A post-hoc analysis of data from the ORION-9, ORION-10, and ORION-11 trials, presented during the 2021 American Heart Association (AHA) Scientific Sessions, showed that inclisiran treatment every 6 months resulted in effective and sustained reduction of approximately 50% in LDL cholesterol (LDL-C) across all body weights when used in addition to other lipid-lowering therapies.1


Dr. Lawrence A. Leiter, Director of the Lipid Clinic, Associate Director of the Clinical Nutrition and Risk Factor Modification Centre, and Associate Scientist in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital in Toronto, presented this analysis. Physician’s Weekly interviewed him to ask why it is important to find lipid-lowering treatments for patients across all BMI ranges.


PW: How can excessive body weight affect the efficacy of inclisiran?

DL: We know that many drugs have their pharmacologic properties altered by excessive body weight, which is why we thought it was important to investigate whether the effects of inclisiran vary by baseline BMI. The adaptation of drug dosages to patients with obesity is a subject of concern. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow, and the affinity of the drug for plasma proteins and/or tissue components. Although inclisiran is metabolized by nucleases, and it is not anticipated to be a substrate for cytochrome P450 enzymes, we know that about 16% of the total dose of inclisiran is cleared through the kidney. We simply did not know how body weight would affect inclisiran efficacy.

How did the research presented at the AHA Scientific Sessions 2021 go about tackling this unmet need?

This was a post-hoc analysis of three published phase III trials, the ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800) studies,2-4 which involved patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or familial hypercholesterolemia. Eligible patients from these trials were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo at baseline, day 90, and every 6-months thereafter. Our analysis included more than 3,500 patients overall. We analyzed the results by baseline BMI (<25, 25-<30, 30-<35 or ≥35 kg/m2). The primary endpoint was percentage change in atherogenic lipids from baseline at Day 510. Safety was assessed during 540 days.

What were the main results of your research? 

There were two co-primary endpoints, both looking at LDL reduction, and the bottom line is that we saw that inclisiran lowered LDL effectively by about 50% in all BMI strata, with similar efficacy across the board.

Safety was also analyzed by stratified BMI groups, and there we saw some increasing risk associated with higher BMI. Treatment-emergent adverse events and treatment-emergent serious adverse events were generally similar between the treatment arms in each BMI group but were reported more frequently with increasing BMI strata. Clinically relevant treatment-emergent adverse events at the injection site were reported more frequently with inclisiran when compared with placebo similarly across BMI strata; all were mild or moderate in nature.


What are the implications of these results?

Inclisiran inhibits the production of PCSK9, and the mode of administration is different than the existing monoclonal antibodies. It will be dosed at baseline, 3 months after start of treatment, and every 6 months thereafter. It is very well tolerated by patients.

We showed that the prescriber need not worry about the BMI of the patient and whether the patient is thin or overweight; one can expect similar and efficacious LDL lowering across all body weights.

What are the next steps to validate these results prospectively?

There is an ongoing outcome study with inclisiran called ORION-4 (NCT03705234), which is looking at the effects of inclisiran on cardiovascular outcomes. I am not personally involved in that trial, but I certainly expect that they will be looking at overall results across various subgroups including BMI. ORION-4 will have the ability to look not just at LDL cholesterol reduction, but also cardiovascular outcomes, which of course is the ultimate name of the game. Those results will be highly informative regarding the important outcome measures going forward.

The ORION program included three large phase III trials, including patients with either ASCVD, ASCVD risk equivalents, or familial hypercholesterolemia, randomly assigned in a blinded fashion to either inclisiran or placebo, and followed for about 18 months. And the studies all showed efficacious LDL-C lowering in the range of about 50% and well tolerated medication.

I think the bottom line is that we have another option to treat patients whose LDL cholesterol remains elevated despite maximally tolerated statin use and dosage. And the hope is that we will achieve decreased medication burden with inclisiran, given the fact that it is going to be administered at baseline, 3 months, and every 6 months thereafter; it will offer a significant advantage for some patients.