PCSK9-targeted siRNA therapy: effective, safe and durable lipid-lowering irrespective of diabetes status
Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial
Introduction and methods
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is associated with CV benefit in individuals with stable CVD [1,2] and recent acute coronary syndromes [3,4] independent of whether they have diabetes [2,3]. Inclisiran, a synthetic siRNA that drives PCSK9-specific mRNA degradation in the liver, has been reported to significantly lower LDL-c levels in individuals with ASCVD or ASCVD risk and high LDL-c levels in the ORION-1 trial [5,6].
The phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose ORION-1 trial randomized eligible subjects (n=501) to either one dose of placebo or inclisiran (200, 300, or 500 mg on day 1) or two doses of placebo or inclisiran (100, 200 or 300 mg on day 1 and 90) on top of standard care and stratified participants based on the presence (n=67) or absence (n=415) of diabetes at baseline.
This post-hoc analysis of the ORION-1 trial assessed whether individuals with and without diabetes at baseline respond differently to inclisiran with regard to changes in lipid profiles, safety, and glycemic control. The primary efficacy endpoint was the percent change from baseline LDL-c at day 180. Secondary efficacy endpoint included the percent change in lipid measure. Adverse events were documented up to day 210.
Inclisiran and LDL-c levels
- The one-dose inclisiran regimen at the highest dose tested (500 mg) resulted in changes in LDL-c between baseline and the day 180 visit of -41.4% (95%CI: -47.0 to -35.9, P<0.0001) in those without diabetes and in -45.8% (95%CI: -62.3 to -29.3, P=0.0031) in those with diabetes, compared to placebo.
- Treatment with two-doses of inclisiran 300 mg resulted in robust reductions in mean LDL-c levels of 52.3% (95%CI: 57.1 to 47.5%, P<0.0001) in those without diabetes and of 55.0% (95%CI: 68.0 to 42.0, P<0.0001) in those with diabetes, from day 14 until day 180, compared to placebo.
- LDL-C remained signiﬁcantly below baseline levels at day 180 with the one-dose inclisiran regimen.
- In the one-dose inclisiran regimen, the LDL-c nadirs normally occurred at day 30. The two-dose inclisiran regimen resulted in further LDL-lowering after the second dose.
Inclisiran and lipid profiles and glycemic control
- In both subjects without and with diabetes, treatment with inclisiran resulted in decreased total cholesterol (up to 32.6% [SD: 11.5] and up to 37.5 [8.8], respectively), atherogenic apoB (up to 40.6 [15.4] and up to 43.1 [10.3]), non-HDL-c (up to 45.7% [15.1] and up to 48.1 [10.5]), and Lp(a) (up to 25.4 [-37.4 to -15.0] and up to 33.3 [-51.7 to 15.9]), as well as in a trend towards increases in HDL-c (≤10.1% [15.5] and ≤11.1 [13.0]), compared to placebo.
- There were no clinically meaningful changes in HbA1c 180 days after treatment initiation, and this persisted over the course of the study.
Inclisiran and adverse events
- The number of adverse events was similar between patients with and without diabetes, and no inclisiran-related cases of myopathy, nor persistent elevations of liver function tests were seen.
Regardless of diabetes status and dose regimen, one or two doses of inclisiran on top of standard care not only yielded extended reduction of LDL-c levels, but this siRNA treatment also improved atherogenic lipid and lipoprotein profiles. Inclisiran treatment was found to be safe and well tolerated. These data suggest that inclisiran may be a viable lipid-lowering alternative in both people with and without diabetes.