Pooled analysis of three trials with PCSK9 siRNA in patients with HeFH or ASCVD
Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis
Introduction and methods
Reasons for failure to achieve LDL-c target levels include poor adherence and suboptimal use of efficacious lipid-lowering regimens . Effective LDL-c lowering therapies in addition to statins that facilitate adherence are of interest as 80% of patients on statins with established ASCVD do not reach guideline recommended LDL-c goals [2-5].
Inclisiran is a siRNA that suppresses PCSK9 translation in the liver and lowers circulating concentrations of PCSK9 and LDL-c with twice-yearly dosing . Three phase 3, placebo-controlled, double-blind, randomized trials investigated the efficacy and safety of inclisiran in patients with heterozygous familial hypercholesterolemia (HeFH) (ORION-9, n=482), ASCVD (ORION-10, n=1561), or ASCVD and ASCVD risk equivalents (ORION-11, n=1617) [7,8]. The current analysis provided patients-level pooled efficacy and safety data from the three trials of inclisiran versus placebo (n=3660). Participants were aged ≥18 years and had elevated LDL-c levels despite receiving maximally tolerated statins with or without other LDL-c-lowering therapies, such as ezetimibe. Participants were randomized 1:1 to receive either inclisiran sodium 300 mg or placebo administered as a subcutaneous injection on days 1 and 90, followed by doses at 6-month intervals, on days 270 and 450. The pre-specified coprimary endpoints included placebo-corrected percentage change in LDL-c from baseline to day 510 and the time-adjusted placebo-controlled percentage change in LDL-c after day 90 up to day 540 (average of all measurements over this time period).
- The placebo-corrected percentage change in LDL-c from baseline to day 510 with inclisiran was -50.7% (95%CI -52.9% to -48.4%, P<0.0001). The corresponding absolute change in LDL-c was -55.1 mg/dl (95%CI -57.4 to -52.8 mg/dl, P<0.0001).
- The time-adjusted placebo-controlled percentage change in LDL-c after day 90 up to day 540 with inclisiran was -50.5% (95%CI -52.1% to -48.9%, P<0.0001). The corresponding absolute change in LDL-c was -52.7 mg/dl (95%CI -54.4 to -50.9 mg/dl, P<0.0001).
- The placebo-corrected percentage change in PCSK9 with inclisiran at day 510 was -80.9% (95%CI -83.8% to -78.0%, P<0.001).
- The placebo-corrected percentage change in total cholesterol, Apo-B and non-HDL-c with inclisiran was -32.4%, -41.7%, and -46.3% respectively (P<0.001 at all time points for all variables).
- Subgroup analyses showed that LDL-c reductions were consistent regardless of intensity of background statin treatment, baseline statin treatment, lipid management treatment or body mass index.
- At day 510, 80.2% of participants treated with inclisiran reached LDL-c <100 mg/dl, compared to 43.6% on placebo. 67.9% treated with inclisiran reached LDL-c <70 mg/dl (vs. 12.4% on placebo), 51.8% reached LDL-c <50 mg/dl (vs. 2.2% on placebo) and 14.0% reached LDL-c <25 mg/dl (vs. 0.3% on placebo).
- More cases of clinically relevant treatment emergent adverse events at the injection site were reported in the incliciran group than in the placebo group (5.0% vs. 0.7%, risk ratio 7.54), although none of the cases were severe or persistent. There were also more cases of bronchitis in the inclisiran group than in the placebo group (4.3% vs. 2.7%, risk ratio 1.55, 95%CI 1.09-2.20). These cases were nearly all mild to moderate. Liver and renal function tests, creatine kinase values, and platelet counts were similar between groups. Other safety outcomes were also similar between groups.
This pooled analysis of ORION-9, ORION-10 and ORION-11 showed that inclisiran administered subcutaneously twice-yearly reduced LDL-c on average by 50.7% compared to placebo in patients with ASCVD, ASCVD risk equivalence, or HeHF on maximally tolerated statins. Injection site reactions and bronchitis occurred more often in the inclisiran group compared to the placebo group. Other safety outcomes were similar between groups.