麻豆传媒

PARIS -- In patients with atherosclerotic cardiovascular disease (ASCVD), LDL cholesterol was halved with a twice-a-year regimen of injectable small interfering RNA (siRNA) that inhibits the PCSK9 protein, according to the ORION-11 trial presented here.

Over four doses of the investigational drug inclisiran, patients had a 54% placebo-adjusted drop in LDL from baseline to day 510 (-49% vs 4% for placebo, P<0.00001), or a time-adjusted average 50% decrease over days 90 to 540 (-48% vs 3%, respectively, P<0.00001), reported Kausik Ray, MD, of Imperial College London.

Temporary injection site reactions were the only safety events of note associated with inclisiran over 18 months in the phase III, double-blinded randomized trial. Rates for other adverse events, as well as all-cause death, were similar between the inclisiran- and placebo-assigned groups.

Drug recipients showed no liver, kidney, muscle, or platelet toxicity compared to placebo, Ray said during a press briefing at the European Society of Cardiology (ESC) congress.

Thus, ORION-11 met all primary and secondary endpoints, the investigator emphasized. This is the largest trial of any siRNA therapy, conducted at 70 sites in seven countries (Europe and South Africa).

Yet the safety issue cannot be resolved in as little as 18 months, cautioned ESC spokesperson François Schiele, MD, PhD, of the University Hospital of Besançon, France.

Researchers really don't know what the potential safety concerns would be for this new class of drugs, commented Robert Harrington, MD, of Stanford Health Care, California, in an interview.

New European guidelines say LDL should be pushed as low as possible, especially in high-risk patients. The thinking now is that it's the magnitude of LDL reduction that directly improves a person's risk profile -- not how it's achieved or by which drug.

The siRNA drug in particular works "not by mopping up the PCSK9 floating around, but by turning the faucet off, stopping PCSK9 production," as described by C. Michael Gibson, MD, MS, of Beth Israel Deaconess Medical Center in Boston, during an ESC satellite symposium sponsored by inclisiran manufacturer The Medicines Company.

It is important that inclisiran can be administered just twice a year -- compared to twice a month with currently available monoclonal antibodies that inhibit PCSK9 or once-daily statins.

"To think that we can prevent chronic disease essentially by vaccinating someone for 6 months and driving LDL levels to remarkably low and risk-reducing levels, I think has the potential to be transformative for how we think about prevention and should be much, much easier for our patients to adhere to," Donald Lloyd-Jones, MD, ScM, of Northwestern University Feinberg School of Medicine in Chicago, told 麻豆传媒. Lloyd-Jones is on the American Heart Association cholesterol guideline writing committee.

Of course, the price would have to be right, a tough lesson that the medical community has learned with PCSK9 inhibitors.

There is no information about what out-of-pocket costs inclisiran might incur, but The Medicines Company CEO Mark Timney said he is "very focused on patient affordability" and that there's no point pushing innovation forward if patients can't access the drugs.

ORION-11 included 1,617 patients with ASCVD (88%) or risk-equivalent individuals (13%) who had elevated LDL despite maximally tolerated statin therapy with or without ezetimibe (Zetia). Investigators prohibited the use of monoclonal PCSK9 inhibitors in the trial.

Ray and collaborators administered an initial 300-mg inclisiran subcutaneous dose, once again at day 90 to "saturate the mechanism" early on, then once every 6 months thereafter, as LDL cholesterol crept upward between injections.

Mean age at enrollment was approximately 66 years and 72% of the cohort were men. Baseline LDL averaged around 106 mg/dL. Inclisiran and placebo groups shared statistically similar baseline characteristics.

Topline phase III data for ORION-9 (in heterozygous familial hypercholesterolemia) and ORION-10 (U.S. patients with ASCVD) are expected later this year -- after which the manufacturer plans to submit inclisiran data for regulatory approval for high-risk patients in the U.S. and Europe, according to a .

A trial is being planned to test inclisiran in primary prevention among people with 10-year risk as low as 7.5% or 10%, according to Ray.

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