Safety and Tolerability of Inclisiran

By Michael H. Crawford, MD. Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco.

SYNOPSIS: A pooled analysis of seven relatively short-term ORION studies of inclisiran vs. placebo for lowering low-density lipoprotein cholesterol that assessed safety and tolerability for up to six years showed that inclisiran has similar rates of adverse events, excluding injection site reactions, as placebo treatment and is associated with fewer major adverse cardiovascular events.

SOURCE: Wright RS, Koenig W, Landmesser U, et al. Safety and tolerability of inclisiran for treatment of hypercholesterolemia in 7 clinical trials. J Am Coll Cardiol 2023;82:2251-2261.

Inclisiran is the first small interfering ribonucleic acid (siRNA) preparation that decreases the production of proprotein convertase subtilisin/kexin type 9 (PCSK9) and has been shown to reduce low-density lipoprotein (LDL) cholesterol after subcutaneous injections, which can be administered twice per year after an initial and a three-month dose. However, the long-term safety and tolerability of this therapy has not been established. Thus, this analysis of data from seven completed and ongoing trials with inclisiran exposure for up to six years is of interest.

The patient-level data from ORION-1, 3, 5, 8, 9, 10, and 11 were pooled for this post-hoc analysis. These trials included patients who received 300 mg of inclisiran subcutaneously or placebo on day 1 and day 90 and then every six months for up to six years. The 5,544 subjects (3,576 inclisiran, 1,968 placebo) had an average age of 64 years, 33% were women, 92% were white, 84% had atherosclerotic cardiovascular disease (ASCVD), and 91% were on a statin drug. Inclisiran treatment lasted two to four years in 72% of the subjects, four to five years in 9% of the subjects, and five to six years in 2% of the subjects.

The primary study endpoint of serious adverse events (hepatic, muscle, kidney, and new diabetes) leading to drug discontinuation were not different for the first 1.5 years in the inclisiran and placebo groups. However, major adverse cardiovascular events (MACE) were numerically greater in the placebo group (6.8/100 vs. 3.8/100 patient years). Injection site adverse events were more frequent in the inclisiran group (9.3%) compared to placebo (1.8%) and were more common in women in the inclisiran group (14% vs. 7%). Treatment-induced anti-drug antibodies were 4.6%, with 1.4% persisting, but they were not related to adverse events. The authors concluded that inclisiran is well tolerated and devoid of serious adverse events precipitating drug discontinuation. These results supported the safety of inclisiran for treating patients with dyslipidemia.

COMMENTARY

Trying to find an LDL cholesterol-lowering drug that patients will accept and continue indefinitely is a challenge. The perception and fear of adverse effects from statins has been a major impediment to their acceptance despite studies showing that adverse effects are not that common. Thus, the search for effective yet well-tolerated drugs continues. The Food and Drug Administration has approved a few new ones in the last few years, the most recent being inclisiran, which is an siRNA that decreases the synthesis of PCSK9 in the liver. It was approved as an adjunct to diet and statins for patients with high LDL cholesterol. An earlier Phase III trial showed that it decreased LDL cholesterol 50% compared to placebo. Since this drug involves RNA, it may get the same guarded reception that the new COVID-19 vaccines did. Thus, this pooled analysis of the ORION trials to date and focusing on adverse effects is of interest.

Inclisiran was well tolerated in combination with statin and other cholesterol-lowering drugs, with adverse event rates nearly identical to placebo for up to six years in some patients. The only difference compared to placebo is that injection site reactions were more common with inclisiran and in women. However, these were largely mild, transient, and rarely led to drug discontinuation. Specific adverse events, such as muscle symptoms, hepatic and renal abnormalities, and new diabetes, also were analyzed, none of which were more frequent with inclisiran.

Although not powered for MACE endpoints, there were fewer in the inclisiran group, as would be expected in an LDL cholesterol-lowering drug. There are three ongoing outcome trials with inclisiran, which will definitively answer this question. Finally, the incidence of autoantibodies to inclisiran was low and usually transient.

There are limitations to this study to consider. Inclisiran increases LDL receptors on the liver, which has been shown in other studies to decrease atherosclerosis. There were no data on atherosclerosis in this pooled analysis. The duration of the placebo-controlled data in this study was only 1.5 years, and few were exposed to inclisiran for more than four years.

Although we do not have data on pricing or insurance coverage, it is noteworthy that the older monoclonal antibodies to PCSK9 drugs are considered pharmacy benefits, since they were administered by the patient or caregiver, whereas inclisiran, which has to be administered by a physician, is considered a medical benefit. Finally, the monoclonal antibody drugs have been reported to decrease LDL cholesterol more than inclisiran (60% vs. 50%). However, they must be given one to two times per month compared to every six months in the maintenance phase of inclisiran. Thus, it will be interesting to see how inclisiran fares against the monoclonal antibody drugs, which also must be injected.