Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis
Author:
Maher Toby M.12, Ford Paul3, Brown Kevin K.4, Costabel Ulrich5, Cottin Vincent6, Danoff Sonye K.7, Groenveld Irene89, Helmer Eric1011, Jenkins R. Gisli1, Milner Julie1213, Molenberghs Geert1415, Penninckx Bjorn3, Randall Matthew J.16, Van Den Blink Bernt8, Fieuw Ann3, Vandenrijn Charlotte3, Rocak Sanda16, Seghers Ineke317, Shao Lixin12, Taneja Amit18, Jentsch Garrit19, Watkins Timothy R.12, Wuyts Wim A.20, Kreuter Michael21222324, Verbruggen Nadia3, Prasad Niyati325, Wijsenbeek Marlies S.26, Chambers Daniel27, Chia Michael27, Corte Tamera27, Glaspole Ian27, Goh Nicole27, Holmes Mark27, Malouf Monique27, Thien Francis27, Veitch Elizabeth27, Bondue Benjamin27, Dahlqvist Caroline27, Froidure Antoine27, Slabbynck Hans27, Wuyts Wim27, Cartagena Salinas Claudia27, Feijoó Seoane Rosa27, Martínez Victor27, Maturana Roxana27, Pavie Gallegos Juana27, Rosenblut Andres27, Silva Rafael27, Undurraga Pereira Alvaro27, Doubkova Martina27, Pauk Norbert27, Plackova Martina27, Sterclova Martina27, Bendstrup Elisabeth27, Shaker Saher B.27, Titlestad Ingrid27, Budweiser Stephan27, Grohé Christian27, Koschel Dirk27, Kreuter Michael27, Prasse Antje27, Weber Michael27, Wirtz Hubert27, Antoniou Katerina27, Daniil Zoe27, Gaga Mina27, Papakosta Despoina27, Izumi Shinyu27, Okamoto Masaki27, Guerreros Benavides Alfredo27, Iberico Barrera Carlos27, Peña Villalobos Alejandro Manuel27, Campo Ezquibela Aranzazu27, Cifrian Martinez Jose Manuel27, Fernandez Fabrellas Estrella27, Leiro Virginia27, Molina-Molina Maria27, Nieto Barbero Asunción27, Sellares Torres Jacobo27, Valenzuela Claudia27, Cheng Shih-Lung27, Kuo Ping-Hung27, Lee Kang-Yun27, Sheu Chau-Chyun27, Gunen Hakan27, Mogulkoc Bishop Nesrin27, Nayci Sibel27, Adamali Huzaifa27, Bianchi Stephen27, Chaudhuri Nazia27, Gibbons Michael27, Hart Simon27, Molyneaux Philip27, Parfrey Helen27, Saini Gauri27, Spencer Lisa G27, Wiscombe Sarah27, Antin-Ozerkis Danielle27, Bascom Rebecca27, Belperio John27, Britt Edward27, Fitzgerald John27, Gomez Manjarres Diana27, Gotfried Mark27, Gupta Nishant27, Hotchkin David27, Kaye Mitchell27, Kreider Mary27, Kureishy Shahrukh27, Lacamera Peter27, Lancaster Lisa27, Lasky Joseph27, Lorch Daniel27, Mannem Hannah27, Morrow Lee27, Moua Teng27, Nambiar Anoop27, Raghu Ganesh27, Raj Rishi27, Ramaswamy Murali27, Reddy Raghu27, Russell Tonya27, Scholand Mary Beth27, Shea Barry27, Suliman Sally27, Swigris Jeff27, Thavarajah Krishna27, Tolle Leslie27, Tomic Rade27, Warshoff Neal27, Wesselius Lewis27, Yung Gordon27, Bergna Miguel27, De Salvo María27, Fernandez Acquier Mariano27, Rodriguez Alicia27, Saez Scherbovsky Pablo27, Assayag Deborah27, Dhar Anil27, Khalil Nasreen27, Morisset Julie27, Provencher Steeve27, Ryerson Chris27, Shapera Shane27, Bourdin Arnaud27, Crestani Bruno27, Lebargy Francois27, Reynaud-Gaubert Martine27, Bonella Francesco Tommaso27, Claussen Martin27, Hammerl Peter27, Karagiannidis Christian27, Keller Claus27, Randerath Winfried27, Stubbe Beate27, Csánky Eszter27, Medgyasszay Balazs27, Muller Veronika27, Adir Yochai27, Bar-Shai Amir27, Berkman Neville27, Fink Gershon27, Kramer Mordechai27, Shitrit David27, Bargagli Elena27, Gasparini Stefano27, Harari Sergio27, Ravaglia Claudia27, Richeldi Luca27, Vancheri Carlo27, Ebina Masahito27, Fujita Masaki27, Ichikado Kazuya27, Inoue Yoshikazu27, Ishikawa Nobuhisa27, Kato Motoyasu27, Kawamura Tetsuji27, Kondoh Yasuhiro27, Nishioka Yasuhiko27, Ogura Takashi27, Owan Isoko27, Saito Takefumi27, Sakamoto Noriho27, Sakamoto Koji27, Shirai Masahiro27, Suda Takafumi27, Tomii Keisuke27, Chung