There is a major need for effective, well-tolerated treatments for idiopathic pulmonary
fibrosis (IPF).To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat
in patients with IPF.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.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.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).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.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.ClinicalTrials.gov Identifiers:
NCT03711162 and NCT03733444.
