Abstract Body (Do not enter title and authors here): Introduction: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is an effective adjunct therapy for reducing low-density lipoprotein cholesterol (LDL-C) in patients with hyperlipidemia. Current approved PCSK9 inhibitors are injectable therapies. Laroprovstat (AZD0780) is an oral, small molecule PCSK9 inhibitor in development to lower LDL-C in patients with hyperlipidemia.
Methods: In this Phase 1 study, the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) properties of laroprovstat were assessed in participants with LDL-C ≥100 mg/dL and ≤190 mg/dL (NCT05384262). Participants were first treated with rosuvastatin 20 mg for three weeks followed by randomization to laroprovstat 1 mg, 30 mg or placebo administered once daily for 28 days. The change from baseline following the rosuvastatin run-in to end of treatment was measured for LDL-C and clinically commonly assessed lipid parameters. Furthermore, a broad panel of apolipoproteins was analyzed with a mass spectrometry-based proteomics method, ApoEdge™.
Results: Laroprovstat was well tolerated with no safety findings of concern. Laroprovstat 30mg accumulated following multiple dosing with ratios of 2.837 for AUC and 2.765 for Cmax . However, there was no evidence of time-dependent PK following 30 mg laroprovstat plus rosuvastatin with a geometric mean ratio (90% CI) of AUCinf Day 1 compared to AUCtau Day 8 of 0.9500 (0.8260, 1.0926). When dosed following a rosuvastatin 20 mg 3-week run-in treatment period, laroprovstat 1 mg and 30 mg reduced LDL-C by 29% (95% CI: 38, 18) and 51% (95% CI: 58, 44). Combined rosuvastatin and laroprovstat treatment resulted in a total approximate reduction in LDL-C of 70% and 80% for laroprovstat 1 mg and 30 mg, respectively. Numerical reductions in total cholesterol, non-HDL-C, and ApoB were also observed with laroprovstat treatment. Decreased levels of ApoB, ApoE, and Apo(a) were also detected with the ApoEdge™ method.
Conclusions: In treatment-naïve hypercholesterolemic patients, rosuvastatin combined with laroprovstat led to nearly 80% LDL-C reduction and was well-tolerated in this Phase 1 study. These data support further development of laroprovstat as the first oral small molecule PCSK9 inhibitor.