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Cited by 100Cystic Fibrosis Research AdvancesPharmacogenetics and Drug MetabolismPharmacovigilance and Adverse Drug Reactions

Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study

Open access
Daines, Cori L., Tullis, Elizabeth, Costa, Stefano, Linnemann, Rachel W., Mall, Marcus A., McKone, Edward F., Polineni, Deepika, Quon, Bradley S. +15 more·2023·European Respiratory Journal
DOI 10.1183/13993003.02029-2022PMC PMC10701091
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Abstract

Background: In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. Methods: In this phase 3, open-label, single-arm extension study, participants with F508del –minimal function (from a 24-week parent study; n=399) or F508del – F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. Results: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV 1 ) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV 1 % pred was +0.07 (95% CI −0.12–0.26) percentage points among the participants. Conclusions: ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 192-week open-label extension of two phase 3 trials, elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was generally safe and well tolerated through a 144-week interim analysis in people with CF and at least one F508del allele. Improvements in lung function, respiratory symptoms, CFTR function, nutritional status, and pulmonary exacerbation rates were sustained, with no mean loss of pulmonary function over 144 weeks.

Key findings

  • Among 506 participants (F/MF n=399; F/F n=107), mean exposure was 151.1±33.7 weeks. Exposure-adjusted adverse event rates were lower than in the 24-week parent study active arm: 586.6 vs 1096.0 events per 100 participant-years for any AE, and 22.4 vs 36.9 events per 100 participant-years for serious AEs.
  • Most AEs were mild (16.4%) or moderate (60.3%); 14 participants (2.8%) had AEs leading to treatment discontinuation. One death occurred due to accidental oxycodone toxicity, considered unrelated to study drug.
  • At Extended Week 144, F/MF participants had mean absolute FEV1 % pred increases of 14.8 (95% CI 13.3–16.3) and 14.1 (95% CI 12.6–15.6) percentage points for prior placebo and prior ELX/TEZ/IVA, respectively; F/F participants had increases of 12.0 (95% CI 9.5–14.5) and 11.6 (95% CI 9.1–14.0) percentage points.
  • Sweat chloride decreased by −50.5 and −47.2 mmol·L−1 in F/MF groups and by −53.4 and −49.9 mmol·L−1 in F/F groups; CFQ-R respiratory domain scores increased by 17.6 and 19.1 points in F/MF and by 13.9 and 18.2 points in F/F. Annualised pulmonary exacerbation rates were 0.20 (95% CI 0.16–0.24) for F/MF and 0.18 (95% CI 0.12–0.26) for F/F. The pooled annualised rate of change in FEV1 % pred was +0.07 (95% CI −0.12–0.26) percentage points.

Methods

  • Phase 3, multicentre, open-label, single-arm extension study (Study 445-105; NCT03525574) enrolling participants ≥12 years with CF and F/MF or F/F genotypes who completed parent Studies 445-102 or 445-103. All received ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h.
  • Primary end-point was safety and tolerability; secondary end-points included absolute changes from parent study baseline in FEV1 % pred, sweat chloride concentration, CFQ-R respiratory domain score, BMI, and pulmonary exacerbations. A prespecified interim analysis was conducted when the last participant reached Week 144.
  • Efficacy analyses were separated by genotype and used mixed-effects models for repeated measures, negative binomial regression for exacerbations, and a post hoc linear mixed-effects model for annualised rate of change in FEV1 % pred.

Limitations

  • The paper states there was no direct comparator group, limiting interpretation of safety and efficacy data; comparisons were made with the placebo group from parent Study 445-102.
  • The paper states participants had to meet specific inclusion criteria for the pivotal trials, so extrapolation to all people with CF likely requires real-world studies.
  • Evident from the text: this is an open-label, single-arm interim analysis, and overlapping SARS-CoV-2 pandemic restrictions might have reduced pulmonary exacerbation incidence; the annualised FEV1 change analysis was post hoc.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1183/13993003.02029-2022

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

16 of 20 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In patients with the F/F genotype, ELX/TEZ/IVA improvements were superior to those seen with TEZ/IVA.

    “In patients with the F/F genotype, these improvements were superior to those seen with TEZ/IVA.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
  • Findingcitation

    During the first 144 weeks of this extension study, the estimated pulmonary exacerbation rate for patients with F/MF genotypes (0.20) was lower than in the ELX/TEZ/IVA arm of the 24-week parent study (0.37).