Man Pyo27, Jeong Sung Hwan27, Park Choon Sik27, Park Jong Sun27, Song Jin Woo27, Uh Soo-Taek27, Chavarria Martinez Uriel27, Montano Gonzalez Efrain27, Ramirez Alicia27, Selman Lama Moises Eduardo27, Bresser Paul27, Kramer Henk27, Mostard Remy27, Nossent Esther27, Veltkamp Marcel27, Wijsenbeek Marlies27, Beckert Lutz27, Chang Catherina L27, Veale Andrew27, Wilsher Margaret27, Bednarek Michal27, Gasior Grzegorz27, Jasieniak-Pinis Grazyna27, Jassem Ewa27, Mroz Robert27, Piotrowski Wojciech27, Abdullah Ismail27, Ambaram Anish27, Irusen Elvis27, Van der Linden Michael27, van Zyl-Smit Richard27, Williams Paul27, Allen James27, Averill Francis27, Belloli Elizabeth27, Brown Anne27, Case Amy27, Chaudhary Sachin27, Criner Gerard27, DeBoer Kevin27, Dilling Daniel27, Dorf Jeffrey27, Enelow Richard27, Ettinger Neil27, Feldman Jeremy27, Gibson Kevin27, Golden Jeffrey27, Hamblin Mark27, Hunninghake Gary27, Karunakara Raj27, Kim Hyun27, Luckhardt Tracy27, Menon Prema27, Morrison Lake27, Oldham Justin27, Patel Nina27, Schmidt Shelley27, Strek Mary27, Summer Ross27, Sussman Robert27, Tita James27, Veeraraghavan Srihari27, Whelan Timothy27, Zibrak Joseph27,
Affiliation:
1. National Heart and Lung Institute, Imperial College London, London, England 2. Keck School of Medicine, University of Southern California, Los Angeles 3. Galapagos NV, Mechelen, Belgium 4. National Jewish Health, Denver, Colorado 5. Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany 6. Reference Center for Rare Pulmonary Diseases, Hôpital Louis Pradel, Hospices Civils de Lyon, and IVPC, INRAE, Claude Bernard University Lyon 1, Lyon, France 7. School of Medicine, Johns Hopkins University, Baltimore, Maryland 8. Galapagos NV, Leiden, the Netherlands 9. CellPoint BV, Oegstgeest, the Netherlands 10. Galapagos Biotech Ltd, Cambridge, England 11. Exscientia, Oxford, England 12. Gilead Sciences, Inc, Foster City, California 13. Alnylam, Maidenhead, England 14. Hasselt University, Hasselt, Belgium 15. KU Leuven, Leuven, Belgium 16. Galapagos GmbH, Basel, Switzerland 17. Argenx, Gent, Belgium 18. Galapagos SASU, Romainville, France 19. BAST GmbH, Heidelberg, Germany 20. Department of Respiratory Medicine, Unit for Interstitial Lung Diseases, University Hospitals Leuven, Leuven, Belgium 21. Center for Interstitial and Rare Lung Diseases, Department of Pneumology, Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany 22. German Center for Lung Research, Heidelberg, Germany 23. Center for Pulmonary Medicine, Department of Pneumology, Mainz University Medical Center, Mainz, Germany 24. Department of Pulmonary, Critical Care, and Sleep Medicine, Marienhaus Clinic Mainz, Mainz, Germany 25. Enterprise Therapeutics, Brighton, England 26. Centre for Interstitial Lung Diseases and Sarcoidosis, Department of Respiratory Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands 27. for the ISABELA 1 and 2 Investigators
Abstract
ImportanceThere is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).ObjectiveTo assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and ParticipantsThe 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.InterventionsPatients 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 MeasuresThe 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).ResultsAt 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 RelevanceZiritaxestat 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 RegistrationClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444
Publisher
American Medical Association (AMA)
Cited by
45 articles.
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