A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

Abstract

Background: Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol.

Methods: In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated.

Results: The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).

Conclusions: In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442 .).

Figure 1. Change in Plasma Levels of Proprotein Convertase Subtilisin–Kexin Type 9 (PCSK9), According to Study Group and Dose Cohort

Shown are the effects (mean percentage changes from baseline) of single or multiple doses of inclisiran or placebo on plasma levels of PCSK9 over time. Baseline values were the average of all the study measurements obtained before the first dose. For the single-dose cohorts, the data for the placebo group include all the participants; for the multiple-dose cohorts, the data for the placebo group are presented according to whether the participants were or were not taking a stable baseline dose of statin cotherapy. I bars represent standard errors. For at least one cohort, only one value (for one participant) is shown at some time points. Participants were followed beyond the last planned visit only if the low-density lipoprotein cholesterol level had not returned to 80% of the baseline value by that time. In the single-dose phase, inclisiran or placebo was administered in one dose on day 0. In the multiple-dose phase, the first dose was administered on day 0 and subsequent doses at the indicated intervals. The 300-mg and 500-mg doses were administered as two monthly doses, the 125-mg dose was administered as four weekly doses, and the 250-mg dose was administered once every 2 weeks for 4 weeks.

Figure 2. Effects on Serum Levels of Low-Density Lipoprotein (LDL) Cholesterol, According to Study Group and Dose Cohort

Shown are the effects (mean percentage changes from baseline) of inclisiran or placebo on the serum levels of LDL cholesterol over time. Baseline values were the average of all the study measurements taken before the first dose. For the single-dose cohorts, the data for the placebo group include all the participants; for the multiple-dose cohorts, the data for the placebo group are presented according to whether the participants were or were not taking a stable baseline dose of statin cotherapy. I bars represent standard errors. For at least one cohort, only one value (for one participant) is shown at some time points. In the single-dose phase, inclisiran or placebo was administered in one dose on day 0. In the multiple-dose phase, the first dose was administered on day 0 and subsequent doses at the indicated intervals. The 300-mg and 500-mg doses were administered as two monthly doses, the 125-mg dose was administered as four weekly doses, and the 250-mg dose was administered once every 2 weeks for two doses.