Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials
Academic Article
Publication Date:
2025
Citation:
Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials / C. Keating, L.M. Yonker, F. Vermeulen, D. Prais, R.W. Linnemann, A. Trimble, T. Kotsimbos, J. Mermis, A.T. Braun, M. O'Carroll, S. Sutharsan, B. Ramsey, M.A. Mall, J.L. Taylor-Cousar, E.F. Mckone, E. Tullis, T. Floreth, P. Michelson, P.R. Sosnay, N. Nair, R. Zahigian, H. Martin, N. Ahluwalia, A. Lam, A. Horsley, S. Krick, K. Mccoy, C. Goss, D. Weiner, J. Billings, C. Ren, J. Atkinson, R. Linnemann, A. Trimble, C. Frederick, T. Liou, H. Escobar, J. Wang, A. Deschamps, D. Froh, J. Chmiel, M. Wurth, L. Yonker, M. Jain, S. Millard, J. Tolle, A. Filbrun, J. Taylor-Cousar, F. Ruiz, C. Brown, B. Quick, P. Brown, J. Kennedy, J. Ruddy, B. Shkolnik, K. Pancham, E. Dimango, S. Fiel, G. Mueller, F. Livingston, A. Braun, B. O'Sullivan, P. Dubin, C. Teneback, T. Kremer, J. Welter, J. Hoppe, R. Jain, F. Calimano, J. Johannes, C. Daines, D. Green, T. Keens, C. Trillo-Alvarez, H. Scher, J. Mermis, B. Morrissey, J. Wallace, C. Barrios, J. Callison, Z. Holliday, R. Klingsberg, O. Efrati, M. Cohen-Cymberknoh, D. Prais, P. Azevedo, E. Quintana-Gallego, J. Wong, P. Mondejar-Lopez, A. Lopez Neyra, A. Amorim, S. Sivam, O. Asensio De La Cruz, M. Waller, C. Forseen, C. Marion, A. Dittrich, J. Lysinger, B. Casserly, C. Luna, S. Brown, J. Singer, D. Schellhase, J. Roberts, C. King, C. Byrnes, F. Ringshausen, H. Hebestreit, M. Lorenz, R. Ruppel, P. Drevinek, S. Dillenhofer, M. Stahl, W. Gleiber, L. Homola, S. Naehrig, F. Stehling, S. Sutharsan, R. Fischer, K. Poplawska, C. Haworth, N. Simmonds, D. Urquhart, J. Duckers, M. Carroll, P. Barry, S. Doe, T. Hilliard, G. Macgregor, N. Patel, N. Withers, D. Peckham, M. Ledson, U. Koser, S. Gartner, E. Blitz Castro, A. Sole Jover, D. Cox, E. Mckone, B. Plant, M. Williamson, B. Elnazir, T. Barbosa, M. Cols Roig, L. Burr, D. Henderson, P. Middleton, T. Kotsimbos, I. De Monestrol, M. Gilljam, U. Lindberg, C. Schwarz, S. Bode, M. Epton, A. Halasz, I. Laki, M. O'Carroll, S. Krick, K. Mccoy, C. Goss, D. Weiner, C. Ren, J. Atkinson, R. Linnemann, A. Trimble, C. Fortner, C. Frederick, T. Liou, H. Escobar, J. Wang, D. Froh, J. Chmiel, M. Wurth, L. Bilodeau, A. Lapey, M. Jain, S. Millard, J. Tolle, K. Moffett, S. Jia, J. Taylor-Cousar, C. Brown, P. Brown, A. Uluer, J. Ruddy, E. Sears, K. Pancham, C. Keating, S. Fiel, G. Mueller, G. Omlor, A. Braun, N. Mehdi, M.G. Tupayachi Ortiz, C. Teneback, T. Kremer, B. Messore, J. Hoppe, R. Jain, A. Lambert, Z. Mukadam, F. Calimano, C. Daines, M. Egan, D. Green, T. Keens, A. Wilhelm, B. Morrissey, S. Reyes, D. Schaeffer, J. Wallace, J. Callison, R. Klingsberg, Z. Szepfalusi, R. Epaud, S. Leroy, R. Fischer