Novel Alnylam/Medicines Co. PCSK9 Inhibitor Lowers Lipids Across the Board

Using RNA interference to inhibit proprotein convertase subtilisin kexin type 9 (PCSK9) synthesis lowers levels of atherogenic lipoproteins across the board, new results suggest.

The findings come from secondary analysis of data from the ORION 1 trial, published in 2017 in the New England Journal of Medicine. The trial showed that long-acting RNA interference within hepatocytes by inclisiran (ALN-PCSsc, Alnylam Pharmaceuticals/The Medicines Company) offers long-lasting reductions in low-density lipoprotein (LDL) cholesterol levels.

As reported by theheart.org | Medscape Cardiology at that time, the phase 2 trial showed that inclisiran injection, tested at various doses, led to a mean reduction in LDL cholesterol from baseline to day 180 of 27.9% to 41.9% vs a 2.1% increase with placebo (P < .001).

The findings suggested that inclisiran could be given as little as once every 6 months, as opposed to an injection every few weeks with the antibody-based PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen).

The current analysis, presented at the European Atherosclerosis Society (EAS) 2018 meeting and published online May 7 in Circulation, are derived from a prespecified secondary analysis looking at the impact of the drug on atherogenic lipoproteins.

At 180 days, inclisiran substantially reduced levels of non–high-density (HDL) cholesterol, apolipoprotein B, and lipoprotein(a) [Lp(a)], among other lipoproteins, and most patients met guideline-recommended targets for non-HDL cholesterol and apolipoprotein B, the researchers report.

Kausik Ray, MD, PhD, the Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, United Kingdom, who presented the results and is also principal investigator, said that the findings in the current analysis “are consistent with what we’ve seen” in the main study.

He told theheart.org | Medscape Cardiology that “the next step is to show safety, and that’s why we’ve recruited 3660 patients across three large international studies, which will report phase 3 safety data and long-term efficacy data.”

They anticipate results of those studies should be available in the second half of 2019, he said, and would form the basis for approval applications to the European Medicines Agency and the US Food and Drug Administration.

Ray is also taking part in ORION IV, a cardiovascular outcomes study starting in 2018 that will involve around 15,000 patients from the United States and United Kingdom who are at high cardiovascular risk and have high HDL cholesterol.

“One of the reasons that I think we’re in a really good position with that is that one of the long-term challenges with all these therapies is keeping people on the study drug,” he said.

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