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 90 days and may be feasible at Q6M thereafter, which 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 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%) 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.