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ORION-1: Inclisiran lowers LDL, PCSK9 in patients with hyperlipidemia, high CV risk
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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
References:
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.
Perspective
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Howard Weintraub, MD
The drug is associated with a dose-dependent reduction in LDL, and at 6 months there still appears to be an effect with even the smallest dose of the medication. At the highest dose, there was a 52.5% reduction in LDL 90 days after the second dose. This is very impressive. With the monoclonal antibodies, patients generally got more LDL reduction if they were already on statin therapy, and in this study, patients were on maximally tolerated statin therapy at least 30 days before screening.
This drug is certainly not inconvenient. It’s hard to argue with taking a drug on a quarterly basis. The only issue that the side-effect profile is a bit worse than it was with the monoclonal antibodies, but 8% of the placebo group also had side effects, so we have to consider whether this has to do with injection-site reactions being more common with the reverse transcriptase injection than it is with the monoclonal antibodies. If the worst that happens is an injection-site reaction that doesn’t evolve into something that gets progressively worse, then I think a lot of people would be willing to take this drug every 3 months vs. every month or every 2 weeks for the monoclonal antibodies or every day for drugs in pill form such as statins.
The efficacy may be a little less than with the monoclonal antibodies, but all we see is short-term data without Kaplan-Meier curves. The next step should be a larger trial of a longer duration. Other drugs designed to interfere with RNA have had issues with potential side effects, so I would expect the FDA to require at least 1 year of investigation. If FOURIER and ODYSSEY OUTCOMES are overwhelmingly positive, it will be tough for the FDA to do more than validate the delivery system because the science of PCSK9 inhibition would then be proved useful.
Long-term LDL reduction has been validated with evolocumab (Repatha, Amgen; Koren MJ, et al. JAMA Cardiol. 2017;doi:10.1001/jamacardio.2017.0747) and ezetimibe (Zetia, Merck) plus statin therapy (Giugliano RP, et al. JAMA Cardiol. 2017;doi:10.1001/jamacardio.2017.0083). This is where we’re going. The data are coalescing to support this contention, and I hope guidelines are written to reflect this very important innovation.
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