Twice-yearly inclisiran, in addition to maximally tolerated statin therapy, was found to be safe and effective in lowering low-density lipoprotein cholesterol (LDL-C) in adult patients with heterozygous familial hypercholesterolemia (FH), atherosclerotic cardiovascular disease (ASCVD), or ASCVD risk equivalents, according to results from a pooled analysis of phase 3 published in the Journal of the American College of Cardiology.
In the current analysis, the researchers used pooling data from 3 phase 3 studies to precisely assess the efficacy of inclisiran treatment and evaluate treatment safety and tolerability in patients with FH or ASCVD.
The 3 trials (ORION-9, -10, and -11; ClinicalTrials.gov Identifiers: NCT03397121, NCT03399370, and NCT03400800, respectively) were placebo-controlled, of an 18-month duration. The pooled analysis included a total of 3660 participants.
Patients receiving background, maximally tolerated statins also received 300 mg inclisiran sodium (n=1833) or placebo (n=1827) in all 3 trials. Inclisiran was administered on days 1, 90, 270, and 450. Change in LDL-C, total cholesterol, non-high-density lipoprotein cholesterol (–HDL-C), proprotein convertase subtilisin-kexin type 9 (PCSK9), and apolipoprotein B were assessed.
Treatment and placebo recipients were aged 64.1and 63.9 years; 66.9% and 68.1% were men; 84.7% and 85.1% had ASCVD; and 19.3% and 20.2% had FH, respectively.
Mean placebo-corrected change of LDL-C in the treatment group was -50.7% (95% CI, -52.9% to -48.4%; P <.0001) at day 510, which corresponded to a decreased LDL-C concentration of -55.1 mg/dL (95% CI, -57.4 to -52.8 mg/dL; P <.0001).
Mean placebo-corrected decrease of PCSK9 in the treatment group was -80.9% (95% CI, -83.8% to -78.0%; P <.001), total cholesterol was -32.4% (95% CI, -33.7% to -31.1%; P <.001), non-HDL-C was -46.3% (95% CI, -48.1% to -44.5%; P <.001), and apolipoprotein B was -41.7% (95% CI, -43.2% to -40.3%; P <.001).
Compared with baseline, at study conclusion, 61.5% of the inclisiran group and 2.2% of the placebo group achieved at least a50% reduction of LDL-C.
In the treatment group, the researchers observed elevated risks for any injection site reaction (odds ratio [OR], 7.54; 95% CI, 4.14-13.71), mild injection site reactions (OR, 6.05; 95% CI, 3.21-11.42), and moderate injection site reactions (OR, 23.86; 95% CI, 3.23-176.15). Treatment-emergent adverse events leading to drug discontinuation (risk ratio [RR], 1.28; 95% CI, 0.83-1.98) or 1 or more serious treatment-emergent adverse events (RR, 0.89; 95% CI, 0.78-1.00) were not significantly elevated in the inclisiran group.
At all study assessments, concentrations of HDL-C were significantly elevated in the inclisiran cohort (P <.001).
A study limitation included the insufficient power to detect serious, rare events. However, additional, larger trials are needed.
Researchers concluded, “Inclisiran administered twice yearly reduces LDL-C on average by 50.7% and was well tolerated, except for self-limiting, mainly mild injection site reactions and bronchitis.”
Disclosure: Several authors declared affiliations with pharmaceutical industry. Please refer to the original article for a full list of authors’ disclosures.
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(9):1182-1193. doi:10.1016/j.jacc.2020.12.058