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

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

Ziritaxestat and Lung Function in Idiopathic Pulmonary Fibrosis

“…The FVC analysis was performed using a random coefficient regression model that included sex, age, height, and stratification factor as covariates . Similar rates of FVC decline were observed with pirfenidone (least-squares mean, −189.0 mL [95% CI, −231.6 to −146.3 mL]) and nintedanib (least-squares mean, −163.1 mL [95% CI, −205.7 to −120.5 mL]); of note, participants not receiving antifibrotic agents had numerically lower declines in FVC (least-squares mean, −149.1 mL [95% CI, −199.5 to −98.6 mL]) . The rate of FVC decline in patients randomized to placebo who were treated with antifibrotics was greater than in the pivotal trials …”

“…If our hypotheses are correct, the phenomena seen in the placebo groups of the ISABELA trials will be reproduced in future trials when antifibrotic agents are used as the standard of care. There are important implications on the interpretation of these results as well as on trial design.…”

“…To the Editor We are writing about the ISABELA 1 and 2 randomized clinical trials that tested 2 doses of ziritaxestat (600 mg or 200 mg) vs placebo in patients with idiopathic pulmonary fibrosis (IPF) who were also receiving treatment with standard of care (the antifibrotics nintedanib or pirfenidone or neither agent). The study was terminated early due to lack of efficacy (no attenuation of forced vital capacity [FVC] decline at 52 weeks) and because of safety concerns.…”

“…Importantly, the ISABELA trials revealed unexpected outcomes in the placebo comparison groups between patients receiving antifibrotics and those not receiving antifibrotics. The FVC analysis was performed using a random coefficient regression model that included sex, age, height, and stratification factor as covariates .…”

“…Importantly, the ISABELA trials revealed unexpected outcomes in the placebo comparison groups between patients receiving antifibrotics and those not receiving antifibrotics. The FVC analysis was performed using a random coefficient regression model that included sex, age, height, and stratification factor as covariates . Similar rates of FVC decline were observed with pirfenidone (least-squares mean, −189.0 mL [95% CI, −231.6 to −146.3 mL]) and nintedanib (least-squares mean, −163.1 mL [95% CI, −205.7 to −120.5 mL]); of note, participants not receiving antifibrotic agents had numerically lower declines in FVC (least-squares mean, −149.1 mL [95% CI, −199.5 to −98.6 mL]) .…”