ORION-1: Inclisiran lowers LDL, PCSK9 in patients with hyperlipidemia, high CV risk
WASHINGTON — Inclisiran, a small interfering RNA that targets PCSK9 messenger RNA, was associated with reduced LDL and PCSK9 in the phase 2 ORION-1 study.
Kausik K. Ray, MD, MPhil, from the Imperial Center for Cardiovascular Disease Prevention, department of primary care and public health at Imperial College London, said in a presentation at the American College of Cardiology Scientific Session that monoclonal antibody PCSK9 inhibitors require 12 to 26 injections per year and adherence to them is no better than that with statins.
“Poor adherence and LDL variability are associated with poor outcomes,” he said. “These limitations are most relevant in high-risk patients with high LDL.”
Inclisiran (The Medicines Company) may be a solution because it inhibits PCSK9 synthesis in the liver and, therefore, requires less frequent administration than the monoclonal antibodies, he said.
In the randomized, double blind, placebo-controlled, multiple-ascending-dose study, 501 patients with elevated LDL at high risk for CV events received a single dose of placebo or inclisiran 200 mg, 300 mg or 500 mg, or two doses of placebo or inclisiran 100 mg, 200 mg or 300 mg.
The primary endpoint was change in LDL between baseline and 180 days. The researchers also published safety data through day 210 and data on LDL and PCSK9 levels through day 240.
Ray and colleagues found that least-squares mean reductions in LDL at 180 days were 27.9% to 41.9% after one dose of inclisiran and 35.5% to 52.6% after two doses of inclisiran (P < .001 vs. placebo for all comparisons).
The greatest LDL reductions were observed in patients assigned two 300-mg doses of inclisiran, with 48% having LDL levels reduced to < 50 mg/dL.
For all inclisiran groups, LDL and PSCK9 remained lower at day 240 vs. at baseline, according to Ray and colleagues.
All results were sustained up to 270 days, Ray said during the presentation.
“All patients responded [to inclisiran],” in contrast to what was seen in trials of monoclonal antibody PCSK9 inhibitors, he said. “The average reduction in LDL percentage terms is 52.6%, with the maximum response of almost 81%. If you translate that into absolute differences in LDL … 90% of people [assigned the highest two-dose regimen of inclisiran] achieve an LDL reduction of more than … 39 mg/dL. The average absolute reduction is 64.2 mg/dL, with a maximum of more than 122 mg/dL.”
Serious adverse events occurred in 11% of those assigned inclisiran vs. 8% of those assigned placebo, whereas injection-site reactions were observed in 5% of patients who received inclisiran.
“The optimal dosage of 300 mg given twice appears to [sustain LDL lowering] for a 6-month dosing interval,” Ray said. “The unique attributes of inclisiran address multiple unmet needs. LDL variability within individuals is virtually eliminated, injection burden is reduced substantially and there is a sustained effect between infrequent injections, perhaps leading to an opportunity to improve patient adherence.” – by Erik Swain
Ray KK, et al. Featured Clinical Research I. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.
Ray KK, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615758.
Disclosure: The study was funded by The Medicines Company. Ray reports receiving personal fees from AbbVie, Algorithm, Amgen, Boehringer Ingelheim, Cerenis, Cipla, Eli Lilly, Esperion, Ionis, Janssen, Kowa, Milan, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Takeda and The Medicines Company, and grants from Amgen, Merck Sharpe & Dohme, Pfizer, Regeneron and Sanofi.