Biner, A. Moeller, D. Salvatore, O. Efrati, M. Cohen-Cymberknoh, D. Prais, L. Johnson, J. Wong, S. Gohy, A. Gramegna, H. Olesen, A. Tissot, C. Marguet, S. Sivam, M. Desai, M. Waller, L. Owens, T. Kherani, C. Marion, J. Lysinger, D. Sands, E. Bakkeheim, E. Tullis, M. Chilvers, B. Quon, L. Lands, M. Parkins, F. Tremblay, A. Maitra, B. Casserly, H. Staples, O. Elidemir, E. Chatziagorou, P. Tirakitsoontorn, D. Grenet, S. Brown, B. Linnane, J.M. Nicholson, K. Manika, A. Tatopoulos, C. Byrnes, R. Ruppel, M. Stahl, T. Pressler, F. Stehling, S. Sutharsan, A. Bagheri-Potthoff, R. Fischer, C. Haworth, N. Simmonds, J. Duckers, J. Legg, A. Horsley, G. Macgregor, D. Peckham, T. Lee, V. Houdouin, S. Ramel, I. Fajac, I. Sermet-Gaudelus, L. Kamphuis, K. Van Der Ent, F. Vermeulen, R. Chiron, P. Reix, E. Van Braeckel, C. Knoop, E. Vanderhelst, I. Durieu, S. Bui, L. Weiss, O. Le Rouzic, R. Van Der Meer, J. Roukema, J. Altenburg, D. Cox, E. Mckone, B. Plant, M. Williamson, P. Robinson, C. Wainwright, L. Burr, D. Henderson, S. Mulrennan, B. Clements, P. Middleton, T. Kotsimbos, G. Taccetti, M. Cipolli, V. Dacco,
abstract:
Background: The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor–tezacaftor–deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor–tezacaftor–deutivacaftor compared with standard of care elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older. Methods: In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor–tezacaftor–ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor–tezacaftor–deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was –3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete. Findings: In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor–tezacaftor–ivacaftor (n=202) or vanzacaftor–tezacaftor–deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6–38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor–tezacaftor–ivacaftor (n=289) or vanzacaftor–tezacaftor–deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5–42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. T
IRIS type:
01 - Articolo su periodico
List of contributors:
C. Keating, L.M. Yonker, F. Vermeulen, D. Prais, R.W. Linnemann, A. Trimble, T. Kotsimbos, J. Mermis, A.T. Braun, M. O'Carroll, S. Sutharsan, B. Ramsey, M.A. Mall, J.L. Taylor-Cousar, E.F. Mckone, E. Tullis, T. Floreth, P. Michelson, P.R. Sosnay, N. Nair, R. Zahigian, H. Martin, N. Ahluwalia, A. Lam, A. Horsley, S. Krick, K. Mccoy, C. Goss, D. Weiner, J. Billings, C. Ren, J. Atkinson, R. Linnemann, A. Trimble, C. Frederick, T. Liou, H. Escobar, J. Wang, A. Deschamps, D. Froh, J. Chmiel, M. Wurth, L. Yonker, M. Jain, S. Millard, J. Tolle, A. Filbrun, J. Taylor-Cousar, F. Ruiz, C. Brown, B. Quick, P. Brown, J. Kennedy, J. Ruddy, B. Shkolnik, K. Pancham, E. Dimango, S. Fiel, G. Mueller, F. Livingston, A. Braun, B. O'Sullivan, P. Dubin, C. Teneback, T. Kremer, J. Welter, J. Hoppe, R. Jain, F. Calimano, J. Johannes, C. Daines, D. Green, T. Keens, C. Trillo-Alvarez, H. Scher, J. Mermis, B. Morrissey, J. Wallace, C. Barrios, J. Callison, Z. Holliday, R. Klingsberg, O. Efrati, M. Cohen-Cymberknoh, D. Prais, P. Azevedo, E. Quintana-Gallego, J. Wong, P. Mondejar-Lopez, A. Lopez