies that were designed to assess theeffects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor(VX-770), a CFTR potentiator, in patients 12 years of age or older who hadcystic fibrosis and were homozygous for the Phe508del CFTRmutation. In bothstudies, patients were randomly assigned to receive either lumacaftor (600 mgonce daily or 400 mg every 12 hours) in combination with ivacaftor (250 mgevery 12 hours) or matched placebo for 24 weeks. The primary end point was theabsolute change from baseline in the percentage of predicted forced expiratoryvolume in 1 second (FEV1) at week 24.

RESULTS

A total of 1108 patients underwentrandomization and received study drug. The mean baseline FEV1 was 61% of thepredicted value. In both studies, there were significant improvements in theprimary end point in both lumacaftor–ivacaftor dose groups; the differencebetween active treatment and placebo with respect to the mean absoluteimprovement in the percentage of predicted FEV1 ranged from 2.6 to 4.0percentage points (P<0.001), which corresponded to a mean relative treatmentdifference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate ofpulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groupsthan in the placebo group; the rate of events leading to hospitalization or theuse of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups aswell. The incidence of adverse events was generally similar in thelumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to anadverse event was 4.2% among patients who received lumacaftor–ivacaftor versus1.6% among those who received placebo.

CONCLUSIONS

These data show that lumacaftor incombination with ivacaftor provided a benefit for patients with cystic fibrosishomozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticalsand others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers,NCT01807923 andNCT01807949.)

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