Using a selective av beta 6 PET ligand to optimise early phase IPF clinical trials

Introduction: The utility of quantitative PET to assess pharmacological target engagement is well established in the brain. However, for application to the lung, respiratory motion, the presence of air and a high blood fraction must be considered. Objective: To assess the feasibility of using a selective αvβ6 PET ligand ([18F]-FBA-A20FMDV2) to detect target engagement in the lungs of IPF patients. Methods: The PETAL study (NCT02052297; RES116235) measured the αvβ6 PET signal in healthy and IPF lungs. Scans were repeated after ~12 days in the IPF cohort to determine intra-subject variability. Volume of distribution (VT) was used to assess uptake of the αvβ6 PET ligand, as it accounts for any distributional changes in the ligand that may be caused by a therapeutic αvβ6 inhibitor. The sample size required to evaluate target engagement in a future trial was statistically estimated. Results: Higher levels of αvβ6 were confirmed in IPF compared to healthy lungs, with increased uptake corresponding to the areas of fibrosis seen on HRCT. Whole lung IPF/healthy VT ratio [95% CI] was 1.59 [1.09, 2.32] without, and 1.17 [0.85, 1.61] with, tissue fraction correction. The intra-subject variability, estimated as the standard deviation of the logarithm of the ratio of VT (Scan2/Scan1), was 0.14 without, and 0.17 with, tissue fraction correction. Assuming the change in signal following treatment of IPF patients with an αvβ6 inhibitor would equate to half of the difference between IPF and healthy levels, a treatment effect would be detectable in 5 subjects. Conclusion: The αvβ6 PET ligand is a potentially important tool for use in IPF clinical studies with as few as 5 subjects required to assess target engagement.