Neyra, A. Amorim, S. Sivam, O. Asensio De La Cruz, M. Waller, C. Forseen, C. Marion, A. Dittrich, J. Lysinger, B. Casserly, C. Luna, S. Brown, J. Singer, D. Schellhase, J. Roberts, C. King, C. Byrnes, F. Ringshausen, H. Hebestreit, M. Lorenz, R. Ruppel, P. Drevinek, S. Dillenhofer, M. Stahl, W. Gleiber, L. Homola, S. Naehrig, F. Stehling, S. Sutharsan, R. Fischer, K. Poplawska, C. Haworth, N. Simmonds, D. Urquhart, J. Duckers, M. Carroll, P. Barry, S. Doe, T. Hilliard, G. Macgregor, N. Patel, N. Withers, D. Peckham, M. Ledson, U. Koser, S. Gartner, E. Blitz Castro, A. Sole Jover, D. Cox, E. Mckone, B. Plant, M. Williamson, B. Elnazir, T. Barbosa, M. Cols Roig, L. Burr, D. Henderson, P. Middleton, T. Kotsimbos, I. De Monestrol, M. Gilljam, U. Lindberg, C. Schwarz, S. Bode, M. Epton, A. Halasz, I. Laki, M. O'Carroll, S. Krick, K. Mccoy, C. Goss, D. Weiner, C. Ren, J. Atkinson, R. Linnemann, A. Trimble, C. Fortner, C. Frederick, T. Liou, H. Escobar, J. Wang, D. Froh, J. Chmiel, M. Wurth, L. Bilodeau, A. Lapey, M. Jain, S. Millard, J. Tolle, K. Moffett, S. Jia, J. Taylor-Cousar, C. Brown, P. Brown, A. Uluer, J. Ruddy, E. Sears, K. Pancham, C. Keating, S. Fiel, G. Mueller, G. Omlor, A. Braun, N. Mehdi, M.G. Tupayachi Ortiz, C. Teneback, T. Kremer, B. Messore, J. Hoppe, R. Jain, A. Lambert, Z. Mukadam, F. Calimano, C. Daines, M. Egan, D. Green, T. Keens, A. Wilhelm, B. Morrissey, S. Reyes, D. Schaeffer, J. Wallace, J. Callison, R. Klingsberg, Z. Szepfalusi, R. Epaud, S. Leroy, R. Fischer Biner, A. Moeller, D. Salvatore, O. Efrati, M. Cohen-Cymberknoh, D. Prais, L. Johnson, J. Wong, S. Gohy, A. Gramegna, H. Olesen, A. Tissot, C. Marguet, S. Sivam, M. Desai, M. Waller, L. Owens, T. Kherani, C. Marion, J. Lysinger, D. Sands, E. Bakkeheim, E. Tullis, M. Chilvers, B. Quon, L. Lands, M. Parkins, F. Tremblay, A. Maitra, B. Casserly, H. Staples, O. Elidemir, E. Chatziagorou, P. Tirakitsoontorn, D. Grenet, S. Brown, B. Linnane, J.M. Nicholson, K. Manika, A. Tatopoulos, C. Byrnes, R. Ruppel, M. Stahl, T. Pressler, F. Stehling, S. Sutharsan, A. Bagheri-Potthoff, R. Fischer, C. Haworth, N. Simmonds, J. Duckers, J. Legg, A. Horsley, G. Macgregor, D. Peckham, T. Lee, V. Houdouin, S. Ramel, I. Fajac, I. Sermet-Gaudelus, L. Kamphuis, K. Van Der Ent, F. Vermeulen, R. Chiron, P. Reix, E. Van Braeckel, C. Knoop, E. Vanderhelst, I. Durieu, S. Bui, L. Weiss, O. Le Rouzic, R. Van Der Meer, J. Roukema, J. Altenburg, D. Cox, E. Mckone, B. Plant, M. Williamson, P. Robinson, C. Wainwright, L. Burr, D. Henderson, S. Mulrennan, B. Clements, P. Middleton, T. Kotsimbos, G. Taccetti, M. Cipolli, V. Dacco, B. Fabrizzi, C. Castellani, E. Eber, D. Appelt, M. Studnicka, I. De Monestrol, M. Gilljam, E. Sapiejka, H. Mazurek, U. Lindberg, M. Engan, A. Sauty, J. Mankikian, M. Epton, A. Halasz, I. Laki, M. O'Carroll
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