Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Boeck, K. De; Chang, Philip M.; Paz-Díaz, Hildegarde; Rubin, J.L.; Yang, Yoojung; Hu, Xingdi; Pasta, David J.; Millar, Stefanie J.; Campbell, Daniel; Wang, Xin; Ahluwalia, Neil; Owen, Caroline A.; Gibson, Ronald L.; Rowe, Steven M.; Lechtzin, Noah; Ahrens, Richard C.; McCoy, Karen; Aitken, Moira L.; Donaldson, Scott H.; McBennett, Kimberly; Pilewski, Joseph M.; Billings, Joanne; Milla, Carlos; Rubenstein, Ronald C.; Rosenbluth, Daniel; Linnemann, Rachel W.; Powers, Michael R.; Fortner, Christopher N.; Frederick, Carla A.; Liou, Theodore G.; Black, Philip; Wang, Janice; Colombo, John L.; Berdella, Maria; Indihar, Maria; Brown, Cynthia; Anstead, Michael; Bilodeau, Lara; Sicilian, Leonard; Jain, Manu; Tolle, James; Moffett, Kathryn; Nasr, Samya Z.; Taylor‐Cousar, Jennifer L.; Barto, Tara Lynn; Antos, Nicholas; Rogers, John; Quick, Bryon; Thompson, Henry; Sawicki, Gregory S.; Barnett, Bruce; Zanni, Robert; Smith, Thomas C.; Schultz, Karen D.; Keating, Claire; Flume, Patrick A.; Omlor, Gregory J.; Ashare, Alix; Voter, Karen Z.; Mehdi, Naima; Ortiz, Maria Gabriela Tupayachi; Gardner, Tonia E; Boas, Steven R.; Messore, Barbara; Zemanick, Edith T.; Jain, Raksha; McCarthy, Michael; Kissner, Dana G.; Patel, Kapilkumar; McNamara, John J.; Philley, Julie V.; Berlinski, Ariel; Calimano, Francisco J.; Chin, Terry; Conrad, Douglas; Daines, Cori; Raissy, Hengameh H.; Keens, Thomas G.; Lascano, Jorge; McWilliams, Bennie; Morrissey, Brian M.; Reyes, Santiago; Chittivelu, Subramanyam; Hussain, Sabiha; Stone, Arvey; Wallace, James M.; Klingsberg, Ross C.; Biller, Julie; Bui, Stéphanie; Sommerburg, Olaf; Bignamini, Elisabetta; Collura, Mirella; Biner, Reta Fischer; Möller, Alexander; Salvatore, Donatello; Belleguic, Chantal; Bentur, Lea; Efrati, Ori; Kerem, Eitan; Prais, Dario; Gallego, Esther Quintana; Barry, Peter J.; Livnat-Levanon, Galit; Asensi, José Ramón Villa; Armstrong, David; Cruz, Oscar A.; Gilchrist, Francis; Tullis, D. Elizabeth; Quon, Bradley S.; Lands, Larry C.; Morrison, Nancy; Lavoie, Annick; Linnane, Barry; Elidemir, Okan; Ringshausen, Felix C.; Kappler, Matthias; Hebestreit, Helge; Mainz, J.G.; Kiefer, Alexander; Koerner-Rettberg, Cordula; Staab, Doris; Gleiber, Wolfgang; Pressler, Tacjana; Stehling, Florian; Hector, Andreas; Sutharsan, Sivagurunathan; Naehrlich, L.; Fischer, Rainald; Downey, D.G.; Davies, Jane; Ketchell, R.I.; Carroll, Mary; Doe, Simon; MacGregor, Gordon; Nash, Edward F.; Withers, Nicholas; Peckham, Daniel; Ledson, M.J.; Kansra, Sonal; Lee, Timothy William Rayner; Delaisi, Bertrand; Rault, G.; Bihan, Jean Le; Hubert, D.; Fajac, Isabelle; Sermet‐Gaudelus, Isabelle; Bakker, Marleen; Arets, B.; Boeck, Christiane De; Chiron, R.; Reix, Philippe; Mainguy, Catherine; Braeckel, Eva Van; Malfroot, Anne; Durieu, I.; Dufeu, Nadine; Prévotat, A.; Meer, Renske van der; Merkus, Petrus; Weersink, Els J.M.; Gomez-Aguero, Isabel Barrio; Gartner, Sílvia; Jover, A; Fernandez, Antonio Alvarez; Cox, Desmond; McKone, Edward F.; Plant, Barry J.; Selvadurai, Hiranjan; Bowler, Simon; Wainwright, Claire; Smith, Daniel J.; Middleton, Peter G.; Wilson, John W.; Volpi, Sonia; Colombo, Carla; Fabrizzi, Benedetta; Lucidi, Vincenzina; Cresta, Federico; Cucchiara, Salvatore; Eber, Ernst; Ellemunter, Helmut; Huttegger, Isidor; Hjelte, Lena; Krantz, Christina; Gilljam, M.

