Durable LDL-C reduction with novel anti-PCSK9 inclisiran
Treatment with inclisiran, a siRNA for PCSK9* knockdown, delivers significant and sustained LDL-C lowering in a dose-dependent manner over 6 to 9 months in patients with high cardiovascular risk, according to the ORION-1** study presented at the ACC.17 Scientific Session held in Washington, DC, US.
Unlike PCSK9 antibody-based therapy which requires 12–26 injections per year, inclisiran requires less frequent injection at a starting regimen of twice every 90 days and may be feasible at Q6M thereafter. This could help circumvent the issue of poor adherence to therapy, which has been associated with poor outcomes and an issue most relevant in high-risk patients with high LDL-C, according to lead investigator Dr Kaushik Ray of Imperial Centre for Cardiovascular Disease Prevention at Imperial College London in UK.
The multicentre double-blind phase II study randomized 501 patients (mean age 63 years, 35 percent female) with elevated LDL-C levels (mean LDL-C, 125.2–133.0 mg/dL) who were at high risk for atherosclerotic cardiovascular disease to receive one of the eight treatments: a single subcutaneous dose of placebo or 200, 300, or 500 mg of inclisiran on day 1; or two subcutaneous doses of placebo or 100, 200, or 300 mg of inclisiran on days 1 and 90. At the start of the study, 73 percent of the patients were on statins and 31 percent were on ezetimibe. [N Engl J Med 2017;doi:10.1056/NEJMoa1615758]
Compared with the baseline, LDL-C decreased by 27.9–41.9 percent at day 180 after a single inclisiran dose vs an increase by 2.1 percent for placebo (p<0.001). For patients who received two doses of inclisiran, LDL-C fell by 35.5–52.6 percent at day 180 from baseline compared with a 1.8 percent increase with placebo (p<0.001).
At 240 days, LDL-C declined by 28.2–36.6 percent from baseline after a single inclisiran dose and 26.7–47.2 percent after two doses of inclisiran.
LDL-C levels remained lower than baseline at day 270 across all studied doses of inclisiran be it a single- or double-dose regimen.
“The greatest reduction (52.6 percent) in LDL cholesterol levels was observed in association with the two-dose 300-mg regimen of inclisiran, a reduction that is in a range similar to that achieved with monoclonal antibodies designed to target PCSK9,” according to Ray, who noted that 48 percent of patients in this regimen group achieved LDL-C levels of <50 mg/dL at day 180.
“The optimal dose of 300 mg given twice as a starting regimen appears to allow for a subsequent 6-month dosing interval,” he added.
The researchers also showed that PCSK9 levels decreased by 53.2–69.1 percent (p<0.001) from baseline at 180 days after a two-dose inclisiran regimen, which remained >40 percent reduced from baseline at 240 days.
There were no safety concerns with inclisiran seeing that the incidence of treatment-emergent adverse events, including transient increase in transaminase, was similar to placebo, except injection site reaction which occurred in 5 percent of the inclisiran-treated patients, according to Ray. Also, no neutralizing antibodies were detected.
Study on CV outcomes with inclisiran in high-risk primary and secondary prevention patients with elevated LDL-C of about 130 mg/dL will be pursued in the ORION-4 study, informed Ray.