From the Journals

Evolocumab’s LDL lowering surpassed inclisiran’s in ORION-3



Patients who received an injection of inclisiran (Leqvio), a small interfering RNA (siRNA) agent, every 6 months for as long as 4 years safely maintained about a 45% reduction from baseline in their level of low-density lipoprotein cholesterol (LDL-C) in an open-label extension study with 382 patients.

In addition to providing the longest reported treatment experience with inclisiran, which received Food and Drug Administration marketing approval a little over a year ago, the results also suggest with the most definitive evidence to date that inclisiran is less effective for lowering LDL-C, compared with a class of medications that reduce LDL-C by a related but distinct mechanism: antibodies that directly inhibit activity of the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, a drug class that includes alirocumab (Praluent) and evolocumab (Repatha). Inclisiran cuts PCSK9 activity by blocking this enzyme’s gene transcription in liver cells thereby interfering with PCSK9 production.

Dr. Kausik K. Ray, professor, Imperial College London Mitchel L. Zoler/MDedge News

Dr. Kausik K. Ray

Results from this study, the ORION-3 trial, provide “the first prospective long-term evaluation of the durability and safety of an siRNA-based therapy to provide clinically meaningful reductions in LDL cholesterol with a convenient dosing schedule,” wrote Kausik K. Ray, MD, and coauthors in a report in The Lancet Diabetes & Endocrinology.

The findings “provide assurance that siRNA-based therapies are safe and have the potential to provide a convenient approach to managing” LDL-C, wrote Dr. Ray, a cardiologist and professor of public health at Imperial College London, and his associates.

Evolocumab surpasses inclisiran in crossover cohort

The new data from ORION-3 study included findings from 92 patients first treated with evolocumab injections every 2 weeks for a year, an intervention that lowered their LDL-C levels by an average of about 60%, compared with their pretreatment level. ORION-3’s study design then crossed these patients to treatment with injections of inclisiran twice a year during 3 further years of follow-up, during which their average LDL levels reset to a roughly 45% drop from baseline, a potentially clinically meaningful difference, commented Robert S. Rosenson, MD, a lipid management specialist who was not involved in the ORION-3 study.

“This is the first evidence that compared the two classes” within a single study, thereby avoiding a problematic cross-study comparison. “That’s why the data are important. They underscore that the monoclonal antibodies are more effective for lowering LDL-C,” compared with inclisiran, said Dr. Rosenson, professor and director of cardiometabolic disorders at the Icahn School of Medicine at Mount Sinai in New York.

The findings “confirm in a trial that the PCSK9 monoclonal antibodies are indeed more potent,” he said in an interview.

But Dr. Rosenson acknowledged that, while this analysis used data on patients treated with evolocumab and then switched to inclisiran collected prospectively in a single study, it has the limitation of involving a comparison that was not prespecified. The primary goal of the evolocumab-to-inclisiran switch included in ORION-3 was to assess the ease, safety, and efficacy of a switch to inclisiran from treatment with a PCSK9 antibody and was not intended to compare the two drug classes.

The roughly 15% absolute difference in LDL-C lowering between the two tested drug classes can have substantial clinical implications for patients who start treatment with highly elevated levels of LDL-C, more than 190 mg/dL, because they have heterozygous familial hypercholesterolemia, are unable to take a statin because of intolerance, or both. The difference in LDL-C reduction with an antibody or with inclisiran could mean the difference between whether or not a patient like this achieves their LDL-C goal level, Dr. Rosenson explained.


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