    “During the first 144 weeks of this extension study, the estimated pulmonary exacerbation rate for patients with F/MF genotypes (0.20) was lower than in the ELX/TEZ/IVA arm of the 24-week parent study (0.37) [18] and the rate of pulmonary exacerbations for participants in both genotype groups was lower than in the previous 24-week interim analysis of this extension study (0.19 versus 0.30) [23].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] source

      The parent study’s Methods describe a 24-week treatment period, and Results > Efficacy report fewer pulmonary exacerbations with ELX/TEZ/IVA. But the 0.37 reported there is the rate ratio versus placebo, not the treatment arm’s estimated exacerbation rate. This source also does not report the extension study’s first 144 weeks or its 0.20 rate (page not provided). (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Participants taking ELX/TEZ/IVA in the parent studies had steady and sustained increases in BMI.

    “Participants taking ELX/TEZ/IVA in the parent studies had steady and sustained increases in BMI [17, 18].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] source

      Results > Efficacy reports a BMI increase of 0.60 kg/m² at week 4 with ELX/TEZ/IVA compared with TEZ/IVA. The Discussion emphasizes that treatment lasted only four weeks and says longer-term outcomes remained to be evaluated. This supports an increase in BMI, but not the claim that increases were steady and sustained. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [18] source

      The Results (Efficacy) report a significant BMI improvement at week 24 in participants taking ELX/TEZ/IVA compared with placebo. Our copy does not establish that BMI rose steadily throughout the study; its explicit statement about sustained improvement concerns lung function, not BMI. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingcitation

    The rate of pulmonary exacerbations for participants in both genotype groups was lower than in the previous 24-week interim analysis of this extension study (0.19 versus 0.30).

    “During the first 144 weeks of this extension study, the estimated pulmonary exacerbation rate for patients with F/MF genotypes (0.20) was lower than in the ELX/TEZ/IVA arm of the 24-week parent study (0.37) [18] and the rate of pulmonary exacerbations for participants in both genotype groups was lower than in the previous 24-week interim analysis of this extension study (0.19 versus 0.30) [23].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Griese, 2020, Safety and efficacy of elexacaftor/tezacaftor/ivacaftor for 24 weeks or longer in people with CF and one or more F508del alleles: interim results of an open-label phase 3 clinical trial, Am J Respir Crit Care Med source
  • Findingown data

    Following initiation of ELX/TEZ/IVA, participants had decreases in sweat chloride concentration that were maintained over the interim analysis period.

    “Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period.”
    Quote in the paperSubstantial claim
  • May combine two claims. 22
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Premisecitation

    In two pivotal phase 3 trials, up to 24 weeks of treatment with ELX/TEZ/IVA was efficacious and safe in patients with cystic fibrosis ≥12 years of age who have at least one F508del allele.

    “The efficacy and safety of the triple combination of ELX, TEZ and IVA (ELX/TEZ/IVA) were established in two phase 3 pivotal trials in people with CF ≥12 years of age who were heterozygous for F508del and a minimal function mutation (F/MF) or had the F/F genotype [17–19].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [17] source
    • cites [18] source

      The Discussion reports that this 24-week phase 3 trial found ELX/TEZ/IVA efficacious and generally safe in patients aged 12 or older with a Phe508del–minimal-function genotype. This paper reports one trial, not two, and does not itself establish efficacy or safety in patients with the F/F genotype; its References list a separate F/F trial. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [19] source

      The Rationale reports efficacy and acceptable safety for VX-445/TEZ/IVA in phase 2 studies of F508del/MF and F508del/F508del patients. The Methods describe phase 3 studies enrolling patients aged ≥12, with 24 weeks planned for F508del/MF and 4 weeks for F508del/F508del. They do not report phase 3 results establishing efficacy and safety. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In both pivotal trials, ELX/TEZ/IVA treatment led to significant improvements in FEV1 % pred, CFQ-R respiratory domain score and sweat chloride concentration.

