During a recent PW Podcast episode, we spoke with Kausik Ray, MD (Imperial College, London) about the ORION-3 trial. Following is a summary of our conversation.
Tell us about ORION-3
Based on results from ORION-9, -10, and -11, we knew that inclisiran was safe for LDL lowering up to 18 months, providing placebo corrected 50% LDL lowering in patients with established CVD. But we didn’t know if repeat dosing over another 4 years, for example, would be associated with any differences in safety or whether the LDL-lowering effects would be attenuated.
Prior to these pivotal studies, we conducted ORION-1, a phase 2 dose-finding study in which about 180 people received inclisiran at one of three dosages (60 received placebo) on days 1 and 90 and were followed for 1 year. A 4-year open-label extension of this study is ORION-3. Patients who received inclisiran in ORION-1 went on to inclisiran sodium 300 mg every 6 months without a loading dose and continued for another 4 years. At day 210 in the open-label extension, these patients achieved 47% LDL lowering from baseline, which is not placebo-corrected and on par with what we saw in inclisiran-treated patients in ORION-9, -10, and -11. The same level of LDL reduction was maintained year to year to year so that the time-averaged reduction in LDL was roughly 44% with two injections per year.
In terms of safety signals, we didn’t see anything new. The most common were injection site adverse events, which were mild to moderate and the same as what we witnessed in ORION-9, -10, and -11. We didn’t see any attenuation effect.
It’s great news for doctors and patients, because we now have two really effective options for LDL lowering. With ORION-9, -10, and -11, we didn’t know the durability of the effect in achieving meaningful reductions with twice yearly dosing because those studies were stopped at 1 year, so we’ve now answered that question. We have some preliminary pooled safety data from those studies showing a 25% lower risk for major cardiovascular events. We look forward to the ongoing cardiovascular outcome trials.
