Twice-yearly injections of an experimental cholesterol-lowering drug, inclisiran, were effective at reducing low-density lipoprotein (LDL) cholesterol, often called bad cholesterol, in patients already taking the maximum dose of statin drugs, according to data of the ORION-10 trial presented Saturday, Nov. 16, at the American Heart Association’s Scientific Sessions 2019.
High levels of LDL cholesterol – which builds up in the walls of the arteries, making them hard and narrow, thereby leading to blockages – causes increased risk of heart attacks and strokes.
“Maintaining low LDL over a sustained period is essential to reduce the risk of heart attacks and stroke,” says R. Scott Wright, M.D., a Mayo Clinic cardiologist and principal investigator of ORION-10 trial.
ORION-10, a phase 3 placebo-controlled, double-blind, randomized study at 145 U.S. sites, enrolled 1,561 participants with established atherosclerotic cardiovascular disease (disease where plaque builds up in the arteries) and elevated LDL (greater than 70 milligrams per deciliters), despite maximum tolerated oral statin therapies.
Participants received inclisiran or placebo by subcutaneous injections at baseline, and then at three months and every six months thereafter.
Inclisiran, developed by The Medicines Company, is a siRNA (small interfering RNA) drug and the only cholesterol-lowering medication in its class. The medication mimics a gene variant and prevents production of the protein PCSK9, which in turn lowers LDL.
Results showed that inclisiran dosed initially, and then again at three months and every six months thereafter, resulted in placebo-adjusted LDL reductions of 58% at day 510 and demonstrated time-averaged, placebo-adjusted LDL reductions of 56% from days 90 through 540.
“The data show that inclisiran dosed twice-yearly achieved durable and potent LDL reductions with an excellent safety profile, and no treatment-related liver or kidney side effects,” Dr. Wright says.
“Twice-yearly administration by a health care professional coincides with typical patient visits, which can help with medication adherence.”
Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.
To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.
DESIGN, SETTING, AND PARTICIPANTS:
Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017.
One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo.
MAIN OUTCOMES AND MEASURES:
Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year.
At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year.
CONCLUSIONS AND RELEVANCE:
Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing.
Provided by Mayo Clinic