Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR

被引：1130

作者：

Wainwright, C. E. ^{[1
]}

Elborn, J. S. ^{[2
]}

Ramsey, B. W. ^{[5
,6
]}

Marigowda, G. ^{[7
]}

Huang, X. ^{[7
]}

Cipolli, M. ^{[8
]}

Colombo, C. ^{[9
]}

Davies, J. C. ^{[3
,4
]}

De Boeck, K. ^{[10
]}

Flume, P. A. ^{[11
]}

Konstan, M. W. ^{[12
]}

McColley, S. A. ^{[15
]}

Mccoy, K. ^{[13
,14
]}

McKone, E. F. ^{[16
,17
]}

Munck, A. ^{[18
]}

Ratjen, F. ^{[19
]}

Rowe, S. M. ^{[20
]}

Waltz, D. ^{[7
]}

Boyle, M. P. ^{[21
]}

机构：

[1] Univ Queensland, Sch Med, Brisbane, Qld, Australia

[2] Queens Univ Belfast, Belfast, Antrim, North Ireland

[3] Royal Brompton & Harefield NHS Fdn Trust, London, England

[4] Univ London Imperial Coll Sci Technol & Med, London, England

[5] Seattle Childrens Hosp, Seattle, WA USA

[6] Univ Washington, Sch Med, Seattle, WA USA

[7] Vertex Pharmaceut, Boston, MA USA

[8] Azienda Osped Univ Integrata, Cyst Fibrosis Ctr, Verona, Italy

[9] Univ Milan, Osped Maggiore Policlinico, Fdn IRCCS Ca Granda, Milan, Italy

[10] Univ Hosp Gasthuisberg, Leuven, Belgium

[11] Med Univ S Carolina, Charleston, SC USA

[12] Case Western Reserve Univ, Sch Med, Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA

[13] Nationwide Childrens Hosp, Dept Pediat, Div Pulm, Columbus, OH USA

[14] Ohio State Univ, Columbus, OH 43210 USA

[15] Northwestern Univ, Stanley Manne Childrens Res Inst, Feinberg Sch Med, Chicago, IL 60611 USA

[16] St Vincents Univ Hosp, Dublin 4, Ireland

[17] Univ Coll Dublin, Sch Med, Dublin 2, Ireland

[18] Univ Paris 07, AP HP, Hop Robert Debre, Paediat Gastroenterol & Resp Dept,CF Ctr, Paris, France

[19] Univ Toronto, Hosp Sick Children, Div Resp Med, Dept Pediat Physiol & Expt Med, Toronto, ON M5G 1X8, Canada

[20] Univ Alabama Birmingham, Birmingham, AL USA

[21] Johns Hopkins Med, Baltimore, MD USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2015年 / 373卷 / 03期

基金：

美国国家卫生研究院;

关键词：

TRANSMEMBRANE CONDUCTANCE REGULATOR; PSEUDOMONAS-AERUGINOSA; POTENTIATOR IVACAFTOR; IN-VITRO; F508DEL-CFTR; MUTATION; EFFICACY; SAFETY; STABILITY;

D O I：

10.1056/NEJMoa1409547

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is the most common CFTR mutation. METHODS We conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects 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 had cystic fibrosis and were homozygous for the Phe508del CFTR mutation. In both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary end point was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV 1) at week 24. RESULTS A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV 1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor-ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV 1 ranged from 2.6 to 4.0 percentage points (P< 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P< 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor-ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor-ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor-ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. CONCLUSIONS These data show that lumacaftor in combination with ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.

引用

页码：220 / 231

页数：12

共 33 条

[1]

[Anonymous], 2002, MOL GEN EP CYST FIBR, P24

[2]

[Anonymous], 2010, EUR CYST FIBR PAT RE

[3] A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial [J].

Boyle, Michael P. ;

Bell, Scott C. ;

Konstan, Michael W. ;

McColley, Susanna A. ;

Rowe, Steven M. ;

Rietschel, Ernst ;

Huang, Xiaohong ;

Waltz, David ;

Patel, Naimish R. ;

Rodman, David .

LANCET RESPIRATORY MEDICINE, 2014, 2 (07) :527-538

[4] Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice [J].

Castellani, C. ;

Cuppens, H. ;

Macek, M., Jr. ;

Cassinian, J. J. ;

Kerern, E. ;

Durie, P. ;

Tullis, E. ;

Assael, B. M. ;

Bombieri, C. ;

Brown, A. ;

Casals, T. ;

Claustres, M. ;

Cutting, G. R. ;

Dequeker, E. ;

Dodge, J. ;

Doull, I. ;

Farrell, P. ;

Ferec, C. ;

Girodon, E. ;

Johannesson, M. ;

Kerem, B. ;

Knowles, M. ;

Munck, A. ;

Pignatti, P. F. ;

Radojkovic, D. ;

Rizzotti, P. ;

Schwarz, M. ;

Stuhnnann, M. ;

Tzetis, M. ;

Zielenski, J. ;

Elborn, J. S. .

JOURNAL OF CYSTIC FIBROSIS, 2008, 7 (03) :179-196

[5] Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis [J].

Cholon, Deborah M. ;

Quinney, Nancy L. ;

Fulcher, M. Leslie ;

Esther, Charles R., Jr. ;

Das, Jhuma ;

Dokholyan, Nikolay V. ;

Randell, Scott H. ;

Boucher, Richard C. ;

Gentzsch, Martina .

SCIENCE TRANSLATIONAL MEDICINE, 2014, 6 (246)

[6] 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 [J].

Clancy, J. P. ;

Rowe, Steven M. ;

Accurso, Frank J. ;

Aitken, Moira L. ;

Amin, Raouf S. ;

Ashlock, Melissa A. ;

Ballmann, Manfred ;

Boyle, Michael P. ;

Bronsveld, Inez ;

Campbell, Preston W. ;

De Boeck, Kris ;

Donaldson, Scott H. ;

Dorkin, Henry L. ;

Dunitz, Jordan M. ;

Durie, Peter R. ;

Jain, Manu ;

Leonard, Anissa ;

Mccoy, Karen S. ;

Moss, Richard B. ;

Pilewski, Joseph M. ;

Rosenbluth, Daniel B. ;

Rubenstein, Ronald C. ;

Schechter, Michael S. ;

Botfield, Martyn ;

Ordonez, Claudia L. ;

Spencer-Green, George T. ;

Vernillet, Laurent ;

Wisseh, Steve ;

Yen, Karl ;

Konstan, Michael W. .

THORAX, 2012, 67 (01) :12-18

[7]

Cystic Fibrosis Foundation, 2012, PAT REG ANN DAT REP

[8] Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation [J].

Davies, Jane C. ;

Wainwright, Claire E. ;

Canny, Gerard J. ;

Chilvers, Mark A. ;

Howenstine, Michelle S. ;

Munck, Anne ;

Mainz, Jochen G. ;

Rodriguez, Sally ;

Li, Haihong ;

Yen, Karl ;

Ordonez, Claudia L. ;

Ahrens, Richard .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2013, 187 (11) :1219-1225

[9] Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation [J].

De Boeck, Kris ;

Munck, Anne ;

Walker, Seth ;

Faro, Albert ;

Hiatt, Peter ;

Gilmartin, Geoffrey ;

Higgins, Mark .

JOURNAL OF CYSTIC FIBROSIS, 2014, 13 (06) :674-680

[10] A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis [J].

Elkins, MR ;

Robinson, M ;

Rose, BR ;

Harbour, C ;

Moriarty, CP ;

Marks, GB ;

Belousova, EG ;

Xuan, W ;

Bye, PTP .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (03) :229-240

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