Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis
Authors: Maher Toby M. , Ford Paul , Brown Kevin K. , Costabel Ulrich , Cottin Vincent , Danoff Sonye K. , Groenveld Irene , Helmer Eric , Jenkins R. Gisli , Milner Julie , Molenberghs Geert , Penninckx Bjorn , Randall Matthew J. , Van Den Blink Bernt , Fieuw Ann , Vandenrijn Charlotte , Rocak Sanda , Seghers Ineke , Shao Lixin , Taneja Amit , Jentsch Garrit , Watkins Timothy R. , Wuyts Wim A. , Kreuter Michael , Verbruggen Nadia , Prasad Niyati , Wijsenbeek Marlies S. ,   ISABELA 1 and 2 Investigators, Chambers Daniel , Chia Michael , Corte Tamera , Glaspole Ian , Goh Nicole , Holmes Mark , Malouf Monique , Thien Francis , Veitch Elizabeth , Bondue Benjamin , Dahlqvist Caroline , Froidure Antoine , Slabbynck Hans , Wuyts Wim , Cartagena Salinas Claudia , Feijoó Seoane Rosa , Martínez Victor , Maturana Roxana , Pavie Gallegos Juana , Rosenblut Andres , Silva Rafael , Undurraga Pereira Alvaro , Doubkova Martina , Pauk Norbert , Plackova Martina , Sterclova Martina , Bendstrup Elisabeth , Shaker Saher B. , Titlestad Ingrid , Budweiser Stephan , Grohé Christian , Koschel Dirk , Kreuter Michael , Prasse Antje , Weber Michael , Wirtz Hubert , Antoniou Katerina , Daniil Zoe , Gaga Mina , Papakosta Despoina , Izumi Shinyu , Okamoto Masaki , Guerreros Benavides Alfredo , Iberico Barrera Carlos , Peña Villalobos Alejandro Manuel , Campo Ezquibela Aranzazu , Cifrian Martinez Jose Manuel , Fernandez Fabrellas Estrella , Leiro Virginia , Molina-Molina Maria , Nieto Barbero Asunción , Sellares Torres Jacobo , Valenzuela Claudia , Cheng Shih-Lung , Kuo Ping-Hung , Lee Kang-Yun , Sheu Chau-Chyun , Gunen Hakan , Mogulkoc Bishop Nesrin , Nayci Sibel , Adamali Huzaifa , Bianchi Stephen , Chaudhuri Nazia , Gibbons Michael , Hart Simon , Molyneaux Philip , Parfrey Helen , Saini Gauri , Spencer Lisa G , Wiscombe Sarah , Antin-Ozerkis Danielle , Bascom Rebecca , Belperio John , Britt Edward , Fitzgerald John , Gomez Manjarres Diana , Gotfried Mark , Gupta Nishant , Hotchkin David , Kaye Mitchell , Kreider Mary , Kureishy Shahrukh , Lacamera Peter , Lancaster Lisa , Lasky Joseph , Lorch Daniel , Mannem Hannah , Morrow Lee , Moua Teng , Nambiar Anoop , Raghu Ganesh , Raj Rishi , Ramaswamy Murali , Reddy Raghu , Russell Tonya , Scholand Mary Beth , Shea Barry , Suliman Sally , Swigris Jeff , Thavarajah Krishna , Tolle Leslie , Tomic Rade , Warshoff Neal , Wesselius Lewis , Yung Gordon , Bergna Miguel , De Salvo María , Fernandez Acquier Mariano , Rodriguez Alicia , Saez Scherbovsky Pablo , Assayag Deborah , Dhar Anil , Khalil Nasreen , Morisset Julie , Provencher Steeve , Ryerson Chris , Shapera Shane , Bourdin Arnaud , Crestani Bruno , Lebargy Francois , Reynaud-Gaubert Martine , Bonella Francesco Tommaso , Claussen Martin , Hammerl Peter , Karagiannidis Christian , Keller Claus , Randerath Winfried , Stubbe Beate , Csánky Eszter , Medgyasszay Balazs , Muller Veronika , Adir Yochai , Bar-Shai Amir , Berkman Neville , Fink Gershon , Kramer Mordechai , Shitrit David , Bargagli Elena , Gasparini Stefano , Harari Sergio , Ravaglia Claudia , Richeldi Luca , Vancheri Carlo , Ebina Masahito , Fujita Masaki , Ichikado Kazuya , Inoue Yoshikazu , Ishikawa Nobuhisa , Kato Motoyasu , Kawamura Tetsuji , Kondoh Yasuhiro , Nishioka Yasuhiko , Ogura Takashi , Owan Isoko , Saito Takefumi , Sakamoto Noriho , Sakamoto Koji , Shirai Masahiro , Suda Takafumi , Tomii Keisuke , Chung Man Pyo , Jeong Sung Hwan , Park Choon Sik , Park Jong Sun , Song Jin Woo , Uh Soo-Taek , Chavarria Martinez Uriel , Montano Gonzalez Efrain , Ramirez Alicia , Selman Lama Moises Eduardo , Bresser Paul , Kramer Henk , Mostard Remy , Nossent Esther , Veltkamp Marcel , Wijsenbeek Marlies , Beckert Lutz , Chang Catherina L , Veale Andrew , Wilsher Margaret , Bednarek Michal , Gasior Grzegorz , Jasieniak-Pinis Grazyna , Jassem Ewa , Mroz Robert , Piotrowski Wojciech , Abdullah Ismail , Ambaram Anish , Irusen Elvis , Van der Linden Michael , van Zyl-Smit Richard , Williams Paul , Allen James , Averill Francis , Belloli Elizabeth , Brown Anne , Case Amy , Chaudhary Sachin , Criner Gerard , DeBoer Kevin , Dilling Daniel , Dorf Jeffrey , Enelow Richard , Ettinger Neil , Feldman Jeremy , Gibson Kevin , Golden Jeffrey , Hamblin Mark , Hunninghake Gary , Karunakara Raj , Kim Hyun , Luckhardt Tracy , Menon Prema , Morrison Lake , Oldham Justin , Patel Nina , Schmidt Shelley , Strek Mary , Summer Ross , Sussman Robert , Tita James , Veeraraghavan Srihari , Whelan Timothy , Zibrak Joseph 
Published: May 2023

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