Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis

Toby Maher; Paul Ford; Kevin Brown; Ulrich Costabel; Vincent Cottin; Sonye Danoff; Irene Groenveld; Eric Helmer; R. Gisli Jenkins; Julie Milner; Geert Molenberghs; Bjorn Penninckx; Matthew Randall; Bernt van den Blink; Ann Fieuw; Charlotte Vandenrijn; Sanda Rocak; Ineke Seghers; Lixin Shao; Amit Taneja; Garrit Jentsch; Timothy Watkins; Wim Wuyts; Michael Kreuter; Nadia Verbruggen; Niyati Prasad; Marlies Wijsenbeek; Daniel Chambers; Michael Chia; Tamera Corte; Ian Glaspole; Nicole Goh; Mark Holmes; Monique Malouf; Francis Thien; Elizabeth Veitch; Benjamin Bondue; Caroline Dahlqvist; Antoine Froidure; Hans Slabbynck; Claudia Cartagena Salinas; Rosa Feijoó Seoane; Victor Martínez; Roxana Maturana; Juana Pavie Gallegos; Andres Rosenblut; Rafael Silva; Alvaro Undurraga Pereira; Martina Doubkova; Norbert Pauk; Martina Plackova; Martina Sterclova; Elisabeth Bendstrup; Saher Shaker; Ingrid Titlestad; Stephan Budweiser; Christian Grohé; Dirk Koschel; Antje Prasse; Michael Weber; Hubert Wirtz; Katerina Antoniou; Zoe Daniil; Mina Gaga; Despoina Papakosta; Shinyu Izumi; Masaki Okamoto; Alfredo Guerreros Benavides; Carlos Iberico Barrera; Alejandro Manuel Peña Villalobos; Aranzazu Campo Ezquibela; Jose Manuel Cifrian Martinez; Estrella Fernandez Fabrellas; Virginia Leiro; Maria Molina-Molina; Asunción Nieto Barbero; Jacobo Sellares Torres; Claudia Valenzuela; Shih-Lung Cheng; Ping-Hung Kuo; Kang-Yun Lee; Chau-Chyun Sheu; Hakan Gunen; Nesrin Mogulkoc Bishop; Sibel Nayci; Huzaifa Adamali; Stephen Bianchi; Nazia Chaudhuri; Michael Gibbons; Simon Hart; Philip Molyneaux; Helen Parfrey; Gauri Saini; Lisa Spencer; Sarah Wiscombe; Danielle Antin-Ozerkis; Rebecca Bascom; John Belperio; Edward Britt; John Fitzgerald; Diana Gomez Manjarres; Mark Gotfried; Nishant Gupta; David Hotchkin; Mitchell Kaye; Mary Kreider; Shahrukh Kureishy; Peter Lacamera; Lisa Lancaster; Joseph Lasky; Daniel Lorch; Hannah Mannem; Lee Morrow; Teng Moua; Anoop Nambiar; Ganesh Raghu; Rishi Raj; Murali Ramaswamy; Raghu Reddy; Tonya Russell; Mary Beth Scholand; Barry Shea; Sally Suliman; Jeff Swigris; Krishna Thavarajah; Leslie Tolle; Rade Tomic; Neal Warshoff; Lewis Wesselius; Gordon Yung; Miguel Bergna; María de Salvo; Mariano Fernandez Acquier; Alicia Rodriguez; Pablo Saez Scherbovsky; Deborah Assayag; Anil Dhar; Nasreen Khalil; Julie Morisset; Steeve Provencher; Chris Ryerson; Shane Shapera; Arnaud Bourdin; Bruno Crestani; Francois Lebargy; Martine Reynaud-Gaubert; Francesco Tommaso Bonella; Martin Claussen; Peter Hammerl; Christian Karagiannidis; Claus Keller; Winfried Randerath; Beate Stubbe; Eszter Csánky; Balazs Medgyasszay; Veronika Muller; Yochai Adir; Amir Bar-Shai; Neville Berkman; Gershon Fink; Mordechai Kramer; David Shitrit; Elena Bargagli; Stefano Gasparini; Sergio Harari; Claudia Ravaglia; Luca Richeldi; Carlo Vancheri; Masahito Ebina; Masaki Fujita; Kazuya Ichikado; Yoshikazu Inoue; Nobuhisa Ishikawa; Motoyasu Kato; Tetsuji Kawamura; Yasuhiro Kondoh; Yasuhiko Nishioka; Takashi Ogura; Isoko Owan; Takefumi Saito; Noriho Sakamoto; Koji Sakamoto; Masahiro Shirai; Takafumi Suda; Keisuke Tomii; Man Pyo Chung; Sung Hwan Jeong; Choon Sik Park; Jong Sun Park; Jin Woo Song; Soo-Taek Uh; Uriel Chavarria Martinez; Efrain Montano Gonzalez; Alicia Ramirez; Moises Eduardo Selman Lama; Paul Bresser; Henk Kramer; Remy Mostard; Esther Nossent; Marcel Veltkamp; Lutz Beckert; Catherina Chang; Andrew Veale; Margaret Wilsher; Michal Bednarek; Grzegorz Gasior; Grazyna Jasieniak-Pinis; Ewa Jassem; Robert Mroz; Wojciech Piotrowski; Ismail Abdullah; Anish Ambaram; Elvis Irusen; Michael van der Linden; Richard van Zyl-Smit; Paul Williams; James Allen; Francis Averill; Elizabeth Belloli; Anne Brown; Amy Case; Sachin Chaudhary; Gerard Criner; Kevin Deboer; Daniel Dilling; Jeffrey Dorf; Richard Enelow; Neil Ettinger; Jeremy Feldman; Kevin Gibson; Jeffrey Golden; Mark Hamblin; Gary Hunninghake; Raj Karunakara; Hyun Kim; Tracy Luckhardt; Prema Menon; Lake Morrison; Justin Oldham; Nina Patel; Shelley Schmidt; Mary Strek; Ross Summer; Robert Sussman; James Tita; Srihari Veeraraghavan; Timothy Whelan; Joseph Zibrak