    “In both trials, ELX/TEZ/IVA treatment led to significant improvements in FEV1 % pred, CFQ-R respiratory domain score and sweat chloride concentration.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [17] source

      The Results > Efficacy section reports statistically significant improvements in ppFEV1, CFQ-R respiratory-domain score, and sweat chloride concentration in this trial of people homozygous for F508del. The paper describes a companion trial in the Discussion but does not report all three outcomes for that trial, so this source alone does not support the claim about both trials. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [18] source

      The Results > Efficacy passages report significant improvements in percentage of predicted FEV1, CFQ-R respiratory domain score, and sweat chloride concentration. But Methods > Participants, Trial Design, and Oversight identifies this paper as reporting one phase 3 trial; it does not establish these outcomes in both pivotal trials. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [19] source

      The Rationale section reports improvements in FEV1 % predicted, CFQ-R respiratory scores, and sweat chloride with VX-445/TEZ/IVA (ELX/TEZ/IVA), but these are phase 2 findings. The Methods section describes the phase 3 trials and their planned endpoints, not results from both pivotal trials; it therefore does not establish the claimed significant improvements in those trials. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the pivotal Studies 445-102 and 445-103, participants who received ELX/TEZ/IVA had rapid and statistically significant increases in FEV1 % pred and CFQ-R respiratory domain score along with significant decreases in sweat chloride concentration.

    “In the pivotal Studies 445-102 and 445-103, participants who received ELX/TEZ/IVA had rapid and statistically significant increases in FEV1 % pred and CFQ-R respiratory domain score along with significant decreases in sweat chloride concentration [17, 18].”
    Quote in the paperNot a substantial claim2 of 2 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Previous studies found symptoms of depression were elevated in people with CF, with Quittner et al. [20] reporting that among 6088 patients with CF, 5-19% of adolescents and 13-29% of adults had elevated symptoms of depression.

    “It is important to note that previous studies found symptoms of depression were elevated in people with CF, with Quittner et al. [20] reporting that among 6088 patients with CF, 5–19% of adolescents and 13–29% of adults had elevated symptoms of depression.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Findingown data

    65 participants (12.8%) had adverse events of blood creatine phosphokinase increased, one of whom had a serious adverse event that resolved without change in study drug dosing.

    “65 participants (12.8%) had AEs of blood creatine phosphokinase increased, one of whom had a serious AE that resolved without change in study drug dosing (supplementary table S6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    82 participants (16.2%) had rash events, of whom 33 were male and 49 were female.

    “82 participants (16.2%) had rash events, of whom 33 were male and 49 were female.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    73 participants discontinued from the extension study, with the majority either changing to commercial ELX/TEZ/IVA (n=24), refusing further dosing (n=18) or having adverse events that led to treatment discontinuation (n=10).

    “A total of 433 participants were still receiving treatment with ELX/TEZ/IVA in this extension study at Week 144; 73 participants discontinued, with the majority either changing to commercial ELX/TEZ/IVA (n=24), refusing further dosing (n=18) or having AEs that led to treatment discontinuation (n=10) (see figure 1 for all participant dispositions).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    One participant discontinued due to an adverse event of rash.

    “One participant discontinued due to an AE of rash.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Seven of the 16 participants with adverse events of elevated blood pressure required medication for elevated blood pressure.

    “All other AEs of elevated blood pressure were nonserious and did not require change in ELX/TEZ/IVA dosing; seven of the 16 participants required medication for elevated blood pressure (supplementary table S8).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    506 participants (399 with F/MF genotypes and 107 with F/F genotype) entered the open-label extension and received at least one dose of ELX/TEZ/IVA, representing 99.2% of participants in the parent studies.

    “Overall, 506 participants (n=399 with F/MF genotypes and n=107 with F/F genotype) entered the open-label extension and received at least one dose of ELX/TEZ/IVA, representing 99.2% of participants in the parent studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    All three participants with rhabdomyolysis adverse events had exercised before onset.

    “Three participants (0.6%) had AEs of rhabdomyolysis that presented with blood creatine kinase elevations; none had symptoms consistent with rhabdomyolysis syndrome, and before onset, all three participants had exercised.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All other adverse events of elevated blood pressure were nonserious and did not require change in ELX/TEZ/IVA dosing.

    “All other AEs of elevated blood pressure were nonserious and did not require change in ELX/TEZ/IVA dosing; seven of the 16 participants required medication for elevated blood pressure (supplementary table S8).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    One participant with type 2 diabetes, chronic kidney disease and a history of hypertension had a serious adverse event of hypertensive urgency which was not considered related to study drug and did not require change in ELX/TEZ/IVA dosing.

    “One participant with type 2 diabetes, chronic kidney disease and a history of hypertension had a serious AE of hypertensive urgency which was not considered related to study drug and did not require change in ELX/TEZ/IVA dosing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    One participant with a medical history of depression had a nonserious adverse event of depression that resolved after treatment discontinuation.

