ISABELA Studies: Plasma Exposure and Target Engagement Do Not Explain the Lack of Efficacy of Ziritaxestat in Patients with Idiopathic Pulmonary Fibrosis

Abstract

Autotaxin (ATX) contributes to the production of lysophosphatidic acid (LPA), which is associated with fibrosis development in idiopathic pulmonary fibrosis (IPF). The ATX inhibitor, ziritaxestat, failed to reduce decline in forced vital capacity (FVC) in patients with IPF in ISABELA 1 and 2 (NCT03711162; NCT03733444), two identically designed Phase 3 studies. In the current analysis, we evaluated pharmacokinetic and pharmacodynamic data from the pooled ISABELA studies to determine whether the lack of efficacy could be attributed to insufficient exposure and/or target engagement. Non‐linear mixed effect modeling was performed to predict ziritaxestat exposure in individual patients and describe its effect on LPA C18:2 levels. We assessed whether there was a correlation between ziritaxestat and ATX concentration and evaluated the relationship between LPA C18:2 reduction and change from baseline in FVC. Ziritaxestat exposure in patients with IPF was numerically lower in those who received ziritaxestat on top of pirfenidone than in those who received ziritaxestat on top of nintedanib or ziritaxestat alone. In most patients, LPA C18:2 reduction was comparable to that reported in healthy volunteers. ATX concentrations increased over time and correlated weakly with ziritaxestat exposure and LPA C18:2 reduction. No correlation between reduction in LPA C18:2 and change from baseline in FVC was apparent. Based on these evaluations, exposure and target engagement are not thought to have contributed to the lack of efficacy observed. We hypothesize that the lack of efficacy of ziritaxestat in the ISABELA program, despite adequate LPA reduction, could be due to the involvement of an alternative pro‐fibrotic pathway.

Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis

“…The failure of the ISABELA-1/2 phase 3 trials stand in contrast to the promising results of the BMS-986278 phase 2 trial, suggesting an association between MOA and clinical outcomes. Increased levels of plasma ATX were detected in participants in ISABELA-1/2, indicative of disease progression or a regulatory feedback loop that has previously been observed in mice treated with an ATX inhibitor [ 106 , 107 ]. Raised ATX levels suggest that the broad effect of ATX inhibition ( e.g.…”