Laroprovstat, the First Oral Small-Molecule PCSK9 Inhibitor for the Treatment of Hypercholesterolemia: Results From a Randomized, Single-Blind, Placebo-Controlled Phase 1 Trial in Treatment-Naïve Patients
Abstract
BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is an effective therapy for reducing low-density lipoprotein (LDL) cholesterol (LDL-C) in adults with hyperlipidemia, including heterozygous familial hypercholesterolemia, thereby lowering cardiovascular risk. Current PCSK9 inhibitors are injectable therapies; no oral small-molecule PCSK9 inhibitor has yet been approved. METHODS: Laroprovstat (AZD0780) is a novel small-molecule identified through structure-based design that binds to the PCSK9 C-terminal domain. The effects of laroprovstat on LDL receptor expression and LDL-C levels were assessed in vitro and in mice expressing human PCSK9 . Safety, tolerability, and pharmacokinetic and pharmacodynamic properties of laroprovstat were assessed in healthy participants with LDL-C ≥70 and ≤190 mg/dL after single ascending doses. Laroprovstat was also assessed in participants with LDL-C ≥100 and ≤190 mg/dL at doses of 1 mg or 30 mg versus placebo administered once daily for 28 days after a rosuvastatin 20 mg run-in treatment period. RESULTS: Laroprovstat does not inhibit the PCSK9–LDL receptor interaction but stabilizes the PCSK9 C-terminal domain, preventing lysosomal trafficking and degradation of LDL receptor. Laroprovstat increased LDL receptor expression and reduced LDL-C levels in mice expressing human PCSK9 . Laroprovstat displayed dose-proportional pharmacokinetics and a half-life suitable for once-daily dosing (≈40 hours). There was no clinically meaningful change in exposure when dosed with a high-fat meal compared with the fasted state (area under the plasma concentration-time curve inf and C max geometric mean reduction of 1.15 [90% CI, 1.11–1.19] and 1.06 [90% CI, 1.00–1.13], respectively). After a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 and 30 mg reduced LDL-C by 29% (95% CI, 18%–38%) and 51% (95% CI, 44%–58%) compared with baseline. Combined rosuvastatin and laroprovstat treatment resulted in a total approximate reduction in LDL-C of 70% and 80% for laroprovstat 1 and 30 mg, respectively. CONCLUSIONS: Laroprovstat was well tolerated with no safety findings of concern and may be dosed with or without food. In treatment-naïve participants with hypercholesterolemia, combined rosuvastatin 20 mg and laroprovstat 30 mg treatment led to an 80% LDL-C reduction, supporting further development of laroprovstat as the first oral small-molecule PCSK9 inhibitor in patients with hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05384262.
Article Details
Authors (29)
Rick B. Vega
Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (R.B.V.).
Gavin O’Mahony
Biopharma Chemistry, Discovery Sciences (G.O.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
April M. Barbour
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences (A.M.B., H.Y.), AstraZeneca, Gaithersburg, MD
Hongtao Yu
Jane Knöchel
Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences (J.K.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Johan Brengdahl
Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (J.B.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Thomas Hochdörfer
Mechanistic Biology and Profiling, Discovery Sciences (T.H.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Linnéa Bergenholm
Drug Metabolism, Pharmacokinetics and Biomarker Bioanalysis, Cardiovascular, Renal and Metabolism (L.B., A.B.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Eva Töppner Carlsson
Bioscience Metabolism, Research & Early Development, Cardiovascular, Renal and Metabolism (E.T.C., A.A., D.L.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Andrea Ahnmark
Bioscience Metabolism, Research & Early Development, Cardiovascular, Renal and Metabolism (E.T.C., A.A., D.L.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Christina Rye Underwood
Bioscience Metabolism, Research and Early Development (C.R.U.), Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Anna Rudvik
Late Cardiovascular, Renal and Metabolism (A.R.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Debra Carter
Global Safety, Cardiovascular, Renal and Metabolism (D.C.), AstraZeneca, Gaithersburg, MD
Johanna Laru
Pharmaceutical Sciences (J.L.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Aspen Gutgsell
Protein Science, Structure and Biophysics, Discovery Sciences, (A.G., S.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Lee Twaddle
Early Phase Clinical Operations (L.T.), Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Pavlo Garkaviy
Early Clinical Development, Cardiovascular, Renal and Metabolism (P.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Anna Bogstedt
Drug Metabolism, Pharmacokinetics and Biomarker Bioanalysis, Cardiovascular, Renal and Metabolism (L.B., A.B.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Eva Hurt-Camejo
Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (E.H.-C., T.M., M.R. A.H., J.B.R.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Tasso Miliotis
Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (E.H.-C., T.M., M.R. A.H., J.B.R.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Maria Ryaboshapkina
Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (E.H.-C., T.M., M.R. A.H., J.B.R.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Andreas Hober
Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (E.H.-C., T.M., M.R. A.H., J.B.R.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Brian Hubbard
Dogma Therapeutics, Boxford, MA (B.H., M.S.-W., V.K.).
Michael Serrano-Wu
Dogma Therapeutics, Boxford, MA (B.H., M.S.-W., V.K.).
Virendar Kaushik
Dogma Therapeutics, Boxford, MA (B.H., M.S.-W., V.K.).
Stefan Geschwindner
Michael C. McCarthy
Center for Astrophysics | Harvard & Smithsonian, 60 Garden Street, Cambridge, Massachusetts 02138-1516, United States
Daniel Lindén
Bioscience Metabolism, Research & Early Development, Cardiovascular, Renal and Metabolism (E.T.C., A.A., D.L.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Jaya B. Rosenmeier
Translational Science and Clinical Development, Cardiovascular, Renal and Metabolism (E.H.-C., T.M., M.R. A.H., J.B.R.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.