{"id":"77edf9d349cf","type":"article","url":"https://hartvaat.nl/2026/05/15/laroprovstat-eerste-orale-pcsk9-remmer-haalt-80-ldl-reductie-in-combinatie-met-r/","title":"Laroprovstat: eerste orale PCSK9-remmer haalt -80% LDL-reductie in combinatie met rosuvastatine (fase 1)","title_en":"","category":"cholesterol","category_label":"Cholesterol","professions":["apotheker","cardioloog","internist"],"tags":["atorvastatine","enlicitide","ezetimibe","hdl-cholesterol","lipidenverlaging","niet-statine-therapie","obicetrapib","pcsk9-remmers","pcsk9-remmers-nieuwe-generatie","ramipril","rosuvastatine","statines"],"journal":"Circulation","doi":"10.1161/CIRCULATIONAHA.125.075973","source_url":"https://doi.org/10.1161/CIRCULATIONAHA.125.075973","authors":["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"],"significance":8,"published":"2026-06-19","source_date":"2026-05-15","image":"","kennis":["https://hartvaat.nl/kennis/lipiden/ldl-cholesterol-mechanisme/","https://hartvaat.nl/kennis/lipiden/genetisch-onderzoek-fh/"],"congress":"","summary_en":"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.","created":"2026-07-03T10:33:04Z","updated":"2026-07-03T13:31:59Z","licence":"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.","body_markdown":"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.","abstract_original":"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."}