Vanzacaftor–tezacaftor–deutivacaftor for children aged 6–11 years with cystic fibrosis (RIDGELINE Trial VX21-121-105): an analysis from a single-arm, phase 3 trial

The Lancet Respiratory Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

SummaryBackgroundIn phase 2 trials in people with cystic fibrosis aged 18 years and older, vanzacaftor–tezacaftor–deutivacaftor has been shown to be a safe effective, once-daily transmembrane conductance regulator (CFTR) modulator. Restoring normal CFTR function early life the potential prevent manifestations of fibrosis. We aimed evaluate safety, tolerability, efficacy, pharmacokinetics children 6–11 years.MethodsIn this multicentre, single-arm, 3 trial (RIDGELINE Trial VX21-121-105), participants were enrolled across 33 clinical sites that care for eight countries (Australia, France, Germany, Netherlands, Sweden, Switzerland, UK, USA). Eligible at least one elexacaftor–tezacaftor–ivacaftor-responsive variant, FEV1 % predicted 60% or higher, stable as determined by investigators. Before study treatment, either on elexacaftor–tezacaftor–ivacaftor 28 days before screening received combination 4-week run-in period. Participants then (<40 kg bodyweight: vanzacaftor 12 mg, tezacaftor 60 deutivacaftor 150 mg orally three fixed-dose tablets once daily; ≥40 20 100 250 two daily (manufactured Patheon Pharmaceuticals, Cincinnati, OH, USA) from day 1 24 weeks. The primary endpoint was safety measured adverse events, vital signs, laboratory values, electrocardiograms, pulse oximetry. Endpoints analysed all who dose vanzacaftor–tezacaftor–deutivacaftor. This is registered ClinicalTrials.gov, NCT05422222, evaluation 6–11-year-old cohort complete.FindingsBetween Feb 6 May 18, 2023, 83 screened, whom five not eligible, 78 6-11 Median age 9·3 (IQR 7·6–10·4), 34 (44%) female, 44 (56%) male, 71 (91%) White, (1%) Black African American, multiple races. analysis these data completed Dec 15, 2023. exposure 168 166–170). 75 (96%) had which mild moderate; most common events generally consistent manifestations, including, cough (36 [46%]), pyrexia (16 [21%]), headache (14 [18%]), infective pulmonary exacerbation (13 [17%]), oropharyngeal pain [17%]). Serious occurred six (8%) (two exacerbation, also failure thrive; participant each adenovirus infection, constipation, test decreased, cough), discontinued due fatigue considered possibly related drug.InterpretationVanzacaftor–tezacaftor–deutivacaftor well tolerated maintained baseline further improved function. Improvements compared values demonstrate opportunity restore physiology development progression Nearly sweat chloride below diagnostic threshold cytstic (<60 mmol/L) more than half levels (<30 mmol/L). Additional long-term are being collected an open-label extension benefits safety. These findings will inform health-care providers regarding initiation modulators.FundingVertex Pharmaceuticals.

Language: Английский

---

Cystic fibrosis: new challenges and perspectives beyond elexacaftor/tezacaftor/ivacaftor

Therapeutic Advances in Respiratory Disease, Journal Year: 2025, Volume and Issue: 19

Published: March 1, 2025

Over the past decade, major clinical advances have been made in healthcare and therapeutic development for cystic fibrosis (CF), a lethal genetic disease caused by mutations gene encoding CF transmembrane conductance regulator (CFTR) protein. CFTR modulators represent innovative treatments that directly target primary defects mutated protein demonstrated significant benefits many people with (pwCF) who are eligible these treatments. In particular, triple combination therapy composed of elexacaftor, tezacaftor, ivacaftor (ETI) has changed landscape significantly improving lung function, quality life, predicted survival rates. Here, we provided comprehensive summary impact ETI on outcomes need further research long-term efficacy, side effects, pregnancy, possible drug–drug interactions, extra-pulmonary manifestations. Moreover, number pwCF unresponsive to drugs or cannot afford their high costs. We, therefore, discussed health inequity issues alternative strategies under aiming obtain effective therapies all pwCF.