doi:10.1001/jama.2023.5355

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Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis

Journal article

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Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis

Toby Maher, Paul Ford, Kevin Brown, Ulrich Costabel, Vincent Cottin, Sonye Danoff, Irene Groenveld, Eric Helmer, R. Gisli Jenkins, Julie Milner, …

JAMA Cardiology, Vol.329(18)

09/05/2023

DOI: https://doi.org/10.1001/jama.2023.5355

PMID: 37159034

Abstract

Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

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Title: Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis
Creators - without role: Toby Maher - University of Southern California
Paul Ford - Galapagos
Kevin Brown - University of Colorado Denver
Ulrich Costabel - Ruhrlandklinik
Vincent Cottin - Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
Sonye Danoff - Johns Hopkins University
Irene Groenveld - Galapagos (Netherlands)
Eric Helmer - Galapagos
R. Gisli Jenkins
Julie Milner - Gilead Sciences
Geert Molenberghs - Hasselt University
Bjorn Penninckx - Galapagos
Matthew Randall
Bernt van den Blink - Galapagos (Netherlands)
Ann Fieuw - Galapagos
Charlotte Vandenrijn - Galapagos
Sanda Rocak
Ineke Seghers - Galapagos
Lixin Shao - Gilead Sciences
Amit Taneja - Galapagos
Garrit Jentsch - Federal Highway Research Institute
Timothy Watkins - Gilead Sciences
Wim Wuyts - KU Leuven
Michael Kreuter - University Hospital Heidelberg
Nadia Verbruggen - Galapagos
Niyati Prasad - Galapagos
Marlies Wijsenbeek - Erasmus MC
Daniel Chambers - Isabela State University
Michael Chia - Isabela State University
Tamera Corte - Isabela State University
Ian Glaspole - Isabela State University
Nicole Goh - Isabela State University
Mark Holmes - Isabela State University
Monique Malouf - Isabela State University
Francis Thien - Isabela State University
Elizabeth Veitch - Isabela State University
Benjamin Bondue - Isabela State University
Caroline Dahlqvist - Isabela State University
Antoine Froidure - Isabela State University
Hans Slabbynck - Isabela State University
Wim Wuyts - KU Leuven
Claudia Cartagena Salinas
Rosa Feijoó Seoane
Victor Martínez - Isabela State University
Roxana Maturana - Isabela State University
Juana Pavie Gallegos
Andres Rosenblut - Isabela State University
Rafael Silva - Isabela State University
Alvaro Undurraga Pereira
Martina Doubkova - Isabela State University
Norbert Pauk - Isabela State University
Martina Plackova - Isabela State University
Martina Sterclova - Isabela State University
Elisabeth Bendstrup - Isabela State University
Saher Shaker - Isabela State University
Ingrid Titlestad - Isabela State University
Stephan Budweiser - Isabela State University
Christian Grohé - Isabela State University
Dirk Koschel - Isabela State University
Michael Kreuter - University Hospital Heidelberg
Antje Prasse - Isabela State University
Michael Weber - Isabela State University
Hubert Wirtz - Isabela State University
Katerina Antoniou - Isabela State University
Zoe Daniil - Isabela State University
Mina Gaga - Isabela State University
Despoina Papakosta - Isabela State University
Shinyu Izumi - Isabela State University
Masaki Okamoto - Isabela State University
Alfredo Guerreros Benavides
Carlos Iberico Barrera
Alejandro Manuel Peña Villalobos
Aranzazu Campo Ezquibela
Jose Manuel Cifrian Martinez
Estrella Fernandez Fabrellas
Virginia Leiro - Isabela State University
Maria Molina-Molina - Isabela State University
