Taladegib for the treatment of idiopathic pulmonary fibrosis (ENV-IPF-101): a multicentre, randomised, double-blind, placebo-controlled, phase 2a trial.

Abstract

The hedgehog (Hh) signalling pathway promotes fibrosis in idiopathic pulmonary fibrosis (IPF), an interstitial lung disease with a high mortality rate. Currently, there is no cure for IPF, and available anti-fibrotics only slow the rate of decline in lung function in IPF. We aimed to assess the safety and efficacy of taladegib (ENV-101), an Hh pathway inhibitor, in IPF in a phase 2a, proof-of-concept clinical trial. ENV-IPF-101 was a randomised, double-blind, placebo-controlled, phase 2a trial conducted at 16 clinical sites in Australia, Canada, Malaysia, Mexico, and South Korea for patients with IPF older than 40 years who were not treated with concurrent IPF therapy. Patients were randomly assigned to taladegib 200 mg or placebo equivalent once daily, orally for 12 weeks, with a 6-week follow-up. The primary outcomes were safety in the intention-to-treat population and change from baseline in forced vital capacity (FVC) in the efficacy-evaluable population. Exploratory outcomes were measures of fibrosis on high-resolution CT (HRCT) in the efficacy-evaluable population. This study is registered with ClinicalTrials.gov, NCT04968574. Between Aug 12, 2021, and July 28, 2023, 41 patients were randomly assigned to the taladegib group (n=21; three [14%] female and 18 [86%] male) or the placebo group (n=20; four [20%] female and 16 [80%] male). All treatment-emergent adverse events possibly or probably related to the study drug were grade 1 or 2, all except one were mild or moderate in severity, and none were serious adverse events. The most common treatment-emergent adverse events in the taladegib group were dysgeusia (12 [57%] of 21), muscle spasms (12 [57%] of 21), and alopecia (11 [52%] of 21); none of these events were reported in the placebo group, for which the most common adverse events reported were diarrhoea (four [20%] of 20), headache (three [15%] of 20), and dizziness (one [5%] of 20). Patients treated with taladegib had an improvement from baseline in FVC and across multiple HRCT-based measures of disease. Between-group differences in change from baseline to week 12 favoured taladegib for the efficacy measures of percent predicted FVC (3·95% [95% CI 0·31-7·60]; p=0·035; mean change from baseline of 1·9% in the taladegib group vs -1·3% for placebo), total lung capacity by HRCT (257·0 mL [95% CI 86·8-427·2]; p=0·0040; mean change from baseline of 206·67 mL in the taladegib group vs -55·58 mL in the placebo group), and percent quantitative interstitial lung disease (p=0·047; mean change from baseline of -9·4% in the taladegib group vs 1·1% in the placebo group). No deaths occurred during the trial. The acceptable safety profile and efficacy analyses of taladegib support further investigation in a phase 2b trial in patients with IPF (WHISTLE-PF). Endeavor BioMedicines.