doi:10.1016/s2213-2600(20)30510-5

Cited by 39 publications

(28 citation statements)

References 38 publications

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“…This study did not show a significant improvement in ppFEV1 decline or the number of PEx, when comparing three years before and after treatment with LUM/IVA. However, the data did indicate an overall acute ppFEV1 improvement and a decline in SwCl concentration after six months, consistent with previous observations in clinical trials [3][4][5][6]. Our results of ppFEV1 decline were different from the original phase 3 open-label extension study of LUM/IVA in pwCF homozygous for the F508del mutation, which showed an average annual ppFEV1 decline of −1.3% compared to −2.3% in untreated matched historical controls after 120 weeks of treatment [5].…”

Section: Discussionsupporting

confidence: 86%

“…Total clinical follow-up was six years, starting from three years before up to three years after treatment initiation, or until censoring in case of (1) treatment discontinuation due to adverse events, (2) transition to elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), (3) lung transplantation, (4) death or (5) participants being lost to follow-up. Transition to TEZ/IVA during the study period was accepted, as its efficacy was considered to be comparable to LUM/IVA [3][4][5][6]. Written informed consent was obtained from all participants.…”

Section: Study Design and Populationmentioning

confidence: 99%

“…Sustained efficacy of treatment was demonstrated in phase 3 open-label extension trials with a two-year follow-up. These trials showed an average absolute reduction in ppFEV1 of 1-1.4% per year [5,6] and a 30-39% lower annualized PEx rate [3][4][5][6]. There is, however, a substantial variability in individual clinical response to CFTR modulators and the reason for this remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

Muilwijk

Bierlaagh

Mourik

et al. 2021

JPM

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The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p < 0.001), with sex (males vs. females IRR: 0.36, 95%CI: 0.21–0.63, p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p < 0.001) and was associated with SwCl at baseline (−0.64, 95%CI: −0.90–−0.37, p < 0.001) and with sex (males vs. females 8.32, 95%CI: 1.82–14.82, p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation.

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Section: Discussionsupporting

confidence: 86%

Section: Study Design and Populationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

Muilwijk

Bierlaagh

Mourik

et al. 2021

JPM

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“…Currently, approved CFTR modulators include the potentiator ivacaftor (for patients with at least one G551D allele, other CFTR gating mutations and responsive mutations based on clinical and/or in vitro assay data); the corrector/potentiator combinations lumacaftor/ivacaftor (for patients homozygous for the F508del mutation) and tezacaftor/ivacaftor (for patients homozygous for the F508del allele, those with an F508del allele plus residual-function mutation and responsive mutations based on clinical and/or in vitro assay data); and the triple-agent CFTR modulator elexacaftor/tezacaftor/ivacaftor (for patients with at least one F508del allele and responsive mutations based on in vitro assay data). In clinical studies, CFTR modulators have improved percentage predicted forced expiratory volume in 1 second (ppFEV 1 ) by 3-14% [15][16][17][18][19][20][21][22], with a sustained effect confirmed in open-label extension studies [23,24]. A real-world study has demonstrated a slowed decline of ppFEV 1 over 5 years [25].…”

Section: Introductionmentioning

confidence: 99%

“…However, for most patients with CF, an improvement in pulmonary function is not necessarily a return to normal and exacerbations still occur, albeit at a lower rate [15,24,25]. In addition, bacteria are not eradicated from the airways over time [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE-CF 1, a randomised, phase II study

et al. 2021

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BackgroundInhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans.ObjectiveWe present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF.ResultsInitially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95%CI –6.6, 4.9) in ppFEV1 and +2.1 units (95%CI –2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers.ConclusionBI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.

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Increasing life expectancy in cystic fibrosis: Advances and challenges

McBennett

Davis

Konstan

2021

Pediatric Pulmonology

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Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Cited by 39 publications

References 38 publications

Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE-CF 1, a randomised, phase II study

Increasing life expectancy in cystic fibrosis: Advances and challenges

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