Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.
Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.
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DOI：
10.1136/thoraxjnl-2011-200393
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发表时间：
2012-01
期刊：
影响因子：
10
通讯作者：
Konstan MW
中科院分区：
文献类型：
--
作者：
Clancy JP;Rowe SM;Accurso FJ;Aitken ML;Amin RS;Ashlock MA;Ballmann M;Boyle MP;Bronsveld I;Campbell PW;De Boeck K;Donaldson SH;Dorkin HL;Dunitz JM;Durie PR;Jain M;Leonard A;McCoy KS;Moss RB;Pilewski JM;Rosenbluth DB;Rubenstein RC;Schechter MS;Botfield M;Ordoñez CL;Spencer-Green GT;Vernillet L;Wisseh S;Yen K;Konstan MW
囊性纤维化跨膜电导调节剂VX-809在体外可增加功能性F508del-CFTR的细胞表面密度。一项随机、双盲、安慰剂对照研究评估了VX-809在F508del-CFTR突变纯合子成年囊性纤维化患者(n=89)中的安全性、耐受性和药效学。受试者被随机分为四个VX-809 28天剂量组(25、50、100和200毫克)或匹配的安慰剂。在接受VX-809和安慰剂治疗的受试者中，不良事件的类型和发生率相似。呼吸事件是最常见的报道，并导致每个积极治疗组中有一名受试者停止治疗。药代动力学数据支持每日一次的口服给药方案。药效学数据表明，VX-809改善了至少一个器官(汗腺)的CFTR功能。VX-809以剂量依赖的方式降低升高的汗氯化物值(p=0.0013)，这在100mg组和200mg组具有统计学意义。以鼻电势差衡量，鼻腔上皮CFTR功能没有统计学意义的改善，肺功能或患者报告的结果也没有统计学上的显著变化。在提供直肠活检标本的亚组中，未成熟的F508del-CFTR未检测到成熟。在这项研究中，在F508del-CFTR纯合子患者中，VX-809与安慰剂28天的副作用相似，并显示出生物活性，对汗腺中的CFTR功能有积极影响。需要更多的数据来确定在汗腺中检测到的VX-809之后CFTR功能的改善如何与呼吸道中可测到的改善和临床益处的长期措施相关联。临床试验编号NCT00865904
VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. Clinical trial number NCT00865904
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DOI：
10.1164/ajrccm.163.7.2004001
发表时间：
2001-06-01
影响因子：
24.7
作者：
Clancy, JP;Bobök, Z;Bedwell, DM
通讯作者：
Bedwell, DM
影响因子：
9.6
作者：
Quittner, Alexandra L.;Modi, Avani C.;Montgomery, A. Bruce
通讯作者：
Montgomery, A. Bruce
DOI：
10.1513/pats.200703-043br
发表时间：
2007-08-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Rowe, Steven M;Accurso, Frank;Clancy, John P
通讯作者：
Clancy, John P
DOI：
10.1073/pnas.0904709106
发表时间：
2009-11-03
影响因子：
11.1
作者：
Van Goor, Fredrick;Hadida, Sabine;Negulescu, Paul
通讯作者：
Negulescu, Paul
影响因子：
6.8
作者：
Rowe, Steven M.;Clancy, John P.
通讯作者：
Clancy, John P.