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PHILADELPHIA -- The investigational drug inclisiran can further halve LDL cholesterol in patients with atherosclerotic cardiovascular disease (ASCVD) already on lipid-lowering therapies, according to the ORION-10 trial presented here.

By inhibiting the PCSK9 protein with small interfering RNA (siRNA), the injectable drug was associated with a -51% change in LDL cholesterol compared to +1% with placebo at day 510, reported R. Scott Wright, MD, of Mayo Clinic in Rochester, Minnesota.

Inclisiran's effect was consistent across the 18-month course of ORION-10, time-averaged change in LDL cholesterol over days 90-540 being -51% (vs +3% with placebo, P<0.00001), Wright showed here in a late-breaking study presentation at the American Heart Association (AHA) meeting.

Additionally, inclisiran did not lead to more serious adverse events (AEs) -- such as death and cancer -- compared with placebo (22.4% vs 26.3%).

With these "safe and assured" results from this double-blind trial, Wright concluded that inclisiran offers a "meaningful new choice for patients," assuming it gets FDA approval. Drug manufacturer The Medicines Company announced it is filing for inclisiran's U.S. regulatory approval and for European clearance in early 2020.

The drug was previously shown to be safe and effective at 18 months in ORION-11, a trial of 1,617 people with ASCVD or ASCVD-risk equivalents with elevated LDL cholesterol despite statin or ezetimibe (Zetia) therapy.

Safety will need to be proven in the long-term given that inclisiran is potentially a life-long therapy for people, cautioned Karol Watson, MD, PhD, of the University of California Los Angeles, during an AHA press conference.

Wright said he agreed, noting that the "very long" phase III ORION-4 trial looking at clinical outcomes is underway and that people from ORION-10 and ORION-11 are already going into longer-term follow-up.

If inclisiran is approved by FDA, it will be on the market before the outcomes data are there, the investigator predicted.

The drug comes in a pre-filled syringe and is dosed at 300 mg twice a year. The injected siRNA are distributed to the liver, stopping liver cells from producing PCSK9.

Wright suggested that twice yearly administration of the drug coincides with when patients typically make their doctor's visits.

"I would love to say most of my patients come to see me twice a year, but they don't. I don't if it's 'Out of sight, out of mind' or if the patients will be encouraged to continue therapy," Watson countered.

"We know the LDL effect is impressive. I would love to see the HDL effect and the triglyceride effect," she added.

The ORION-10 investigators had included 1,561 high-risk people with ASCVD and a median baseline LDL cholesterol level of 105 mg/dL. Median age was 67 and about 70% of the cohort were men. The prevalence of heterozygous familial hypercholesterolemia (HeFH) was 9%.

Study participants were required to be on maximally-tolerated statins; ezetimibe was permitted for the statin-intolerant, but not monoclonal PCKS9 inhibitors. Randomized to inclisiran or saline-solution placebo, people were given their assigned injections at days 1, 90, 270, and 450.

The two study arms shared similar rates of AEs, along with similar changes in liver and kidney function biomarkers over 18 months.

An exploratory analysis handed inclisiran a numerical reduction in cardiovascular events, or the composite of cardiac death, cardiac arrest, MI, or stroke (7.4% vs 10.2% for placebo), according to Wright.

On the other hand, there was an excess of mild-to-moderate injection-site side effects with the drug (2.6% vs 0.9%).

The reported drops in LDL cholesterol resulted after imputation to account for missing data. That ORION-10 met its primary and secondary endpoints had first been announced in .

Scheduled for presentation later at AHA is ORION-9, a 482-person trial of HeFH patients, that also had positive announced in September.