Language: Английский

---

Intestinal current measurement detects age-dependent differences in CFTR function in rectal epithelium

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 24, 2025

Intestinal current measurement (ICM) provides a sensitive bioassay for assessment of cystic fibrosis transmembrane conductance regulator (CFTR) function in rectal biopsies ex vivo and is used as diagnostic tool (CF). Furthermore, ICM was shown to be detect pharmacological rescue CFTR by modulators people with CF carrying responsive mutations. Results from clinical trials across age groups indicate that the sweat duct may age-dependent children reaching higher levels than adults. However, little known about dependency intestinal epithelium. We investigated CFTR-mediated chloride secretion 258 without 72 pancreatic-insufficient 1 month 68 years age. Change transepithelial short-circuit response cyclic adenosine monophosphate (cAMP)-mediated (100 μM IBMX, µM forskolin, basolateral) cholinergic carbachol, stimulation assessed readout using perfused micro-Ussing chambers. quantitative real-time PCR morphometric analysis epithelial cells lining crypts surface mucosa were performed assess regulation at gene expression cell densities. found tissues, determined cAMP-mediated well chloride-secretory responses highest during infancy early childhood declined (both P < 0.001). Although, there no difference currents CF, potassium-secretory induced also reduced increasing Transcript analyses showed mRNA slightly increased (P 0.05). Morphometric demonstrated expressing colonocytes crypt base decreased A secondary data our previous studies on effects lumacaftor/ivacaftor F508del -homozygous aged 12 older 2-11 year old correlations change secretory 0.01 0.05, respectively). These results demonstrate epithelium this likely due decline number base. findings suggest differences explain functional modulator therapies compared adult CF.

Language: Английский

---

Perspectives in MicroRNA Therapeutics for Cystic Fibrosis

Non-Coding RNA, Journal Year: 2025, Volume and Issue: 11(1), P. 3 - 3

Published: Jan. 12, 2025

The discovery of the involvement microRNAs (miRNAs) in cystic fibrosis (CF) has generated increasing interest past years, due to their possible employment as a novel class drugs be studied pre-clinical settings therapeutic protocols for fibrosis. In this narrative review article, consider and comparatively evaluate published laboratory information development miRNA-based We miRNAs involved upregulation CFTR, inhibition inflammation and, finally, exhibiting antibacterial activity. suggest that antago-miRNAs ago-miRNAs (miRNA mimics) can proposed validation settings.

Language: Английский

---

Psychometric validation of the Cystic Fibrosis Impact Questionnaire (CF-IQ): A patient-reported outcome assessing impacts of cystic fibrosis

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0317775 - e0317775

Published: Jan. 24, 2025

The Cystic Fibrosis (CF) Impact Questionnaire (CF-IQ) was qualitatively developed to assess the impact of CF in context treatment advancements and increased longevity. This study reports CF-IQ validation. In this noninterventional validation study, people with completed 40-item validating patient-reported outcome measures (PROMs) via electronic diaries at enrollment (baseline) 4-week follow-up. Validation consisted modern methods focus groups finalize structural validity, classical internal consistency [1–3], test-retest reliability [4,5], concurrent validity [5], known-groups [5] CF-IQ. At baseline, 214 adults survey; 193 follow-up survey. Unidimensional item response theory (IRT) models were separately fit 5 prespecified domains (Control Burden Treatment Impacts, Physical Activity Social Emotional Work/School Limitation Impacts). IRT local dependence (LD) statistics identified 17 redundant items. Two independent CF-patient (14 total patients) confirmed these findings, items dropped. Each domain defined on final 23 achieved criterion exact model as measured by root mean squared error approximation (RMSEA, values = 0), Internal (Cronbach’s α) ranged from 0.81 0.89, 4 acceptable reliability, intraclass correlation coefficient (ICC) ≥ 0.7, for all domains, established. novel is a psychometrically robust PROM capturing patient-centric impacts current standard care.

Language: Английский

---

Airways and Inhalational Lung Disease

IDKD Springer series, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 11

Published: Jan. 1, 2025

Language: Английский

---

How Effectively Can Oxidative Stress and Inflammation Be Reversed When CFTR Function Is Pharmacologically Improved?

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 310 - 310

Published: March 4, 2025

A critical challenge in the age of advanced modulator therapies is to understand and determine how effectively chronic oxidative stress stress-induced inflammation can be reversed physiological balance restored when CFTR function pharmacologically improved. The triple therapy with elexacaftor-tezacaftor-ivacaftor (ETI) suggests that activity individuals at least one F508del mutation partially about 50% normal levels. Although incomplete, partial recovery has been shown drastically lower sputum pathogen content, enhance microbiome diversity, markers within first year treatment adolescents adults cystic fibrosis. However, despite these advancements, residual airway infection, persist, levels similar other lung conditions, like non-CF bronchiectasis. This persistence highlights necessity for innovative antioxidant anti-inflammatory treatments, particular disease. To address this issue, emerging multi-omics technologies offer valuable tools investigate impact on various molecular pathways. By analyzing changes gene expression, epigenetic modifications, protein profiles metabolic processes airway-derived samples, it could possible uncover mechanisms driving persistent inflammation. These insights pave way identifying new therapeutic targets fully restore health overall balance.

