Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR : a randomised, placebo-controlled phase 3 trial

Ratjen, Félix; Hug, Christopher; Marigowda, Gautham; Tian, Simon; Huang, Xin; Stanojevic, Sanja; Robinson, Paul D.; Waltz, David A.; Davies, Jane C.; Rosenfeld, Margaret; Starner, Timothy D.; Retsch‐Bogart, George; Chmiel, James F.; Orenstein, David M.; Milla, Carlos; Rubenstein, Ronald C.; Walker, Seth; Cornell, Alexandra; Asfour, Fadi; Black, Philip; Colombo, John L.; Froh, D.; McColley, Susanna A.; Ruiz, Fadel; Quintero, Diana; Casey, Alicia; Mueller, Gary A.; Flume, Patrick A.; Livingston, F. R.; Rock, Michael J.; O’Sullivan, Brian; Schmidt, H. Joel; Lahiri, Thomas; McNamara, John J.; Chidekel, Aaron; Sass, Laura A.; Keens, Thomas G.; Schaeffer, David F.; Solomon, Melinda; Chilvers, Mark; Lands, Larry C.; Junge, S.; Griese, Matthias; Staab, Doris; Pressler, Tacjana; Koningsburggen-Rietschel, Silke van; Naehrlich, Lutz; Reid, Alastair; Balfour‐Lynn, Ian M.; Urquhart, Don S.; Lee, Timothy J.; Munck, À.; Sermet-Gaudelus, Isabelle; Boeck, Christiane De; Reix, Philippe; Malfroot, Anne; Bui, Stéphanie; Selvadurai, Hiranjan; Robinson, Philip; Wainwright, Claire; Clements, Barry; Hilton, Jodi; Hjelte, Lena

doi:10.1016/s2213-2600(17)30215-1

Cited by 264 publications

(246 citation statements)

References 36 publications

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“…The safety profile observed was similar to that during prior trials, except for a higher rate of transaminase elevations in these younger patients 19 , 20 . Recommendations for co-administration of lumacaftor-ivacaftor and strong CYP3A inhibitors have been modified to starting at lower than established dose, according to patient’s age, for the first week of treatment to allow for the steady-state induction effect of lumacaftor prior to increasing to the usual recommended daily dose 26 .…”

Section: Safety Evaluationsupporting

confidence: 55%

“…An open label study showed no statistically significant increase in ppFEV1, but showed improvement in lung clearance index (LCI), indicating reduction of ventilation inhomogeneity, a sensitive marker of small airways disease 19 . A larger placebo controlled study showed a significant increase in ppFEV1 compared to placebo, though on a similar scale to that in the open-label study, as well as improvement in LCI 20 .…”

Section: Clinical Applications Including Key Efficacy Datamentioning

confidence: 89%

“…Two phase III trials of lumacaftor 200 mg and ivacaftor 250 mg BID were conducted in children 6–11 years old 19 , 20 . The primary endpoint was safety.…”

Section: Clinical Applications Including Key Efficacy Datamentioning

confidence: 99%

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The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis

Guevara

McColley

2017

Expert Opinion on Drug Safety

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Introduction: Lumacaftor-ivacaftor is indicated for treatment of cystic fibrosis (CF) in patients homozygous for the Phe-508del cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. In clinical trials, treated patients showed improved pulmonary function, reduced pulmonary exacerbations, and other benefits. This article reviews safety of this therapy. Areas covered: Safety findings in ivacaftor, lumacaftor and combined therapy trials, and reported subsequently through post-approval evaluation, were accessed by PubMed and Google searches using key words “VX-770”, “ivacaftor”, “VX-809”, and “lumacaftor”. Transaminitis was seen in ivacaftor and combination trials. Non-congenital cataracts were seen in pre-clinical animal studies and in children taking ivacaftor and combined therapy. Dyspnea occurs in some patients taking lumacaftor and combined therapy and usually resolves without stopping treatment. Lumacaftor is a strong inducer of CYP3A while ivacaftor is a CYP3A sensitive substrate. Combination therapy can decrease systemic exposure of medications that are substrates of CYP3A, decreasing therapeutic effect. Co-administration of lumacaftor-ivacaftor with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index is not recommended. Expert opinion: Lumacaftor-ivacaftor therapy may be associated with ocular and hepatic side effects. Specific recommendations for monitoring are available. Dyspnea occurs, especially during initiation of treatment. Potential drug interactions should be evaluated in patients taking combination therapy. The risk benefit ratio of lumacaftor-ivacaftor favors therapy.

