Analysis of ORION-1 Phase II trial of inclisiran shows reduction of atherogenic lipoproteins.-The Medicines Company.

The Medicines Company announced that the results of a pre-specified analysis of secondary endpoints from the ORION-1 Phase II study were presented at the 86th European Atherosclerosis Society Congress (EAS 2018) and accepted for publication in Circulation, the journal of the American Heart Association. Investigators examined inclisiran�s effects beyond LDL-C and showed that it also reduces atherogenic lipoproteins in a profound and sustained manner.

Atherogenic lipoproteins � non-HDL-C, ApoB, VLDL-C and Lp(a) � have each been associated with an increased risk of heart attacks and strokes, particularly in high-risk patients. The reductions, which were generally dose-dependent, were achieved most clearly with a 300 mg dose of inclisiran given on Day-1 and Day-90, and were sustained to the pre-specified time of assessment (180 days) and beyond (at least 210 days). This is the same starting dose of inclisiran being utilized in the Phase III trials (the Phase III dose of inclisiran is 300 mg given on Day-1 and Day-90 and then every six months thereafter). The Phase III trials, which are assessing a range of markers of disease risk, including LDL-C as the primary endpoint and other atherogenic proteins as secondary endpoints, are expected to report results in the second half of 2019.

The new findings were presented in a late-breaking session at EAS 2018, being held in Lisbon, Portugal, by the Principal Investigator for the ORION-1 and ORION-11 trials, Professor Kausik Ray, Professor of Public Health, Imperial College London, United Kingdom, and honorary consultant cardiologist, Imperial College NHS Trust. Professor Ray is the first author of the abstract accepted for publication in Circulation. Commenting on the findings, Professor Ray said, �This completes the picture of inclisiran�s effects on bad cholesterol � so called atherogenic lipoproteins. The data are quite similar to those for monoclonal antibodies directed against PCSK9. We know that elevated LDL cholesterol carries an increased risk for patients, but it does not account for all 'bad cholesterol'. While we encourage patients to make lifestyle changes, such as exercising regularly and eating a healthy diet, if we are looking solely at LDL cholesterol, we may be underestimating risk. In ORION-1, we found that inclisiran was able to reduce non-HDL cholesterol and other atherogenic lipoproteins, such as Apolipoprotein B, in a significant and sustained way.�

In the presentation, Professor Ray reported that the selected starting dose for inclisiran in the Phase III trials achieved guideline-recommended goals for ApoB and non-HDL-C for high- and very high-risk patients in 68% to 90% of patients, compared to 25 to 49% of patients given placebo (all p-values <0.0001 - this effect was highly consistent across patients and stable and sustained for up to 210 days after initial treatment.>

See-"Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Pre-Specified Secondary End Points in ORION 1"- Kausik K. Ray, Robert M. Stoekenbroek, David Kallend, Lawrence A. Leiter, Ulf Landmesser, R. Scott Wright, Peter Wijngaard, John J. Kastelein https://doi.org/10.1161/CIRCULATIONAHA.118.034710 Circulation. 2018;CIRCULATIONAHA.118.034710 Originally published May 7, 2018.