Language: Английский

---

Elexacaftor/Tezacaftor/Ivacaftor Efficacy in a Cohort of Italian Patients with CFTR Rare Mutations

International Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 5(1), P. 11 - 11

Published: March 10, 2025

Background: Cystic Fibrosis is an inherited disorder caused by mutations in the Transmembrane conductance Regulator (CFTR) gene, encoding a chloride and bicarbonate channel widely expressed epithelia. Loss of CFTR function leads to dehydration epithelium surface with thicker mucus secretions from tissues. The lungs, pancreas, liver, intestines, sweat glands are most common affected organs. However, pulmonary disease remains main cause morbidity mortality. Fortunately, elexacaftor/tezacaftor/ivacaftor (ETI) therapy showing unprecedented clinical benefits patients (CF) carrying at least one F508del mutation gene. almost 35% CF population living Mediterranean area still lacks effective modulator therapies because elevated incidence (pw)CF harboring rare (RMs), different F508del. Methods: Twenty-three pwCF RM including N1303K underwent off-label ETI treatment for 6-12 months. Respiratory terms FEV1 FVC was measured after 3, 6, 12 months treatment. In addition, we analyzed concentration, body mass index (BMI), quality life before Possible adverse effects were recorded. Results: All included this program displayed substantial improvement respiratory function. particular, showed similar that observed subjects mutation, although concentration not significantly decreased. No severe effect reported. Conclusions: This study strengthens efficacy other variants. Since these RMs have been approved Europe, may promote inclusion variants list responsive ETI.

Language: Английский

---

Cystic fibrosis–related kidney disease—emerging morbidity and disease modifier

Pediatric Nephrology, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Abstract Cystic fibrosis (CF) is a life-shortening multisystem disease resulting from mutations in the cystic transmembrane conductance regulator (CFTR) gene, causing most devastating phenotypes airway and pancreas. Significant advances treatment for CF lung disease, including expanded use of high-efficiency modulator therapies (HEMT) such as Trikafta, have dramatically increased both quality life expectancy people with (PwCF). With these advances, long-term extrapulmonary manifestations are more frequently recognized. Pseudo-Barter syndrome, acute kidney injury (AKI) induced by medications or dehydration, amyloidosis, nephrolithiasis, IgA diabetic nephropathies been previously reported PwCF. Newer data suggest that chronic (CKD) new morbidity aging population, affecting 19% over age 55. CKD carries high risk premature death cardiovascular complications. Studies CFTR dysfunction increases kidneys’ vulnerability to caused downstream effects CF. Improving mutant function HEMT may help tease apart responses extrinsic factors those intrinsically related gene mutations. Additionally, given novelty approaches, potential off-target their currently unknown. We review evolving complications PwCF propose term CF-related disease. hope this will increase awareness about changing phenotype prevent condition. Graphical abstract

Language: Английский

---

The established chest MRI score for cystic fibrosis can be applied to contrast agent-free matrix pencil decomposition functional MRI: a multireader analysis

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: March 18, 2025

Established morpho-functional chest magnetic resonance imaging (MRI) detects abnormalities in lung morphology and perfusion people with cystic fibrosis (pwCF) using a dedicated scoring system. Functional assessment is performed contrast-enhanced (CE) MRI. Novel matrix pencil decomposition MRI (MP-MRI) contrast agent-free alternative, but further validation of this technique needed. The aim study was to evaluate the applicability validated score for CE MP multireader approach. Twenty-seven pwCF (mean age 20.8 years, range 8.4-45.7 years) underwent including same examination. Nine blinded radiologists different experience levels assessed applied CE- MP-MRI. Inter-reader agreement scores MP-MRI were compared each other score. Differences according readers' also analyzed. overall lower than (6.2 ± 3.3 vs. 6.9 2.0; p < 0.05) strong correlation between both (r = 0.74; 0.01). intraclass coefficient (ICC) as measure inter-reader good significant scores, higher (0.75, 0.001) (0.61, 0.001). Bland-Altman analysis revealed difference more extreme values 0.62, showed moderate 0.73, 0.01) 0.55, We did not find radiological level. established can be novel interreader reliability. remaining may explained by lack routine visual favor an automated use noninvasive outcome measure.

Language: Английский

---