Background: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia.
Methods: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540.
Results: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.
Conclusions: Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).
Copyright © 2020 Massachusetts Medical Society.
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Epub 2020 Mar 18. N Engl J Med. 2020. PMID: 32187462 Clinical Trial.
Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.N Engl J Med. 2017 Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758. Epub 2017 Mar 17. N Engl J Med. 2017. PMID: 28306389 Clinical Trial.
Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.JAMA Cardiol. 2019 Nov 1;4(11):1067-1075. doi: 10.1001/jamacardio.2019.3502. JAMA Cardiol. 2019. PMID: 31553410 Free PMC article.
Inclisiran for the treatment of dyslipidemia.Expert Opin Investig Drugs. 2018 Mar;27(3):287-294. doi: 10.1080/13543784.2018.1442435. Epub 2018 Feb 22. Expert Opin Investig Drugs. 2018. PMID: 29451410 Review.
Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia.Diseases. 2018 Jul 13;6(3):63. doi: 10.3390/diseases6030063. Diseases. 2018. PMID: 30011788 Free PMC article. Review.