Asunción Nieto Barbero
Jacobo Sellares Torres
Claudia Valenzuela - Isabela State University
Shih-Lung Cheng - Isabela State University
Ping-Hung Kuo
Kang-Yun Lee
Chau-Chyun Sheu
Hakan Gunen - Isabela State University
Nesrin Mogulkoc Bishop
Sibel Nayci
Huzaifa Adamali - Isabela State University
Stephen Bianchi - Isabela State University
Nazia Chaudhuri - Isabela State University
Michael Gibbons - Isabela State University
Simon Hart - Isabela State University
Philip Molyneaux - Isabela State University
Helen Parfrey - Isabela State University
Gauri Saini - Isabela State University
Lisa Spencer - Isabela State University
Sarah Wiscombe - Isabela State University
Danielle Antin-Ozerkis - Isabela State University
Rebecca Bascom - Isabela State University
John Belperio - Isabela State University
Edward Britt
John Fitzgerald - Isabela State University
Diana Gomez Manjarres
Mark Gotfried - Isabela State University
Nishant Gupta - Isabela State University
David Hotchkin - Isabela State University
Mitchell Kaye - Isabela State University
Mary Kreider - Isabela State University
Shahrukh Kureishy - Isabela State University
Peter Lacamera - Isabela State University
Lisa Lancaster - Isabela State University
Joseph Lasky - Isabela State University
Daniel Lorch - Isabela State University
Hannah Mannem - Isabela State University
Lee Morrow - Isabela State University
Teng Moua - Isabela State University
Anoop Nambiar - Isabela State University
Ganesh Raghu - Isabela State University
Rishi Raj - Isabela State University
Murali Ramaswamy - Isabela State University
Raghu Reddy - Isabela State University
Tonya Russell - Isabela State University
Mary Beth Scholand - Isabela State University
Barry Shea - Isabela State University
Sally Suliman - Isabela State University
Jeff Swigris - Isabela State University
Krishna Thavarajah - Isabela State University
Leslie Tolle - Isabela State University
Rade Tomic - Isabela State University
Neal Warshoff - Isabela State University
Lewis Wesselius - Isabela State University
Gordon Yung - Isabela State University
Miguel Bergna - Isabela State University
María de Salvo - Isabela State University
Mariano Fernandez Acquier
Alicia Rodriguez - Isabela State University
Pablo Saez Scherbovsky
Deborah Assayag - Isabela State University
Anil Dhar - Isabela State University
Nasreen Khalil - Isabela State University
Julie Morisset - Isabela State University
Steeve Provencher - Isabela State University
Chris Ryerson - Isabela State University
Shane Shapera - Isabela State University
Arnaud Bourdin - Université de Montpellier, Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Bruno Crestani - Isabela State University
Francois Lebargy - Isabela State University
Martine Reynaud-Gaubert - Isabela State University
Francesco Tommaso Bonella - Isabela State University
Martin Claussen - Isabela State University
Peter Hammerl - Isabela State University
Christian Karagiannidis - Isabela State University
Claus Keller - Isabela State University
Winfried Randerath - Isabela State University
Beate Stubbe - Isabela State University
Eszter Csánky - Isabela State University
Balazs Medgyasszay - Isabela State University
Veronika Muller - Isabela State University
Yochai Adir - Isabela State University
Amir Bar-Shai - Isabela State University
Neville Berkman - Isabela State University
Gershon Fink - Isabela State University
Mordechai Kramer - Isabela State University
David Shitrit - Isabela State University
Elena Bargagli - Isabela State University
