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Twice-yearly inclisiran injection shows durable LDL improvement: ORION-11
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PARIS — Inclisiran, an investigational cholesterol-lowering therapy in the small-interfering RNA class, achieved durable and potential LDL reduction with twice-yearly injections, according to new data from the ORION-11 study.
Moreover, inclisiran sodium 300 mg (The Medicines Company) administered twice yearly was well tolerated and safe, with an adverse event profile similar to treatment with placebo, Kausik K. Ray, MD, MPhil, from the Imperial Center for Cardiovascular Disease Prevention and Imperial College London, said during a late-breaking presentation at the European Society of Cardiology Congress.
ORION-11 is the first pivotal phase 3 clinical study of inclisiran. The study was conducted at 70 sites in seven countries and randomly assigned 1,617 patients to placebo or inclisiran, on top of maximally tolerated statin therapy. Each participant received inclisiran or matching placebo initially, again at 3 months and then every 6 months thereafter.
For the primary efficacy endpoints of ORION-11, inclisiran delivered placebo-adjusted LDL reductions of 54% (P < .0001) at day 510 and demonstrated time-averaged placebo-adjusted LDL reductions of 50% (P < .0001) from days 90 through 540, according to findings presented here.
The overall adverse event profiles of the placebo- and inclisiran-treated groups in ORION-11 were similar. The proportion of patients experiencing at least one serious treatment-emergent adverse event was 22.5% with placebo vs. 22.3% with inclisiran. The incidence of death (1.9% vs. 1.7%) and malignancies (2.5% vs. 2%) was similar between the placebo and inclisiran groups, respectively. The researchers observed a difference between placebo and inclisiran in the incidence of fatal and nonfatal MI (2.7% vs. 1.2%) and fatal and nonfatal strokes (1% vs. 0.2%).
Inclisiran works on the liver and is excreted through the kidney, but no concerns emerged on laboratory tests during the study, Ray said. Clinically relevant elevations in liver function tests (alanine aminotransferase [ALT]: 0.5% vs. 0.5%; aspartate aminotransferase [AST]: 0.5% vs. 0.2%) and serum creatinine increases (1.4% vs. 0.6%) were similar between the placebo and inclisiran groups, respectively.
Inclisiran is delivered via injection, and the incidence of injection site reactions was higher than with placebo, at 4.7% vs. 0.5%. However, Ray said, the majority of injection site reactions were mild and transient.
Patients enrolled in ORION-11 had atherosclerotic CVD or ASCVD risk equivalents and elevated LDL despite maximally tolerated doses of statin therapy, with or without ezetimibe. According to the researchers, this population is representative of a high-risk cohort of ASCVD and risk-equivalent patients. The mean age was 65 years and 72% were men. Eighty-seven percent of patients enrolled had diagnosed ASCVD. The average baseline LDL was 106 mg/dL in the total population. At baseline, nearly all patients were already on statins, with 90% on high-intensity statins.
“Inclisiran achieves durable and potent LDL cholesterol reductions with only two-times-yearly injections,” Ray said here. The new data demonstrate “an excellent safety profile in a high CV risk population.”
Administration of inclisiran “lends itself to routine clinical practice,” he said. “Administration by health care providers potentially coincides with typical 6-month patients visits. ... Injections could be administered by a physician. This enables providers control over medical nonadherence. It offers patients the choice for add-on therapies — 365 additional pills a year, or 26 injections a year or two injections a year.”
Patients who completed their respective phase 3 studies are now enrolling into ORION-8, an open-label, long-term extension study in which patients completing ORION-9, ORION-10 and ORION-11 will receive inclisiran for 3 years to evaluate the efficacy, safety and tolerability of long-term dosing of inclisiran. – by Katie Kalvaitis
Reference:
Ray KK. Late Breaking Science in Prevention 1. Presented at: European Society of Cardiology Congress; Aug. 31-Sept. 4, 2019; Paris.
Disclosure: Ray reports consulting/royalties/owner/stockholder for AbbVie, Akcrea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cerenis, Cipla, Daiichi Sankyo, Dr. Reddy’s, Eli Lilly, Esperion, Kowa Pharmaceuticals, MSD, Novo Nordisk, Pfizer, Regeneron, Sanofi, Silence Therapeutics and The Medicines Company; lectures for Algorithm, Cipla, Dr. Reddy’s and Zuelling Pharma; and research contracts with Amgen, MSD, Regeneron and Pfizer.
Perspective
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Athena Poppas, MD, FACC
These data are compelling because one of the challenges we have as physicians is patient adherence, whether it’s pills or injections. We know from multiple other studies that with noncompliance for difficult-to-control hypertension, for example, a large percentage — 20% to 30% — can be due to issues with compliance, for a variety of reasons such as cost, access, trust or memory in older people. But, if we had a drug that was a twice-a-year injectable, the compliance could be significantly improved. A few questions remain: the ORION-11 study met its safety and effectiveness endpoints, so we’d like to drill down on those data. I think another issue is whether the company will dramatically reduce the projected cost, which may be fairly prohibitive for patients, as well as for insurers or for population health management. If you can improve compliance and significantly drive down the cost with no change in safety or efficacy, that would be helpful.
Perspective
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Carl J. Pepine, MD, MACC
I am impressed by the results of ORION-11. It is important to note that nearly all patients were on high-intensity statins at baseline. On top of that, they were able to reduce LDL by 54%, which is impressive. The LDL reduction appears to persist through 6 months, so it looks like it would require dosing of inclisiran twice a year. The results showed directional changes in events, without any hint of serious adverse effects, except some local skin reactions. I think patients are going to be fairly receptive to that. Based on the acceptance of the PCSK9 inhibitors by patients, for which they were trained to do their own subcutaneous injection dosing, inclisiran would not require a self-administered option. Rather, inclisran requires a health care worker to deliver the injection. Therefore, the compliance issue is removed. Patients could come to the office every 6 months to have continuing clinical care for their CVD and also receive a shot. Added to that, the complexity of the manufacturing of this molecule is much less; consequently, I anticipate it will be marketed at a much lower price compared with the monoclonal antibodies. There are other trials underway by the company that will be finished within the next 2 to 3 years. I look forward to having more information on this novel therapy then.
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