Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2–5 Years with Cystic Fibrosis and at Least One <i>F508del</i> Allele

Goralski, Jennifer L.; Hoppe, Jordana E.; Mall, Marcus; McColley, Susanna A.; McKone, Edward F.; Ramsey, Bonnie; Rayment, Jonathan H.; Robinson, Phil; Stehling, Florian; Taylor‐Cousar, Jennifer L.; Tullis, Elizabeth; Ahluwalia, Neil; Chin, Anna; Chu, Chenghao; Lu, Mengdi; Niu, Tao; Weinstock, Tanya G.; Ratjen, Félix; Rosenfeld, Margaret

doi:10.1164/rccm.202301-0084oc

Cited by 47 publications

(20 citation statements)

References 29 publications

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“…Ivacaftor and its combination CFTR modulator were generally well tolerated and had similar safety profiles in phase 3 studies involving younger age groups (Table 2). Compared with placebo, elexacaftor-tezacaftor-ivacaftor had a similar incidence of adverse events (93.1% vs 96.1%) including headache (17%), upper respiratory tract infection (16%), abdominal pain (14%), diarrhea (13%), exanthem (10%), increased alanine transaminase (10%), or aspartate transaminase (9%) . Serious adverse events were less common in the treatment group (13.9% vs 20.9%) .…”

Section: Discussion and Observationsmentioning

confidence: 97%

“…Elexacaftor-tezacaftor-ivacaftor is approved for patients aged 2 years or older; approximately 90% of people with cystic fibrosis, including for those with variants that have demonstrated in vitro culture response to treatment . This technique known as theratyping has increased access to therapy with modulator drugs among people with rare (<1%) CFTR variants …”

Section: Discussion and Observationsmentioning

confidence: 99%

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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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Section: Discussion and Observationsmentioning

confidence: 97%

Section: Discussion and Observationsmentioning

confidence: 99%

Cystic Fibrosis

Ong

Ramsey

2023

JAMA

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“…Recently, two clinical trials documented the safety and efficacy of ETI in children ≥6 years with at least one F508del mutation ( Zemanick et al, 2021 ; Mall et al, 2022 ). More recently, the results of the phase 3 open label trial including children aged 2–5 years taking ETI therapy were published ( Goralski et al, 2023 ), demonstrating a significant improvement in LCI 25 as well as reduced sweat chloride concentrations after 24 weeks of treatment. Outside clinical studies, compliance regarding the reliable drug intake is less closely monitored and as such more likely to be variable than under study conditions.…”

Section: Discussionmentioning

confidence: 99%

Real-life impact of highly effective CFTR modulator therapy in children with cystic fibrosis

et al. 2023

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Introduction: Recently, cystic fibrosis transmembrane regulator modulator therapy with elexacaftor/tezacaftor/ivacaftor has become available for children with cystic fibrosis (CF) carrying at least one F508del mutation.Objective: To assess the intermediate term effects of elexacaftor/tezacaftor/ivacaftor in children with cystic fibrosis in a real-world setting.Methods: We performed a retrospective analysis of records of children with cystic fibrosis, who started elexacaftor/tezacaftor/ivacaftor between 8/2020 and 10/2022. Pulmonary function tests, nutritional status, sweat chloride and laboratory data were assessed before, 3 and 6 months after the start of elexacaftor/tezacaftor/ivacaftor respectively.Results: Elexacaftor/tezacaftor/ivacaftor was started in 22 children 6–11 years and in 24 children 12–17 years. Twenty-seven (59%) patients were homozygous for F508del (F/F) and 23 (50%) patients were transitioned from ivacaftor/lumacaftor (IVA/LUM) or tezacaftor/ivacaftor (TEZ/IVA) to elexacaftor/tezacaftor/ivacaftor. Overall, mean sweat chloride concentration decreased by 59.3 mmol/L (95% confidence interval: −65.0 to −53.7 mmol/L, p < 0.0001) under elexacaftor/tezacaftor/ivacaftor. Sweat chloride concentration also decreased significantly after transition from IVA/LUM or TEZ/IVA to elexacaftor/tezacaftor/ivacaftor (−47.8 mmol/l; 95% confidence interval: −57.6 to −37.8 mmol/l, n = 14, p < 0.0001). Sweat chloride reduction was more marked in children with the F/F than in those with the F/MF genotype (69.4 vs 45.9 mmol/L, p < 0.0001). At 3 months follow-up, body-mass-index-z-score increased by 0.31 (95% CI, 0.2–0.42, p < 0.0001) with no further increase at 6 months. BMI-for-age-z-score was more markedly improved in the older group. Overall pulmonary function (percent predicted FEV1) at 3 months follow-up increased by 11.4% (95% CI: 8.0–14.9, p < 0.0001) with no further significant change after 6 months. No significant differences were noted between the age groups. Children with the F/MF genotype had a greater benefit regarding nutritional status and pulmonary function tests than those with the F/F genotype. Adverse events led to elexacaftor/tezacaftor/ivacaftor dose reduction in three cases and a temporary interruption of therapy in four cases.Conclusion: In a real-world setting, elexacaftor/tezacaftor/ivacaftor therapy had beneficial clinical effects and a good safety profile in eligible children with cystic fibrosis comparable to previously published data from controlled clinical trials. The positive impact on pulmonary function tests and nutritional status seen after 3 months of elexacaftor/tezacaftor/ivacaftor therapy was sustained at 6 months follow-up.

