Challenges in developing effective treatments for idiopathic pulmonary fibrosis: Lessons from the ISABELA trials


Diffuse Lung Disease & Lung Transplant Network

Interstitial Lung Disease Section

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease that affects an estimated 100,000 people in the United States alone. Despite the availability of two approved antifibrotic drugs, nintedanib and pirfenidone, there is still a need for effective treatments to improve patient outcomes.

The ISABELA 1 and 2 trials were two Phase III clinical trials designed to evaluate ziritaxestat, a novel autotaxin inhibitor, in patients with IPF. Unfortunately, both trials were terminated early after an interim analysis revealed a lack of efficacy and safety concerns. Specifically, neither dose of ziritaxestat showed any benefit on the rate of decline for FVC over 52 weeks. Moreover, the treatment with ziritaxestat showed no benefit on the reported secondary outcomes. Patients in the ziritaxestat groups experienced worse outcomes in terms of time to first respiratory- related hospitalization, respiratory- related mortality, and first acute IPF exacerbation. Pooled data for both trials showed higher all-cause mortality for the ziritaxestat groups in relation to placebo (Maher T, et al. JAMA. 2023;329[18]:1567).

These disappointing results highlight the challenges of developing effective treatments for IPF. The complexity of IPF as a disease, with multiple pathways contributing to its pathogenesis, makes it difficult to identify effective therapeutic targets. In addition, clinical trials for new treatments must also account for the availability of approved antifibrotic therapies, which creates an added challenge for clinical trial design.

Matthew Huang, MD
Section Fellow-in-Training

Brad Bemiss, MD
Section Member-at-Large

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