Proprotein convertase subtilisin-like/kexin
type 9 (PCSK9) is a
key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated
target for the treatment of hypercholesterolemia and coronary artery
disease. In this paper, we describe a series of novel cyclic peptides
derived from an mRNA display screen which inhibit the protein–protein
interaction between PCSK9 and LDLR. Using a structure-based drug design
approach, we were able to modify our original screening lead 2 to optimize the potency and metabolic stability and minimize
the molecular weight to provide novel bicyclic next-generation PCSK9
inhibitor peptides such as 78. These next-generation
peptides serve as a critical foundation for continued exploration
of potential oral, once-a-day PCSK9 therapeutics for the treatment
of cardiovascular disease.
Proprotein
convertase subtilisin-like/kexin type 9 (PCSK9) is a
key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated
target for the treatment of hypercholesterolemia and coronary artery
disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely
potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules
such as 44 demonstrated sufficient oral bioavailability
to maintain therapeutic levels in rats and cynomolgus monkeys after
dosing with an enabled formulation. We demonstrated target engagement
and LDL lowering in cynomolgus monkeys essentially identical to those
observed with the clinically approved, parenterally dosed antibodies.
These molecules represent the first report of highly potent and orally
bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles
favorable for potential development as once-daily oral lipid-lowering
agents. In this manuscript, we detail the design criteria and multiparameter
optimization of this novel series of PCSK9 inhibitors.
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.
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