Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor

Abstract

Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. Methods: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (low density lipoprotein cholesterol). Results: MK-0616 displayed high affinity ( K i = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84–103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple–oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43–85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. Conclusions: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.

New Chapter in the PCSK9 Book: Oral Inhibition of PCSK9 Binding to the LDL Receptor With a Macrocyclic Peptide

“…15 The cyclic peptide MK-0616 may present an alternative to currently available PCSK9 inhibitors, especially for patients who prefer oral medications or who cannot access the subcutaneous formulations. In the study by Johns et al, 11 MK-0616 demonstrated the ability to effectively decrease LDL-C levels, both as monotherapy and in combination with statin treatment. According to the data on other PCSK9 inhibitors, it is likely that MK-0616 will also prove to be effective in preventing cardiovascular disease and reducing the incidence of adverse cardiovascular events.…”

“…Furthermore, 2 phase 1 studies were performed to evaluate the pharmacodynamics and safety profile of MK-0616 in humans. 11 In the first study, 60 healthy male volunteers received a single-ascending dose of the drug, whereas the second study tested a multiple-risingdose regimen in statin-treated patients. In the first study, participants were given a single dose during a specific period.…”

Beyond 20 in the 21st Century: Prospects and Challenges of Non-canonical Amino Acids in Peptide Drug Discovery

“…17 In turn, Merck recently disclosed the structure of MK-0616, an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, which in a recent Phase 2b study, significantly reduced LDL-C in patients with hypercholesterolemia. 18 Potency and protease stability were obtained through introduction of a fluorinated tryptophan, D-Ala (AA2), α-Me-Pro (AA8), and cross-linking, ultimately yielding an oral MP inhibitor at a fraction of the size of current monoclonal antibody injectables.…”

“…For Chugai, their first clinical macrocyclic peptide for intracellular rat sarcoma virus (RAS) inhibition was identified through incorporation of multiple N -substituted ncAAs, reducing the polar surface area and improving membrane permeability . In turn, Merck recently disclosed the structure of MK-0616, an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, which in a recent Phase 2b study, significantly reduced LDL-C in patients with hypercholesterolemia . Potency and protease stability were obtained through introduction of a fluorinated tryptophan, d -Ala (AA2), α-Me-Pro (AA8), and cross-linking, ultimately yielding an oral MP inhibitor at a fraction of the size of current monoclonal antibody injectables.…”

Correction to “Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment”

“…An error has been identified in Figure regarding the structure and caption of MK-0616 ( 5 ). The functional group on the terminal aryl is incorrectly depicted as −OH; the correct functional group is −OCH 3 on the terminal aryl ring. , The corrected Figure is shown below:…”