Abstract Body (Do not enter title and authors here): Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, leading to their degradation and decreasing serum LDL-cholesterol (LDL-C) to reduce risk of coronary heart disease. We aimed to investigate the safety, tolerability, pharmacodynamic characteristics of RN0191, a novel structure small interfering RNA that inhibits PCSK9 mRNA translation process, in healthy Chinese adults with elevated LDL-C who were not on lipid-lowering treatment.
Methods: We did a randomized, single-blind, placebo-controlled, Phase 1 dose-ascending study in healthy Chinese volunteers with serum LDL-C≥100 mg/dL (2.6 mmol/L). Subjects were randomly assigned in a 6:2 ratio to receive single subcutaneous injection of RN0191 (dose ranging from 60mg to 600mg) or placebo. Primary endpoint was the safety and tolerability of RN0191. Secondary endpoints included RN0191's pharmacodynamic effects on PCSK9, LDL-C and other lipid biomarkers. All subjects were masked to treatment assignment. The study registered in ClinicalTrials.gov (NCT06132360) and is still on-going.
Results: Of 32 subjects, 24 were randomly allocated to receive a single dose (60mg/200mg/400mg/600mg) of RN0191 (6 in each active arm) and 8 to placebo. The analysis spans all cohorts at Day 56 post-administration. All the adverse events are mild or moderate. There is no severe treatment-emergent AE (TEAE), death or TEAE leading to study discontinuation. The numbers of subjects affected by TEAEs in each cohort of RN0191 (3,4,2,2) are similar to that of placebo (3). The interim data indicates a profound dose-dependent lowering impact of RN0191 on several key lipid biomarkers. Substantial PCSK9 protein reduction is demonstrated in a dose-dependent manner. In high dose (400 mg and 600 mg) cohorts, mean maximal decreases of PCSK9 level of 85.84% on Day 21 and 86.14% on Day 28 are achieved respectively. Notably, LDL-C exhibits progressively greater reductions across escalating doses. The mean maximal decreases of LDL-C are achieved as 54.65% of 400mg cohort on Day 42 and 51.35% of 600mg cohort on Day 21 respectively. Additionally, a significant lipoprotein (a) reduction is observed with mean maximal lowering level of 43.95% at 400mg cohort on Day 21 and 52.95% at 600mg on Day 28 respectively.
Conclusions: The preliminary safety and efficacy profile of RN0191 underscoring its comprehensive lipid-lowering capacity as a promising therapeutic candidate for managing dyslipidemia.