Inclisiran safely reduces LDL by 45% over 4 years: ORION-3
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CHICAGO — In adults with atherosclerotic CVD or a risk equivalent, twice-yearly inclisiran injections were associated with a 44% reduction in LDL that was sustained over 4 years with no new safety signals observed, researchers reported.
“What we knew before was that in 3,600 patients in three trials with a dosing interval of day 1, day 90 and then every 6 months, we could reduce LDL by 51% over placebo,” Kausik K. Ray, MD, MPhil, from the Imperial Centre for Cardiovascular Disease Prevention and Imperial College London, told Healio. “Because the drug has such a long effect, there was only a 15-month or 1-year observation window where you were actually testing the twice-a-year regimen. Unless you look at several more years after that, we could not say for certain that it would work, although we thought it would. We did not know what happens with repeat exposure to the risk complex. Does the effect wear off? Is there biological escape? Is there an adverse effect of this? We could have started from scratch; however, we had the advantage of the ORION-1 patients.”
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As Healio previously reported, initial data from ORION-3 demonstrated inclisiran injections (Leqvio, Novartis) administered twice per year safely reduced LDL by at least 50% out to 3 years. In the phase 2, open-label extension study, researchers analyzed data from patients who completed the ORION-1 study and were previously treated with any dose of inclisiran. Participants had ASCVD or an ASCVD risk equivalent and elevated LDL despite maximally tolerated lipid-lowering therapy. The primary endpoint was percentage LDL change from baseline, defined as day 1 of ORION-1 to day 210 of ORION-3, LDL and PCSK9 levels, other secondary efficacy endpoints and safety, assessed up to 4 years.
The findings were presented during a featured science presentation at the American Heart Association Scientific Sessions.
Of the 290 patients enrolled in the ORION-3 inclisiran-only arm, 80.3% completed the study. The median duration of exposure from ORION-1 through ORION-3 was 4.5 years. The mean age of participants was 63 years, 63.6% were men and 50% were aged 65 years or older. The mean baseline LDL in ORION-1 was 128.9 mg/dL.
Among participants with baseline and day 210 LDL measurements, mean percentage change in LDL from baseline to day 210 of ORION-3 was 47.5% (95% CI, 50.69 to 44.27). LDL reductions were sustained during the 4-year study period.
Researchers also observed a consistent reduction of PCSK9 from baseline through 4 years, ranging from 61.7% to 77.8%. The percentage change from baseline to 4 years was 69.5% (95% CI, 71.19 to 67.89).
“We showed after 1 year and 210 days, the LDL reduction is 47.5% and there is no loss of efficacy,” Ray said in an interview. “Then, in years 1, 2, 3 and 4, you are seeing this consistent 45% or so lowering of LDL. Remember, these are people taking background statin therapy. Perhaps the most interesting thing is, over that 4-year horizon, you can talk about achieving in the window LDL lowering of 44% with eight or nine injections.”
Ray said drug-related adverse events were mild to moderate and self-limited; most were adverse events at the injection site.
“Now, we can think about a 10-year horizon,” Ray told Healio. “[A clinician] can say to patients, ‘I can lower your LDL by 45% with two injections a year.’ We can do this with 20 injections [over 10 years].
“We know that the individual benefits will vary,” Ray said. “For people at high CV risk with high LDL, this is going to be a key additional treatment.”
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Ray KK, et al. FS.09: The present and future of lipid lowering. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
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