ORION-11: Inclisiran Shows Promise, Safety in Largest Cohort to Date

PARIS, France—Inclisiran, the investigational, twice-yearly small interfering RNA (siRNA) injectable, has cleared another hurdle on the road to clinical use with new data showing that the drug halved LDL-cholesterol levels at 18 months versus placebo, with a similar safety profile.

The efficacy of the drug, manufactured by The Medicines Company, has previously been tested in smaller-scale trials including ORION-1, which included 501 patients with or at high risk for atherosclerotic cardiovascular disease (ASCVD) and showed an LDL-cholesterol reduction of 52.6% after 6 months and 30-40% at 1 year with good safety outcomes. The large ORION-4 outcomes trial is underway.

Kausik Ray, MD (Imperial College, London, England), presented the 1,617-patient ORION-11 data here at the European Society of Cardiology Congress 2019.

“This is a game changer for LDL-lowering,” Ray told TCTMD. “It's just been really, really positive because the safety profile is unbelievable. It's better than I could have imagined.”

The manufacturer is hoping for US Food and Drug Administration approval by 2021, which he thinks is a reasonable time line.

At that point, inclisiran will be “at the same stage that we had for the ‘mAbs’ and they got licensed so it's exactly the same principle,” he said. “The safety data looks so clean, [the FDA would] have no reason not to. Just because you don't know X, you wouldn't necessarily hold back on it provided you have enough information available at that time and you have an ongoing study, which is usually what they do.”

This is a game changer for LDL-lowering. Kausik Ray

Yet because inclisiran lowers LDL not by blocking PCSK9 like evolocumab and alirocumab, but by preventing its generation through the liver, Christopher Granger, MD (Duke Clinical Research Institute, Durham, NC), who was not involved in the study, told TCTMD that additional longer-term safety data are needed to be totally confident in its clinical applicability.

“If it pans out the way it's looking like it pans out, it could be transformative,” he said. “The fact of the matter is that in general practice we have this huge problem with getting patients to take these drugs consistently, and to have this drug, especially if it's modest in cost and if it's integrated into healthcare systems in an appropriate way, I think it could be—maybe ‘transformative’ is too strong—but it could be a major step forward in better application of prevention therapy for atherosclerotic cardiovascular disease.”

An Important New Tool

For ORION-11, Ray and colleagues randomized 1,617 patients with or at high risk for ASCVD already on maximally tolerated statins to receive placebo or four injections of inclisiran over 18 months (days 1, 90, 270, and 450). Of note, 7% of patients were taking concomitant ezetimibe over the course of the study.

By the study’s end, day 510, LDL cholesterol had been reduced by 50% (time-averaged) over placebo (P < 0.00001).

The rate of any treatment-emergent adverse events was similar between the placebo and inclisiran arms, as were the rates of serious adverse events (22.5% vs 22.3%). There were only 38 instances of a protocol-defined skin event at the injection site (4.19%)—23 mild and 15 moderate—in the study group, and there were no other differences with regard to liver or kidney function.

Granger shared Ray’s excitement for the data. “It’s very exciting—potentially one of the most exciting reports at this whole meeting, I think, was ORION-11, assuming it pans out,” he said. “The chances are very high that it will end up being safe over the long term and associated with improved clinical outcomes, and then we'll have an important new tool.”

Imagining a scenario in which inclisiran could be accessed like the flu vaccine, Granger said the challenge will be “figuring out how we deliver this drug to a large population of patients at need. We need to develop models of how to do that. Do we use pharmacies? Do we use a combination of cardiology and primary care clinics? How do we get this type of a drug delivered in a systematic way?”

It's very exciting—potentially one of the most exciting reports at this whole meeting, I think, was ORION-11, assuming it pans out. Christopher Granger

This is especially important given the economic challenges patients face when prescribed a PCSK9 inhibitor only to find the costs prohibitive. “The PCSK9 inhibitors frankly are a good example of how not to introduce a class of drugs into clinical practice,” Granger said. “It was a huge frustration for us as practicing cardiologists to have this very expensive new drug and literally take hours to go through the process of trying to get preapproval [and] figure out how to get these delivered to patients in an effective way.”

If the pricing is “appropriate” for inclisiran once available, “we’ll have a new way to much more systematically give a prevention drug in a way in which we know it'll be effective, [and] I think that's a great model,” he added.

Ray said he does not yet know what the price of inclisiran will be, but the manufacturers will likely set it lower than that of PCSK9 inhibitors. “If you've got any sense you would, wouldn't you?” he said. “One would think you'd probably have to because that's been the biggest barrier to uptake.”