# Laroprovstat: eerste orale PCSK9-remmer haalt -80% LDL-reductie in combinatie met rosuvastatine (fase 1)

*geplaatst 2026-06-19 · Cholesterol · Circulation · doi 10.1161/CIRCULATIONAHA.125.075973 · https://hartvaat.nl/2026/05/15/laroprovstat-eerste-orale-pcsk9-remmer-haalt-80-ldl-reductie-in-combinatie-met-r/*

Fase 1 gerandomiseerde, single-blind, placebo-gecontroleerde studie naar laroprovstat (AZD0780), de eerste orale small-molecule PCSK9-remmer. Anders dan injecteerbare PCSK9-antilichamen remt laroprovstat niet de PCSK9-LDLR-interactie maar stabiliseert het de PCSK9 C-terminus, wat lysosomale afbraak van de LDL-receptor voorkomt. In gezonde deelnemers met LDL ≥70 en ≤190 mg/dL waren farmacokinetiek dosis-evenredig en geschikt voor eenmaal-daagse dosering (halfwaardetijd ~40 uur), zonder voedingsinteractie. Na een 3-weekse run-in met rosuvastatine 20 mg verlaagde laroprovstat 1 mg LDL met 29% en 30 mg met 51% ten opzichte van baseline. De gecombineerde rosuvastatine + laroprovstat-behandeling gaf in totaal ~70% en ~80% LDL-reductie. Veiligheid was goed zonder zorgwekkende signalen. De resultaten ondersteunen verdere ontwikkeling als eerste orale PCSK9-remmer.

## English: 

Phase 1 randomised, single-blind, placebo-controlled trial of laroprovstat (AZD0780), the first oral small-molecule PCSK9 inhibitor. Unlike injectable PCSK9 antibodies, laroprovstat does not block the PCSK9-LDLR interaction but stabilises the PCSK9 C-terminal domain, preventing lysosomal degradation of the LDL receptor. In healthy participants with LDL-C ≥70 and ≤190 mg/dL, pharmacokinetics were dose-proportional and suitable for once-daily dosing (half-life ~40 hours), with no food interaction. After a 3-week run-in with rosuvastatin 20 mg, laroprovstat 1 mg reduced LDL by 29% and 30 mg by 51% versus baseline. Combined rosuvastatin + laroprovstat resulted in total LDL reductions of ~70% and ~80%. Safety was favourable with no concerning signals. The results support further development as the first oral PCSK9 inhibitor.

## Abstract (original, from the publication)

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 (AUCinf and Cmax 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, 38%-18%) and 51% (95% CI, 58%-44%) 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-naive 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.

Auteurs: Rick B Vega, Gavin O'Mahony, April M Barbour, Hongtao Yu, Jane Knöchel, Johan Brengdahl, Thomas Hochdörfer, Linnéa Bergenholm, Eva Töppner Carlsson, Andrea Ahnmark, Christina Rye Underwood, Anna Rudvik, Debra Carter, Johanna Laru, Aspen Gutgsell, Lee Twaddle, Pavlo Garkaviy, Anna Bogstedt, Eva Hurt-Camejo, Tasso Miliotis, Maria Ryaboshapkina, Andrease Hober, Brian Hubbard, Michael Serrano-Wu, Virendar Kaushik, Stefan Geschwindner, Michael C McCarthy, Daniel Lindén, Jaya B Rosenmeier

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Bron: Circulation, https://doi.org/10.1161/CIRCULATIONAHA.125.075973. Bijgewerkt 2026-07-03T13:31:59Z. Citeer vrij, met bronvermelding en een link naar hartvaat.nl (de url van het record). Samenvattingen zijn redactioneel werk van HartVaat; de oorspronkelijke publicaties blijven van hun uitgevers (doi). Geen medisch advies.