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Section: Safety Evaluationsupporting

confidence: 55%

Section: Clinical Applications Including Key Efficacy Datamentioning

confidence: 89%

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The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis

Guevara

McColley

2017

Expert Opinion on Drug Safety

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“…Early intervention to minimise the chronic loss of lung function and potentially increase survival are essential, and thus there is a need for early childhood studies of lumacaftor‐ivacaftor. Studies have now been performed in children aged 6–11 years, resulting in change of approval overseas to include children down to age 6 years . In that study, children in the active arm were dosed with lumacaftor 200 mg/ivacaftor 250 mg every 12 h for 24 weeks.…”

Section: Cftr Modulator Therapymentioning

confidence: 99%

“…LCI is said to be a more sensitive measure of lung function than spirometry in reflecting early abnormalities in the smaller airways and is calculated using a multiple‐breathe inert gas washout . In addition to decreases in LCI (which is a positive effect), children in the active group showed decreases in sweat chloride and maintained spirometric lung function where available . Of interest was the observation of increased faecal elastase, suggesting partial restoration of pancreatic function, as has been observed with ivacaftor monotherapy .…”

Section: Cftr Modulator Therapymentioning

confidence: 99%

Cystic fibrosis: novel therapies, remaining challenges

Coulthard

2018

Pharmacy Practice and Res

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Developments in the treatment of cystic fibrosis (CF) over the past 50 years have seen survival extend from death in the first decade of life to an expected median survival now approaching 50 years of age. Adults with CF now outnumber children, a dramatic shift if one considers that many adult CF clinics were only established in the 1980s. Together with speciality multidisciplinary clinics, new medicines and their aggressive application have played a pivotal role in this achievement. Although there is still no clinically available cure, novel therapies targeting the underlying basic defects have resulted in major beneficial clinical outcomes and quality of life for those living with CF, albeit at significant cost. Although this review concentrates on currently available novel pharmacological therapies, the important role of potential ‘cures’, such as gene therapy, must not be overlooked. The complex drug interactions of the new agents, the need for detailed patient education and research opportunities in CF in general support the role of the specialist pharmacist in CF clinics.

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Cystic Fibrosis

Ong

Ramsey

2023

JAMA

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ImportanceCystic fibrosis, a genetic disorder defined by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects more than 30 000 individuals in the US and approximately 89 000 worldwide. Absent or decreased function of the CFTR protein is associated with multiorgan dysfunction and shortened life expectancy.ObservationsCFTR is an anion channel in the apical membrane of epithelial cells. Loss of function leads to obstructed exocrine glands. Of people with cystic fibrosis in the US, approximately 85.5% have the gene variant F508del. Manifestations of cystic fibrosis in patients with the F508del gene variant begin in infancy with steatorrhea, poor weight gain, and respiratory symptoms (coughing, wheezing). As people with cystic fibrosis age, chronic respiratory bacterial infections cause loss of lung function and bronchiectasis. With the availability of universal newborn screening in multiple countries including the US, many people with cystic fibrosis are asymptomatic at diagnosis. With multidisciplinary care teams that included dietitians, respiratory therapists, and social workers, treatment of cystic fibrosis can slow disease progression. Median survival has improved from 36.3 years (95% CI, 35.1-37.9) in 2006 to 53.1 years (95% CI, 51.6-54.7) in 2021. Pulmonary therapies for patients with cystic fibrosis consist of mucolytics (eg, dornase alfa), anti-inflammatories (eg, azithromycin), and antibiotics (such as tobramycin delivered by a nebulizer). Four small molecular therapies, termed CFTR modulators, that facilitate CFTR production and/or function have received regulatory approval. Examples are ivacaftor and elexacaftor-tezacaftor-ivacaftor. For example, in patients with 1 F508del variant, the combination of ivacaftor, tezacaftor, and elexacaftor improved lung function from −0.2% in the placebo group to 13.6% (difference, 13.8%; 95% CI, 12.1%-15.4%) and decreased the annualized estimated rate of pulmonary exacerbations from 0.98 to 0.37 (rate ratio, 0.37; 95% CI, 0.25-0.55). Improved respiratory function and symptoms have lasted up to 144 weeks in postapproval observational studies. An additional 177 variants are eligible for treatment with the elexacaftor-tezacaftor-ivacaftor combination.ConclusionCystic fibrosis affects approximately 89 000 people worldwide and is associated with a spectrum of disease related to exocrine dysfunction, including chronic respiratory bacterial infections and reduced life expectancy. First-line pulmonary therapies consist of mucolytics, anti-inflammatories, and antibiotics, and approximately 90% of people with cystic fibrosis who are 2 years or older may benefit from a combination of ivacaftor, tezacaftor, and elexacaftor.

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Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR : a randomised, placebo-controlled phase 3 trial

Abstract: Vertex Pharmaceuticals.

Cited by 264 publications

References 36 publications

The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis

The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis

Cystic fibrosis: novel therapies, remaining challenges

Cystic Fibrosis

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