Novel PCSK9 Inhibitor Lowers Lipids Across the Board

Liam Davenport

May 15, 2018

LISBON, Portugal — 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 LDL 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.

"But the real game-changer about this, should we show the safety data, is actually the convenience," Ray added. "Two injections a year could be delivered by a nurse to make sure the patient gets it. That's really the added value, we think, from a public health perspective."

Gene Silencing

In his presentation, Ray pointed out that the three principal approaches for reducing LDL cholesterol levels via the LDL receptor. The first is hydroxymethyl glutaryl coenzyme A reductase inhibition via statins, which leads to increased LDL receptor synthesis.

This second is to transiently block extracellular PSCK9 binding to the LDL receptor with PCSK9 inhibitors, and the third is to block PSCK9 synthesis via gene silencing, inhibiting all intracellular and extracellular PCKS9 functions.

ORION 1 investigated the third approach with inclisiran. Patients were randomly assigned to a one-dose starting regimen of placebo or inclisiran at 200 mg, 300 mg, or 500 mg given on day 1 or a two-dose starting regimen of placebo or inclisiran at 200 mg, 300 mg, or 500 mg given on days 1 and 90.

The study involved 497 patients who were treated and 483 who completed follow-up. Most (73%) were also taking statins, and 31% were receiving ezetimibe at study entry. The groups were well balanced in terms of baseline characteristics.

For this secondary analysis, the team looked at changes in non-HDL cholesterol, apolipoprotein B, very-low-density lipoprotein (VLDL) cholesterol, Lp(a), total cholesterol, triglycerides, HDL cholesterol, and apolipoprotein A1.

As in the primary analysis, the 300-mg dose of inclisiran offered the largest incremental gain. For example, the percentage change in non-HDL cholesterol from baseline to day 180 was –35.2% with the one-dose regimen and –46.0% with the two-dose regimen (P < .001 vs placebo for both).

There were also significant reductions in VLDL cholesterol with inclisiran 300 mg, at –23.8% with the one-dose regimen (P < .001 vs placebo) and –16.0% with the two-dose regimen (P < .05 versus placebo).

The reductions in Lp(a) with the 300-mg dose were –14.3% and –25.6%, respectively (P < .001 vs placebo for both), while those for triglycerides were –12.2% and –14.2%, respectively (P < .05 vs placebo for both).

HDL cholesterol levels rose significantly with inclisiran 300 mg, by 8.8% with the one-dose regimen (P < .05 vs placebo), and 8.6% with the two-dose regimen (P < .01). Apolipoprotein A1 levels rose significantly with the two-dose 300-mg regimen, by 6.2% (P < .05).

The researchers also found that patients given 300 mg inclisiran were substantially more likely to reach guideline-recommended goals.

For example, in the one-dose group, 73% of inclisiran recipients met the apolipoprotein B target of less than 80 mg/dL vs 19% of those given placebo (P < .0001), while 83% and 58%, respectively, met the goal of less than 100 mg/dL (P = .019).

The non-HDL cholesterol goal of less than 100 mg/dL was met by 62% of patients receiving inclisiran 300 mg vs 6% of the placebo group, while 78% and 33%, respectively, met the goal of less than 130 mg/dL (P < .0001 for both).

Similar, if slightly larger, differences were seen with the two-dose inclisiran 300-mg regimen.

Ray concluded that the 300-mg, two-dose regimen, which has been selected for phase 3 trials, lowered atherogenic lipoproteins to a degree similar to that seen with the monoclonal antibody PCSK9 inhibitors.

He said that with this dosage, every patient in their analysis achieved reductions in non-HDL cholesterol and apolipoprotein B, with most reaching goal, although the individual changes in Lp(a), VLDL cholesterol, and triglycerides were "more variable."

Michelle L. O'Donoghue, MD, Brigham and Women's Hospital, Boston, Massachusetts, who was not involved in the study, told theheart.org | Medscape Cardiology that inclisiran represents "a very interesting and exciting class of drugs."

"Here you've got another class of drugs that inhibit PCSK9 but through a different mechanism of action and with prolonged effects," she said.

"One of the really exciting components of inclisiran is the idea that you might just be able to offer an injection every 6 months to somebody and have a profound and lasting effect on their LDL concentration."

Referring to the current secondary analysis, O'Donoghue added, "We see the effects as well as on Lp(a) concentration, so that'll be another interesting area as the larger phase 3 trial launches."

The ORION 1 study was funded by funded by Alnylam Pharmaceuticals and The Medicines Company. Ray reports research grants from Amgen, Sanofi, Regeneron, MSD, and Pfizer and consultancy work for Amgen, Sanofi, Regeneron, MSD, Pfizer, Astra Zeneca, Lilly, The Medicines Company, Kowa, IONIS, Takeda, Novo Nordisk, Boehringer Ingelheim, Esperion, Cipla, Algorithm, Abbvie, Resverlogix, Cerenis. O' Donoghue reports receiving research grant support from GlaxoSmithKline, Eisai, Merck & Co, Janssen, Amgen, The Medicines Company, and AstraZeneca.

European Atherosclerosis Society (EAS) 2018. Presented May 7, 2018.

Circulation. Published online May 7, 2018. Abstract

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