Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study

McNamara, John J.; McColley, Susanna A.; Marigowda, Gautham; Liu, Fang; Tian, Simon; Owen, Caroline A.; Stiles, David; Li, Chonghua; Waltz, David A.; Wang, Linda T.; Sawicki, Gregory S.

doi:10.1016/s2213-2600(18)30460-0

Cited by 110 publications

(105 citation statements)

References 25 publications

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“…Moreover, an observational study measured certain CFTR biomarkersnasal potential differences and intestinal current measurementsand demonstrated that co-treatment with lumacaftor/ivacaftor results in partial correction of F508del-CFTR function to similar levels of the lower range of CFTR activity usually observed in patients with residual function mutations (Graeber et al, 2018). More recently, co-treatment with lumacaftor/ivacaftor has been extended for F508delhomozygous patients aged ≥2 years after phase III clinical trials demonstrating safety and efficacy in younger patients (Milla et al, 2017;Ratjen et al, 2017;McNamara et al, 2019). A clinical trial has also evaluated the effects of lumacaftor/ ivacaftor in patients carrying A455E in at least one allele (NCT03061331), since this mutation has demonstrated an increase in CFTR PM abundance and function after corrector treatments in cell models (Dekkers et al, 2016a;Dekkers et al, 2016b;Lopes-Pacheco et al, 2016).…”

Section: Correctors: Rescuing the Protein Folding Processing And Trmentioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Section: Correctors: Rescuing the Protein Folding Processing And Trmentioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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“…LCI, measured as an optional endpoint, improved, but failed to reach statistical significance. 32 The drug combination was generally safe and well tolerated in this age group.…”

Section: Lumacaftor Plus Ivacaftormentioning

confidence: 82%

Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis

Cuyx

Boeck

2019

Semin Respir Crit Care Med

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Detailed knowledge of how mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disturb the trafficking or function of the CFTR protein and the use of high-throughput drug screens have allowed novel therapeutic strategies for cystic fibrosis (CF). The main goal of treatment is slowly but surely shifting from symptomatic management to targeting the underlying CFTR defect to halt disease progression and even to prevent occurrence of CF complications. CFTR potentiators for patients with class III mutations, mutation R117H (and in United States also for patients with specific residual function mutations) and the combination of a CFTR modulator plus a potentiator for patients homozygous for F508del, are the two classes of modulators that are in use in the clinic. Approval of these therapeutics has progressively expanded to include both younger patients and a wider range of CFTR mutations. For a significant proportion of patients with CF, current treatment is however still insufficient or unavailable.This review provides an overview of the clinical trial results and the real-life efficacy data of approved CFTR modulators. In addition, we discuss the entire pipeline of CFTR modulators: novel potentiators and correctors, amplifiers, stabilizers, and read-through agents. Furthermore, we discuss other strategies to improve CFTR function like nonsense-mediated decay inhibitors, modified transfer ribonucleic acids, antisense oligonucleotides, and genetic therapies.CFTR modulators are already changing the face of CF and the pipeline of new therapies continues to be exciting.

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“…In 2018, results of a study of infants 12 to < 24 months old led to its approval in this age group . Similarly, lumacaftor/ivacaftor for F508del homozygotes was first approved in 2015, and after interim studies in ages 6 to 11 years were extended to ages 2 to 5 years in 2018 . Interestingly, the uptake for prescription of these two medicines differed.…”

Section: Cftr Modulatorsmentioning

confidence: 99%

“…1 Similarly, lumacaftor/ivacaftor for F508del homozygotes was first approved in 2015, and after interim studies in ages 6 to 11 years were extended to ages 2 to 5 years in 2018. 2 Interestingly, the uptake for prescription of these two medicines differed. Using the CF Foundation Patient Registry (CFFPR), the uptake for ivacaftor prescriptions in patients with G551D was 64% within 6 months and 80% within 1…”

Section: Cftr Modulatorsmentioning

confidence: 99%

“…Lumacaftor/ivacaftor demonstrated safety, tolerability and efficacy in 57 patients 2 to 5 years of age homozygous for deltaF508 mutation, with improvements in sweat chloride, fecal elastase, and immunoreactive trypsinogen. 2 Growth parameters were maintained at normal for age. No changes were seen in microbiology, FEV1pp, and lung clearance index.…”

Section: Lumacaftor/ivacaftormentioning

confidence: 99%

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Cystic fibrosis year in review 2018, part 1

Savant

McColley

2019

Pediatric Pulmonology

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Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study

Cited by 110 publications

References 25 publications

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis

Cystic fibrosis year in review 2018, part 1

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