Ziritaxestat Fails to Demonstrate Efficacy for Treatment of IPF in 2 Trials

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The phase 3 clinical trials evaluating ziritaxestat for treating idiopathic pulmonary fibrosis showed no improvement in clinical outcomes leading to the termination of the trials due to lack of efficacy.

The results of 2 phase 3 clinical trials that evaluated the efficacy and safety of ziritaxestat in patients with idiopathic pulmonary fibrosis (IPF) demonstrated no significant difference in clinical outcomes between the drug and placebo.

The debilitating lung disease is characterized by the progressive scarring of lung tissue, leading to respiratory dysfunction and reduced quality of life. Effective and well-tolerated treatments for IPF are urgently needed, according to the study.

For this investigation, a team led by Toby Maher, MD, PhD, National Heart and Lung Institute, Imperial College London, Keck School of Medicine, University of Southern California, aimed to assess the efficacy and safety of the autotaxin inhibitor ziritaxestat among this patient population.

The ISABELA Clinical Trials

The ISABELA 1 and ISABELA 2 trials enrolled a total of 1,306 patients with IPF across multiple regions. The study reported the trials were prematurely terminated due to a decision by an independent data and safety monitoring committee, which concluded that the benefit to risk profile of ziritaxestat no longer supported the continuation of the studies.

The primary outcome measure, the annual rate of decline for forced vital capacity (FVC) at week 52, did not show any improvement with ziritaxestat compared with the placebo in either trial.

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 compared with -147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo. The difference between the 2 groups was only 22.7 mL (95% CI, −52.3 to 97.6 mL).

Similarly, 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 compared with -176.6 mL (95% CI, −211.4 to −141.8 mL) in the placebo, with a minimal between-group difference of 2.8 mL (95% CI, −46.9 to 52.4 mL).

Investigators reported these findings demonstrated a lack of efficacy of ziritaxestat in improving lung function decline in patients with IPF.

Evaluating Treatment Options for IPF

It was also reported that ziritaxestat did not demonstrate any significant benefit over placebo in terms of disease progression, time to first respiratory-related hospitalization, or improvement in health-related quality of life, as assessed by the St George's Respiratory Questionnaire total score.

According to the data, all-cause mortality rates did not show a clear advantage for ziritaxestat, with varying rates observed across the treatment and placebo groups in both trials. In ISABELA 1, the mortality rate was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo. In ISABELA 2, the mortality rate was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.

“Even though the ISABELA trials failed, they demonstrate the potential value of observing data for 52 weeks or longer and provide information regarding the utility of different clinical outcomes,” investigators noted.

“In addition, information collected during the trials, such as the faster than anticipated rate of decline for FVC in the patients taking standard of care therapy, adverse events associated with standard of care, and treatment patterns (eg, the proportion of patients switching or initiating standard of care therapy during the trials), may help inform the design of future IPF studies.”


Maher TM, Ford P, Brown KK, et al. Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials. JAMA. 2023;329(18):1567–1578. doi:10.1001/jama.2023.5355