Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis
Toby M. Maher, Paul Ford, Kevin M. Brown, Ulrich Costabel, Vincent Cottin, Sonye K. Danoff, Irene Groenveld, Eric Helmer, Gísli Jenkins, Julie Milner, Geert Molenberghs, Björn Penninckx, Matthew J. Randall, Bernt van den Blink, Ann Fieuw, Charlotte Vandenrijn, Sanda Rocak, Ineke Seghers, Lixin Shao, Amit Taneja, Garrit Jentsch, Timothy R. Watkins, Wim Wuyts, Michael Kreuter, Nadia Verbruggen, Niyati Prasad, Marlies Wijsenbeek, ISABELA 1 and 2 Investigators, Daniel C. Chambers, Michael Chia, Tamera J. Corte, Ian Glaspole, Nicole Goh, Mark Holmes, M.A. Malouf, Francis Thien, Elizabeth Veitch, Benjamin Bondue, Caroline Dahlqvist, Antoine Froidure, Hans Slabbynck, Wim Wuyts, Claudia Cartagena Salinas, Rosa Feijoó Seoane, Victor D. Martínez, Roxana Maturana, Juana Pavie Gallegos, Andrés Rosenblüt, Rafael Silva, Alvaro Undurraga Pereira, Martina Doubková, Norbert Pauk, Martina Plačková, Martina Šterclová, Elisabeth Bendstrup, Saher Burhan Shaker, Ingrid Louise Titlestad, Stephan Budweiser, Christian Grohé, Dirk Koschel, Michael Kreuter, Antje Prasse, Michael Weber, Hubert Wirtz, Κατερίνα Αντωνίου, Zoe Daniil, Mina Gaga, Despoina Papakosta, Shinyu Izumi, Masaki Okamoto, Alfredo Guerreros Benavides, Carlos Barrera, Alejandro Manuel Peña Villalobos, Aranzazu Campo Ezquibela, José M. Cifrián, Estrella Fernández Fabrellas, Virginia Leiro, María Molina‐Molina, Asunción Nieto Barbero, Jacobo Sellarés, Claudia Valenzuela, Shih-Lung Cheng, Ping‐Hung Kuo, Kang‐Yun Lee, Chau‐Chyun Sheu, Hakan Günen, Nesrin Moğulkoç, Sibel Naycı, Huzaifa Adamali, Stephen Bianchi, Nazia Chaudhuri, Michael Gibbons, Simon P. Hart, Philip L. Molyneaux, Helen Parfrey, Gauri Saini, Lisa Spencer, Sarah Wiscombe, Danielle Antin‐Ozerkis, Rebecca Bascom
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.