A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.

The therapy of idiopathic pulmonary fibrosis: what is next?

“…This idea was supported by a phase I study (NCT01725139) of omipalisib, a strong inhibitor of the PI3K/Akt pathway (GSK2126458), a potential PI3K/mammalian target of rapamycin (mTOR) inhibitor [125]. In a recently published study, omipalisib showed an acceptable tolerability profile in an IPF cohort [126]. [42,129].…”

PET/MRI attenuation estimation in the lung: A review of past, present, and potential techniques

“…25 In this regard, accurate regional quantification appears even more important than in the focal pathology (eg lung nodule, cancer), since the metabolic activity can be used for na€ ıve assessment and longitudinal studies to monitor possible treatments. 26 In addition, estimation of, and correction for, the regional air fraction, which can be obtained from density maps, is important to be able to characterize different lung diseases. 27 Finally, the reproducibility of parameters needs to be consistent in the light of further image analysis of radiomic features such as textural information and inaccurate lung attenuation estimation may mislead or influence the values of radiomic features.…”

Molecular endpoints for establishing target engagement by novel idiopathic pulmonary fibrosis therapies

“…There are limitations to the approach and findings reported by LUKEY et al [15]. The design as a pharmacological and pharmacodynamic study, which generally requires a relatively small sample size to achieve significant endpoints, did not inform whether omipalisib impacts clinically meaningful endpoints such as change in FVC or survival.…”

“…The recent publication by LUKEY et al [15], also in this issue of the European Respiratory Journal, illustrates approaches investigators are using to overcome uncertainties when developing novel IPF therapies. Building on preclinical studies implicating the PI3K/Akt/mTOR axis in lung fibrosis [16], this phase 2 study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of the PI3K/ mTOR inhibitor omipalisib in patients with IPF.…”