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“…Positive changes in BMI z‐scores from baseline were also noted after 24 weeks (Δ 0.29) 68 and 96 weeks (Δ 0.27) 69 of lumacaftor/ivacaftor in children 2–5 years, whereas, in toddlers aged 1 to ≤ 2 years on lumacaftor/ivacaftor for 24 weeks, BMI z ‐score was maintained compared to baseline (Δ 0.04) 70 . ETI has led to significant gains in weight and BMI in the tested populations of patients, 71,72 including children aged 6–11 years in whom BMI z ‐score increased on average by 0.37 after 24 weeks of therapy 73 whereas, in younger children (2–5 years) on ETI for 24 weeks, BMI z ‐score remained stable (Δ 0.10) 74 . Consistent with results from ivacaftor studies, initiation of dual therapies or ETI in toddlers, 70 preschoolers 68,69,75 and older children 67,73,74,76–78 led to minimal changes in height z ‐scores from baseline values, which, on average, were close to normal for age.…”

Section: From Early Life To Childhoodmentioning

confidence: 93%

“…ETI has led to significant gains in weight and BMI in the tested populations of patients, 71,72 including children aged 6–11 years in whom BMI z ‐score increased on average by 0.37 after 24 weeks of therapy 73 whereas, in younger children (2–5 years) on ETI for 24 weeks, BMI z ‐score remained stable (Δ 0.10) 74 . Consistent with results from ivacaftor studies, initiation of dual therapies or ETI in toddlers, 70 preschoolers 68,69,75 and older children 67,73,74,76–78 led to minimal changes in height z ‐scores from baseline values, which, on average, were close to normal for age. These findings suggest that the use of modulators does not noticeably impact linear growth, which maintains its age‐appropriate trajectory.…”

Section: From Early Life To Childhoodmentioning

confidence: 99%

Nutritional management of people living with cystic fibrosis throughout life and disease continuum: Changing times, new challenges

Mailhot

Denis

Beauchamp‐Parent

et al. 2023

J Human Nutrition Diet

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Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding for the ion channel cystic fibrosis transmembrane conductance regulator (CFTR). The management of CF disease has evolved in recent decades from treating downstream disease manifestations affecting the airways, the lungs and the gastrointestinal system to addressing the CFTR gene defect. The advent of CFTR modulators, which correct the functionality of the defective CFTR, contributes to reshaping the landscape of CF demographics, prognosis and therapies, including nutritional management. A spectrum of clinical manifestations is emerging within the same patient population where undernutrition and nutritional deficiencies coexist with excessive weight gain and metabolic derangements. Such contrasting presentations challenge current practices, require adjustments to traditional approaches, and involve more individualised interventions. This narrative review examines the current state of knowledge on the nutritional management of people living with cystic fibrosis from early life to adulthood in the era of CFTR modulation.

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Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2–5 Years with Cystic Fibrosis and at Least One F508del Allele

Cited by 47 publications

References 29 publications

Cystic Fibrosis

Cystic Fibrosis

Real-life impact of highly effective CFTR modulator therapy in children with cystic fibrosis

Nutritional management of people living with cystic fibrosis throughout life and disease continuum: Changing times, new challenges

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