Stefano Gasparini - Isabela State University
Sergio Harari - Isabela State University
Claudia Ravaglia - Isabela State University
Luca Richeldi - Isabela State University
Carlo Vancheri - Isabela State University
Masahito Ebina - Isabela State University
Masaki Fujita - Isabela State University
Kazuya Ichikado - Isabela State University
Yoshikazu Inoue - Isabela State University
Nobuhisa Ishikawa - Isabela State University
Motoyasu Kato - Isabela State University
Tetsuji Kawamura - Isabela State University
Yasuhiro Kondoh - Isabela State University
Yasuhiko Nishioka - Isabela State University
Takashi Ogura - Isabela State University
Isoko Owan - Isabela State University
Takefumi Saito - Isabela State University
Noriho Sakamoto - Isabela State University
Koji Sakamoto - Isabela State University
Masahiro Shirai - Isabela State University
Takafumi Suda - Isabela State University
Keisuke Tomii - Isabela State University
Man Pyo Chung - Isabela State University
Sung Hwan Jeong - Isabela State University
Choon Sik Park
Jong Sun Park - Isabela State University
Jin Woo Song - Isabela State University
Soo-Taek Uh
Uriel Chavarria Martinez
Efrain Montano Gonzalez
Alicia Ramirez
Moises Eduardo Selman Lama
Paul Bresser - Isabela State University
Henk Kramer - Isabela State University
Remy Mostard
Esther Nossent - Isabela State University
Marcel Veltkamp - Isabela State University
Marlies Wijsenbeek - Erasmus MC
Lutz Beckert - Isabela State University
Catherina Chang - Isabela State University
Andrew Veale - Isabela State University
Margaret Wilsher - Isabela State University
Michal Bednarek
Grzegorz Gasior - Isabela State University
Grazyna Jasieniak-Pinis - Isabela State University
Ewa Jassem - Isabela State University
Robert Mroz - Isabela State University
Wojciech Piotrowski - Isabela State University
Ismail Abdullah - Isabela State University
Anish Ambaram - Isabela State University
Elvis Irusen - Isabela State University
Michael van der Linden
Richard van Zyl-Smit - Isabela State University
Paul Williams - Isabela State University
James Allen - Isabela State University
Francis Averill - Isabela State University
Elizabeth Belloli - Isabela State University
Anne Brown - Isabela State University
Amy Case - Isabela State University
Sachin Chaudhary - Isabela State University
Gerard Criner - Isabela State University
Kevin Deboer - Isabela State University
Daniel Dilling - Isabela State University
Jeffrey Dorf - Isabela State University
Richard Enelow - Isabela State University
Neil Ettinger - Isabela State University
Jeremy Feldman - Isabela State University
Kevin Gibson - Isabela State University
Jeffrey Golden - Isabela State University
Mark Hamblin
Gary Hunninghake - Isabela State University
Raj Karunakara - Isabela State University
Hyun Kim - Isabela State University
Tracy Luckhardt - Isabela State University
Prema Menon
Lake Morrison - Isabela State University
Justin Oldham - Isabela State University
Nina Patel - Isabela State University
Shelley Schmidt - Isabela State University
Mary Strek - Isabela State University
Ross Summer - Isabela State University
Robert Sussman - Isabela State University
James Tita - Isabela State University
Srihari Veeraraghavan - Isabela State University
Timothy Whelan - Isabela State University
Joseph Zibrak - Isabela State University
Publication Details: JAMA Cardiology, Vol.329(18)
Identifiers: 9937317009311
Academic Unit: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Language: English
Resource Type: Journal article
Local Fields: hal-04096929