EP-036 - ESTIMATING TARGET ENGAGEMENT USING SINGLE POST-DOSE TIMEPOINT TO SUPPORT FURTHER CLINICAL DEVELOPMENT.

E. Caratzas¹, H. Chandasana², T. Angel², C. O'Hare³, M. Magee², B. Swift⁴; ¹University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, ²GlaxoSmithKline, Collegeville, PA, USA, ³GlaxoSmithKline, San Francisco, CA, USA, ⁴GlaxoSmithKline, Durham, NC, USA.

Background: Human genetic studies have identified mutations in the hydroxysteroid 17-β-dehydrogenase-13 (HSD17B13) gene that are protective against development of both alcohol-related and nonalcohol-related liver disease1. GSK4532990 is a small interfering ribonucleic acid (siRNA)-based therapeutic that selectively targets HSD17B132. The objective of this analysis was to utilize the hepatic HSD17B13 protein levels at baseline and a single post-dose liver biopsy in patients with NASH or suspected NASH to support Phase 2 dose selection.

Methods: Hepatic HSD17B13 protein levels, GSK4532990 PK, and serum ALT data were obtained from a Phase1/2a study (NCT04202354) in healthy participants and patients that received subcutaneous doses of 25 to 200 mg.
A population PK-PD model, with an effect compartment and indirect response was utilized to describe reduction of ALT and protein. PK and effect compartment parameters for ALT were fixed to estimate the drug effect parameters on HSD17B13 protein knockdown. HSD17B13 decay rate was fixed utilizing a clinically derived estimate3.

Results: An inhibitory indirect response model with an Imax effect described the decrease in HSD17B13 protein levels on Day 71. Model simulations confirmed dose-dependent protein knock-down and tracked with the estimated half-life of HSD17B13. Simulations with varying baseline protein levels did not change the percent change from baseline. Rather, the relative change was dependent on the half-life, indicating that simulated doses induced complete or near complete protein down-regulation. Increasing the dose from 100 mg to 200 mg led to a prolonged duration of effect.

Conclusion: Prediction of target engagement with a single post-dose timepoint is challenging. This unique model-based approach was used to estimate target engagement and guide dose selection.

1. Abul-Husn, N. S., Cheng, X., Li, A. H., Xin, Y., Schurmann, C., Stevis, P., Liu, Y., Kozlitina, J., Stender, S., Wood, G. C., Stepanchick, A. N., Still, M. D., McCarthy, S., O'Dushlaine, C., Packer, J. S., Balasubramanian, S., Gosalia, N., Esopi, D., Kim, S. Y., Mukherjee, S., … Dewey, F. E. (2018). A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease. The New England journal of medicine, 378(12), 1096–1106. https://doi.org/10.1056/NEJMoa1712191
2. Lung Yi Mak, Man Fung Yuen, Christian Schwabe, Ki Tae Yoon, Jeong Heo, Russell Scott, Jeon-Hoon Lee, Jung Il Lee, Young Oh Kweon, Martin Weltman, Stephen A. Harrison, Brent A. Neuschwanter-Tetri , Kenneth Cusi, Rohit Loomba, Eric Garcia-Medel, Min Yi, Javier San Martin, Marco Wong, James Hamilton, Ed Gane. ARO-HSD, an investigational RNAi therapeutic, demonstrates reduction in ALT and hepatic HSD17B13 mRNA and protein in patients with NASH or suspected NASH. AASLD. November 13 – 16, 2021. Available at: https://www.natap.org/2021/AASLD/AASLD_99.htm
3. Decaris, M., Li, K., Emson C., et al (2017). Identifying Nonalcoholic Fatty Liver Disease Patients with Active Fibrosis by Measuring Extracellular Matrix Remodeling Rates in Tissue and Blood. Hepatology, 65(1) 78-88.