ORION pooled analysis: Inclisiran safely lowers LDL in high-risk patients
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A pooled analysis of three phase 3 trials assessing inclisiran found that the agent safely lowered LDL in patients with several conditions including atherosclerotic CVD, heterozygous familial hypercholesterolemia and ASCVD risk equivalents, according to data presented at the American College of Cardiology Scientific Session.
“Inclisiran (Novartis) remains a novel approach to reduce LDL cholesterol,” R. Scott Wright, MD, consultant in the divisions of structural heart disease and preventive cardiology and professor of medicine at Mayo Clinic, said during the presentation. “With twice-yearly administration, it provides a robust, potent and durable reduction in LDL over 18 months on top of maximally tolerated oral lipid-lowering agents.”
Analysis of three trials
Researchers pooled data from 1,833 patients (median age, 65 years; 67% men) assigned inclisiran and 1,827 patients (median age, 65 years; 68% men) assigned placebo from the ORION-9, ORION-10 and ORION 11 trials to assess the efficacy of the drug to lower PSCK9, LDL and lipids.
As Healio previously reported, patients with heterozygous FH treated with inclisiran in the ORION-9 trial had reductions in LDL at 510 days and at an average of the period between 90 days 540 days independent of their underlying genotype. The ORION-10 trial found that inclisiran demonstrated sustained LDL reductions with twice-yearly dosing in high-risk patients with atherosclerotic CVD. Inclisiran also achieved durable and potential LDL reduction with twice-yearly injections in patients with ASCVD or ASCVD risk equivalents in the ORION-11 trial.
“[Inclisiran] is a small interfering double-stranded RNA which harnesses the body’s natural processes of RNA interference,” Wright said during the presentation. “Inclisiran has been modified for durability and low immunogenicity and has an attached [N-Acetyl-D-galactosamine] complex which allows it to be specifically delivered to the hepatocytes where it can inhibit the translation of messenger RNA into production of the PCSK9 protein.”
Primary effectiveness endpoints of this analysis included LDL reductions at 510 days and at an average of 90 days and 540 days. Secondary effectiveness endpoints included LDL change over time and changes in PCSK9 and other lipids. The researchers also assessed composite major adverse CV events, defined as resuscitated cardiac arrest, CV death, stroke and nonfatal MI.
Compared with placebo, inclisiran reduced LDL by 55% at 510 days and by 52% in the average of 90 days and 540 days. An LDL less than 70 mg/dL was achieved by 76% of patients assigned inclisiran vs. 14% assigned placebo. An LDL less than 50 mg/dL was attained by 58% of patients in the inclisiran group vs. 2% in the placebo group.
“Some clinicians worry about additional therapies lowering LDL too much and think that an LDL less than 25 might not be safe or necessary,” Wright said during the presentation. “In our trial, only 16% of patients had an LDL less than 25 mg/dL.”
Inclisiran also reduced apolipoprotein B (42%), PCSK9 (83%), non-HDL (46%) and lipoprotein(a)(20%; P for all < .001).
Patients assigned inclisiran had slightly higher rates of injection site reactions compared with those assigned placebo (5% vs. 0.7%), which were mild or moderate, remained for a short amount of time and did not reoccur once a patient had this reaction, according to the presentation.
The rate of major adverse CV events was significantly lower in patients assigned inclisiran compared with those assigned placebo (7.1% vs. 9.4%; P < .05).
“Most of these lower rates were driven by nonfatal MI, which was lower in the inclisiran group than it was in placebo,” Wright said during the presentation.
Reductions in LDL were consistent across a range of subgroups in forest plot analyses. Wright and colleagues observed no differences in adverse outcomes between groups.
“We believe that twice-yearly administration will coincide with typical twice-yearly visits that patients make with health care providers in the United States, thus assuring health care providers the opportunity to promote adherence and talk about the importance secondary and primary prevention in patients,” Wright said during the presentation.
“We are excited by the results we have seen to date with inclisiran, and we look forward to the potential opportunity to make the first and only LDL-C lowering treatment in the small interfering RNA class available to patients with ASCVD and familial hypercholesterolemia,” David Platt, MD, vice president of U.S. Clinical Development and Medical Affairs in the Cardiovascular, Renal and Metabolism Medical Unit of Novartis Pharmaceuticals, said in a press release from the company.
Potential implications
In the discussion portion of the presentation, Jennifer G. Robinson, MD, professor in the department of epidemiology and director of the Preventive Intervention Center at The University of Iowa College of Public Health in Iowa City, said, “We have so much data now on what is the next step for secondary prevention. ... What do you do next? It’s going to come down to what is the magnitude of risk reduction for that patient, the absolute risk reduction benefit and what is the cost? The first choice matters because after you reduce risk 25% or 30%, the next drug you add has incrementally less benefit. All of this is ripe for some sort of network meta-analysis to help us make better choices to personalize therapy in our patients.”
Sekar Kathiresan, MD, cardiologist at Massachusetts General Hospital, professor of medicine at Harvard Medical School (on leave) and chief executive officer of Verse Therapeutics, said adoption may be difficult in a crowded field of LDL-lowering therapies.
“Assuming this drug gets approved this year, a physician or cardiologist with a patient in front of them, has high-dose statin, maybe even ezetimibe, with an LDL over 100 mg/dL, already established cardiovascular disease and they want to bring their LDL down to much lower levels. They’ll be facing a choice between the approved monoclonal antibodies that have clinical outcome trial data vs. inclisiran where the approval will be based initially on LDL,” he said. “I understand that the outcome trial is underway already, but in the absence of the outcome data for inclisiran, why should a cardiologist choose inclisiran over the approved monoclonal antibodies?”
Wright said that inclisiran may be appropriate to prescribe ahead of the outcome data if one believes that LDL lowering is a mechanism. He said, “It’s going to depend on a couple of factors. One, if you accept the data on LDL lowering — and I do believe that almost all of the secondary prevention benefit with lipid therapies is driven by LDL lowering — you will feel comfortable prescribing it ahead of the outcome data, as was common with the statin drugs early on. Secondly, it is more convenient to administer than the intravenous monoclonal antibodies, two times per year vs. 26 times per year.” – by Darlene Dobkowski
Reference:
Wright RS, et al. Featured Clinical Research I. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Disclosures: The ORION studies are funded by The Medicines Company. Wright reports he received consultant fees/honoraria from AstraZeneca Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, The Medicines Company and Sanofi Regeneron. Robinson reports she has received institutional research support from and consulted for Amarin, AstraZeneca, Eli Lilly, The Medicines Company, Novartis, Novo Nordisk and Pfizer. Kathiresan is co-founder of Verve Therapeutics. Platt is an employee of Novartis.