    “In the current extension study, one participant with a medical history of depression had a nonserious AE of depression that resolved after treatment discontinuation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The overall exposure-adjusted rates of adverse events and serious adverse events were lower than those in the 24-week parent study.

    “The overall exposure-adjusted rates of AEs and serious AEs were lower than those in the 24-week parent study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For most participants, adverse events were mild or moderate in severity and generally consistent with common manifestations of CF.

    “For most participants, AEs were mild or moderate in severity and generally consistent with common manifestations of CF.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rash events were mainly nonserious and manageable.

    “Rash events were mainly nonserious, manageable and occurred more frequently in female participants than male participants.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The clinical trial protocol, SARS-CoV-2-related protocol addendum and informed consent forms were approved by independent ethics committees for each region or site, as required by local regulations.

    “The clinical trial protocol, SARS-CoV-2-related protocol addendum and informed consent forms were approved by independent ethics committees for each region or site, as required by local regulations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.

    “These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    An interim analysis with prespecified analyses was conducted after the last patient completed the Week 144 visit.

    “An interim analysis with prespecified analyses was conducted after the last patient completed the Week 144 visit.”
    • Also stated in: § Methods · plain
      “A prespecified interim analysis was conducted when the last participant reached the Week 144 visit.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Safety was monitored by an independent data safety monitoring committee.

    “Safety was monitored by an independent data safety monitoring committee, and data collection and analysis were performed by Vertex Pharmaceuticals in collaboration with the authors and the VX17-445-105 Study Group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study.

    “ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study.”
    • Also stated in: § Safety · plain
      “ELX/TEZ/IVA treatment was generally safe and well tolerated.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Exposure-adjusted adverse event rates in the extension study are comparable to those in the 24-week parent study despite differences in study design, treatment duration, and calendar time, including the SARS-CoV-2 pandemic.

  • Classified as probably not a substantial claim.

    Premisecitation

    Reducing the number of pulmonary exacerbations is critical to averting the progressive lung function decline seen in patients with CF.

    “Reducing the number of pulmonary exacerbations is critical to averting the progressive lung function decline seen in patients with CF [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] source

  • May combine two claims.

    Interpretationown data

    This result suggests ELX/TEZ/IVA generally leads to rapid improvement in nutritional status which is then maintained over time.

    “This result suggests ELX/TEZ/IVA generally leads to rapid improvement in nutritional status which is then maintained over time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    All improvements in efficacy outcome measures were sustained through the end of the 144-week interim analysis period, establishing the durability of treatment response and disease-modifying benefits with ELX/TEZ/IVA.

    “Crucially, all these improvements in efficacy outcome measures were sustained through the end of the 144-week interim analysis period, establishing the durability of treatment response and disease-modifying benefits with ELX/TEZ/IVA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The reduction in pulmonary exacerbations observed in the parent study was maintained in this 144-week extension, supporting the durable benefits of ELX/TEZ/IVA.

    “Nonetheless, it is clear that the reduction in pulmonary exacerbations observed in the parent study was maintained in this 144-week extension, supporting the durable benefits of ELX/TEZ/IVA.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    For this reason, safety and efficacy results were compared with the placebo treatment group in the parent Study 445-102.

    “For this reason, safety and efficacy results were compared with the placebo treatment group in the parent Study 445-102.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Participants in this extension study had to meet specific inclusion criteria for enrolment into the pivotal trials and therefore extrapolation of these results to all people with CF will likely require studies of real-world usage of ELX/TEZ/IVA.

    “Additionally, it should be noted the participants in this extension study had to meet specific inclusion criteria for enrolment into the pivotal trials and therefore extrapolation of these results to all people with CF will likely require studies of real-world usage of ELX/TEZ/IVA.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    At the time of this interim analysis, 433 participants of the 506 originally enrolled remained in the study.

    “At the time of this interim analysis, 433 participants of the 506 originally enrolled remained in the study; 73 participants discontinued, with the majority either changing to commercial ELX/TEZ/IVA (n=24), refusing further dosing (n=18) or having AEs that led to treatment discontinuation (n=10).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    ELX/TEZ/IVA was generally safe and well tolerated through Week 144 of this extension study, with a safety profile consistent with the pivotal 24-week parent study.

    “In conclusion, ELX/TEZ/IVA was generally safe and well tolerated through Week 144 of this extension study, with a safety profile consistent with the pivotal 24-week parent study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    ELX/TEZ/IVA treatment led to sustained and clinically meaningful improvements in lung function, respiratory symptoms, CFTR function and nutritional status in this extension study.

