Abstract B082: Evaluation of the effects of an oral Notch inhibitor, LY3039478, on QT interval, and absolute and pilot relative bioavailability studies conducted in healthy subjects
Authors: Yuen Eunice , Posada Maria , Smith Claire , Thorn Katharine , Greenwood Dale , Burgess Michelle , Benhadji Karim , Ortega Demetrio , Chinchen Louise , Suico Jeffrey 
Published: August 2018

Abstract
Background: LY3039478 is an oral, potent small-molecule Notch inhibitor being investigated for the treatment of advanced cancers. The effect of single doses on corrected QT interval, absolute and relative bioavailability were explored in three studies (Table 1). These studies were conducted in healthy subjects to mitigate the confounding effects of disease state and concomitant medication, while avoiding nonbeneficial drug exposures in cancer patients.
Table 1. Designs for three clinical studies of LY3039478 in healthy subjects Study ParametersNCT02659865 Eudra CT No. 2016-001073-33 Study 1Study 2Study 3Completed subjects (N)141312Overall designSingle ascending dose; investigator-subject blinded, placebo-controlled, randomized 3 period cross-over; 25, 50 and 75 mgPilot relative bioavailability; randomized 2 period cross-over open-label; 50 mgAbsolute bioavailability; single-period open label; 75mg oral and 350µg IV infusionFormulationFormulated capsuleFormulated capsule, drug in capsuleFormulated capsule, and IV infusion13C15N2H-LY3039478
Materials and Methods: In all studies, LY3039478 pharmacokinetic (PK) samples were serially collected up to 48 hours postdose. Particularly in study 1, these PK samples were time-matched to triplicate Holter electrocardiogram extractions. Noncompartmental analyses were used to calculate the PK parameters, and mixed-effects models were used for statistical inference. Results: In Study 1, exposures increased with dose and were proportional in the 25-75 mg dose range. The regression slope of placebo-adjusted QT Interval corrected for heart rate using Fridericia’s equation (QTcF) and LY3039478 plasma concentration was approximately zero (-0.001, 90% confidence interval (CI) [-0.006, 0.003]), indicating no significant linear association between the two parameters. In Study 2, the estimated ratios of geometric mean exposures (test/reference) were 1.31 (90% CI [1.23, 1.40]) for area under the plasma concentration-time curve from time zero to infinity (AUC(0-∞)) and 1.20 (90% CI [1.07, 1.35]) for maximum plasma concentration (Cmax), after a single 50 mg dose. Higher exposures were achieved with the formulated capsule versus the drug in capsule. In Study 3, the geometric least squares mean absolute bioavailability of LY3039478 after oral administration was 0.572 (90% CI [0.532, 0.615]). Conclusions: LY3039478 was well tolerated in healthy volunteers when administered as single oral doses of up to 75 mg, and after a single IV dose of 350 µg 13C15N2H-LY3039478. There was no evidence of QTcF prolongation effect from LY3039478 in the dose range 25 to 75 mg. The AUC(0-∞) and Cmax of LY3039478 administered as the formulated capsule (test) was approximately 30% and 20% higher, respectively, than the drug in capsule (reference) in healthy subjects. The absolute bioavailability of a 75 mg oral dose of LY3039478 was 0.57.
Citation Format: Eunice Yuen, Maria Posada, Claire Smith, Katharine Thorn, Dale Greenwood, Michelle Burgess, Karim Benhadji, Demetrio Ortega, Louise Chinchen, Jeffrey Suico. Evaluation of the effects of an oral Notch inhibitor, LY3039478, on QT interval, and absolute and pilot relative bioavailability studies conducted in healthy subjects [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B082.