In patients with idiopathic pulmonary fibrosis (IPF), the autotaxin inhibitor ziritaxestat did not improve clinical outcomes compared with placebo, according to studies terminated early for futility. Results did not differ between patients who were or were not receiving standard-of-care treatment with pirfenidone or nintedanib.
ISABELA 1 and ISABELA 2 were identically designed, phase 3, randomized clinical trials conducted in Africa, the Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1,306 patients with IPF were randomized to oral ziritaxestat 200 mg or 600 mg or to placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.
Based on a primary outcome of the annual rate of decline for forced vital capacity (FVC) at week 52, the studies showed: “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.”
Editorial: “Moving forward with … lessons [learned in these trials] will be challenging, especially as IPF therapies improve and trials need to increase in size and duration to detect smaller treatment effects while patients are continuing to receive standard of care treatment,” editorialists write. “Innovative approaches to clinical trial design, including adaptive trials and bayesian analyses, may enhance trial efficiency, and we expect that these approaches will be increasingly used. Large trials like the ISABELA trials should collect multidimensional data that will generate new insights about the underlying disease and response to therapy. Industry partners should consider making these data publicly available so that even if the investigational therapy fails, the knowledge generated will ensure the success of future studies.
“There is an urgent need for better treatments for IPF. There are many promising drugs in development, stemming from an investment in research into the mechanisms driving lung fibrosis. It is our hope that innovative approaches to clinical trials will improve their efficiency and safety while accelerating the approval of effective therapies so that patients living with IPF may benefit.”