    “In this extension study of ELX/TEZ/IVA in participants ≥12 years of age with at least one F508del allele, ELX/TEZ/IVA treatment was generally safe and well tolerated, and led to sustained and clinically meaningful improvements in lung function, respiratory symptoms, CFTR function and nutritional status.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    73 participants discontinued, with the majority either changing to commercial ELX/TEZ/IVA (n=24), refusing further dosing (n=18) or having adverse events that led to treatment discontinuation (n=10).

    “At the time of this interim analysis, 433 participants of the 506 originally enrolled remained in the study; 73 participants discontinued, with the majority either changing to commercial ELX/TEZ/IVA (n=24), refusing further dosing (n=18) or having AEs that led to treatment discontinuation (n=10).”
    Quote in the paperNot a substantial claim
32 of 32

  • The paper relies on this without support.

    Exposure-adjusted adverse event rates in the extension study are comparable to those in the 24-week parent study despite differences in study design, treatment duration, and calendar time, including the SARS-CoV-2 pandemic.

    “The exposure-adjusted rates of AEs and serious AEs in the extension study were lower than those seen in participants with F/MF genotypes in the active arm of the 24-week parent study that forms the basis of the ELX/TEZ/IVA safety profile (table 2 and supplementary tables S2 and S3).”

  • The paper relies on this without support.

    Parent study baseline characteristics are an appropriate baseline for assessing long-term changes in the extension study.

    “Baseline characteristics are based on data obtained at parent study baseline, which was defined as the most recent nonmissing measurement before the first dose of study drug in the parent study treatment period (Study 445-102 or Study 445-103).”

  • The paper relies on this without support.

    People with cystic fibrosis are likely to require long-term treatment with ELX/TEZ/IVA or similar CFTR modulator regimens.

    “Because people with CF are likely to require long-term treatment with ELX/TEZ/IVA or similar CFTR modulator regimens, safety and efficacy data spanning several years, as demonstrated in this study, are crucial for making informed patient care decisions.”
3 of 3

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Authors
Daines, C. L., Tullis, E., Costa, S., Linnemann, R. W., Mall, M. A., McKone, E. F., Polineni, D., Quon, B. S., Ringshausen, F. C., Rowe, S. M., Selvadurai, H., Taylor-Cousar, J. L., Withers, N. J., Ahluwalia, N., Moskowitz, S. M., Prieto-Centurion, V., Tan, Y. V., Tian, S., Weinstock, T., Xuan, F., Zhang, Y., Ramsey, B., & Griese, M.
Affiliations
  • University of Arizona (US)
  • St. Michael's Hospital (CA)
  • University of Messina (IT)
  • Emory University (US)
  • German Center for Lung Research (DE)
  • St. Vincent's University Hospital (IE)
  • Washington University in St. Louis (US)
  • University of British Columbia (CA)
  • Medizinische Hochschule Hannover (DE)
  • University of Alabama at Birmingham (US)
  • Children's Hospital at Westmead (AU)
  • Royal Devon & Exeter NHS Foundation Trust (GB)
  • Vertex Pharmaceuticals (United States) (US)
  • Seattle Children's Hospital (US)
Corresponding author
Daines, Cori L.
ORCID
Venue
European Respiratory Journal
Publisher
European Respiratory Society (ERS)
Published
2023-11-09
Volume
62
Issue
6
Pages
2202029
ISSN
  • 0903-1936 (ISSN-L)
  • 1399-3003
DOI
10.1183/13993003.02029-2022
PMC
PMC10701091
OpenAlex
W4388524266
Semantic Scholar
7aa8d0e2a8ea98f2d87e755d15c07a09560d1fb4
Cited by
100
References
25
Citations by year
2026: 27 · 2025: 42 · 2024: 30 · 2023: 1
FWCI
18.33
Type
journal article
Language
en
Open access
Licence
Locations
  • European Respiratory Journal (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
Funders
Vertex Pharmaceuticals
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords
cystic fibrosis, F508del mutation, CFTR modulator therapy, long-term safety, long-term efficacy, open-label extension, adverse events, FEV1, sweat chloride, pulmonary exacerbations, body mass index, Cystic Fibrosis Questionnaire-Revised, treatment discontinuation
MeSH terms
Alleles, Aminophenols, Cystic Fibrosis, Humans, Indoles, Mutation, Pyrazoles, Pyridines, Pyrrolidines, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-04.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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