Physicians' Academy for Cardiovascular Education

Sustained LDL-c lowering up to 360 days with siRNA directed against PCSK9 in phase 2 study

ORION 1: LDL-C Reduction From 6 to 9 Months Following Single or Second Injection of Inclisiran, a Novel siRNA Compound: Primary Efficacy and Safety Outcomes of the ORION 1 Trial

Presented at ACC.17 by Kausik Ray

Mar. 16, 2017 - news

Background

In recent years, major progress has been made in the treatment of atherosclerotic CV disease (ASCVD). PCSK9 inhibition is now a validated target for reduction of LDL-c and ASCVD. A drawback of PCSK9 monoclonal antibody (mAb) therapy may be that it requires 12-26 injections per year. Adherence data with PCSK9 mAbs shows no substantial improvement over statins. This is a problem, as poor adherence and LDL-c variability are associated with poor outcomes. This is most relevant in high risk patients with high LDL-c.

Inclisiran is a novel agent that may address unmet needs. It works via RNA interference (RNAi), and prevents synthesis of PCSK9 protein in the liver. In a Phase I trial, 300 mg inclisiran lowered LDL-c by 50-60% for 84 days (n=69). The ORION-1 study aimed to evaluate optimal dosing regimens in patients with elevated LDL-c and high CV risk. Two dosing regimens were tested, each at three doses of inclisiran: one with a dose of study drug at day 1 and primary evaluation at day 180, and another with a dose at day one and a second dose at day 90, and primary evaluation at day 180. End of study visit was at day 210 and extended follow-up was done at day 360. 483 patients completed the study, out of 501 who were randomised and 497 who were treated.

Main results

Conclusion

This study shows that 300 mg given twice as a starting regimen, then followed by a 6-monthly regimen, seems to be a safe and effective regimen to lower LDL-c. The unique attributes of inclisiran address multiple unmet needs, since LDL-c variability within individuals is practically eliminated by this approach. Furthermore, it reduces injection burden substantially. A sustained effect between infrequent injections is seen. The dosing regimen provides an opportunity to improve patient adherence.

These results may translate into a considerable reduction of CV endpoints, which will be tested in the ORION-4 outcomes study in patients with high risk and average LDL-c of about 130 mg/dL.

Disclosures

Our coverage of ACC.17 is based on the information provided during the congress.

This study was published today in NEJM