By Michael H. Crawford, MD

Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco

SYNOPSIS: A pooled analysis of three trials of inclisiran in patients with atherosclerotic cardiovascular disease or its risk equivalent showed impressive reductions in LDL cholesterol with subcutaneous injections.

SOURCE: Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol 2021;77:1182-1193.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers LDL cholesterol receptor levels by inhibiting their ability to be recycled to the cell surface, which hinders the removal of LDL particles from circulation. Current monoclonal antibodies targeting PCSK9 are quite effective in lowering LDL levels but require subcutaneous injections every two to four weeks. Inclisiran is a double-stranded RNA molecule that suppresses PCSK9 translation in the liver and lowers circulating concentrations of PCSK9 and LDL. Three Phase III placebo-controlled, double-blind, randomized trials of inclisiran injected subcutaneously every six months showed the drug lowers LDL by about 50% and is well tolerated. This report provides pooled patient-level data.

The authors of ORION-9 studied patients with heterozygous familial hypercholesterolemia. The authors of ORION-10 studied patients with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL levels. The authors of ORION-11 studied subjects with ASCVD or its equivalent and elevated LDL. Inclusion criteria for the three studies were elevated LDL levels > 70 mg/dL for those with ASCVD or > 100 mg/dL for the rest on maximally tolerated doses of statins, with or without other agents or documented intolerance to two statins. In all three studies, inclisiran 300 mg was injected on days 1, 90, 270, and 450. The primary endpoint was the change in LDL from baseline and compared to placebo levels. The pooled study population included 3,660 participants, and 94% of subjects completed the protocol. ASCVD was present in 85% of the subjects, and 92% were on statins. The mean LDL level at baseline was 112 mg/dL in the inclisiran group and 111 mg/dL in the placebo group.

Compared to placebo, inclisiran cut LDL levels by 51% at day 510. Injection site-related adverse events were more common in the inclisiran group (5% vs. 0.7% in the placebo group). These were predominantly mild (67%); none were severe. There were no significant changes in laboratory values for liver and kidney function nor creatine kinase values or platelet counts. The authors concluded that in subjects with familial hypercholesterolemia, ASCVD, or ASCVD equivalents, inclisiran injected twice-yearly in addition to maximally tolerated statin therapy is safe and efficacious for reducing LDL levels to target.

COMMENTARY

All clinicians recognize statin adherence is a challenge for many reasons: too many pills, perceived muscle symptoms, fear of liver injury, and more. The monoclonal antibodies against PCSK9 are a major advance in this regard, but an injection every two to four weeks is not acceptable to everyone. Thus, the development and early success of these inclisiran trials is encouraging. An injection every six months is likely to be better accepted and could correspond to patients’ routine physician visits. The paucity of adverse effects is reassuring. Other than mild to moderate injection site symptoms, the only other adverse effect detected was an increase in bronchitis (5% vs. 2.7%), which is of uncertain significance. Of course, with this relatively small group of subjects studied for less than two years, rare adverse effects may not have been detected.

Inclisiran lowered LDL to < 100 mg/dL in 100% of subjects, to < 70 mg/dL in 68% of subjects, and to < 50 mg/dL in 52%. Also, inclisiran lowered the levels of other atherogenic lipids, such as total cholesterol, Apo-B, and non-HDL cholesterol. These robust effects should profoundly affect atherosclerosis and related major adverse cardiovascular events. Clinicians await the clinical outcome trials, but the initial data are encouraging for eventual FDA approval.