BPS 2025
Discovery of the Highly Potent and Orally Bioavailable Cyclic Peptide PCSK9 Inhibitor MK-0616
Tom Tucker
Principal Scientist, Merck and Co., Inc.
ABSTRACT
Modalities Chemistry Group, Department of Medicinal Chemistry, Merck & Co, Inc., West Point, PA 19486, USA
Proprotein convertase subtilisin-like/Kexin type 9 (PCSK9) is a clinically well-validated and critically important target for treating high LDL-cholesterol and potential coronary artery disease. Two antibody-based and one siRNA based anti-PCSK9 therapeutics have been approved by the FDA for treating high LDL-cholesterol levels and have demonstrated excellent clinical efficacy for lowering LDL levels and preventing adverse cardiac events. However, all of these therapies are parenterally delivered and to date an efficacious, orally dosed anti-PCSK9 therapeutic has not been approved. We focused our efforts on discovering and optimizing novel, orally bioavailable cyclic peptide agents based on leads derived from an mRNA display screening campaign. From the mRNA display screening, we were able to identify moderately potent inhibitor leads. Guided by structural data, we were able to optimize our early leads to enhance metabolic stability, potency, and engineer out several unfavorable off-target activities to provide advanced next generation development candidates. Using an enabled formulation-based approach, we demonstrated acceptable oral bioavailability and good overall pharmacokinetics for these molecules, and using a Target Engagement assay were able to build clear PK/PD relationships in primates. Final optimization of candidate molecules to address formulation-related issues led to the discovery of MK-0616, which is currently undergoing clinical investigation as an LDL-cholesterol-lowering agent. In this talk, we will detail the systematic optimization of these molecules guided by structural data, leading to the discovery of the clinical compound.
BIO
After completing my education, I joined the Medicinal Chemistry Department of Rorer Central Research (now a part of Sanofi-Aventis) in 1984. In 1989, I moved to Merck Research Laboratories in West Point, PA. I began my career at Merck working in the peptide/peptidomimetic space, transitioned into small molecule therapeutics for about 17 years, then moved on to conjugate based siRNA Delivery, and finally then back into the peptide drug discovery space in 2012. I am currently a Principal Scientist in the Peptide /Modalities Drug Discovery Team at MRL West Point. I am the author/co-author of over 50 publications, an inventor on over 70 patents, and have presented frequently at various external meetings. During my career, I have been directly associated with two molecules that have become FDA approved drugs, both in the HIV antiviral therapeutic space: the first-generation non-nucleoside reverse transcriptase inhibitor Stocrin™ / Sustiva™ (Efavirenz); and the second-generation non-nucleoside reverse transcriptase inhibitor Pifeltro™ (Doravirine). I also was a key contributor to the design and synthesis of MK-0616, an oral cyclic peptide therapeutic that is currently undergoing Ph 3 clinical trials. My current research interests are focused on the design and development of novel peptide therapeutics.