Inclisiran Slashes LDL in ASCVD Patients: ORION-10

PHILADELPHIA, PA—The latest data on inclisiran, an investigational, twice-yearly small interfering RNA (siRNA) injectable, more than halved LDL-cholesterol levels in a population of patients with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL over 18 months compared with placebo. Again, there were no demonstrated safety risks.

Results with the drug, manufactured by The Medicines Company, was last presented at the European Society of Cardiology Congress in August, where 1,617 patients with or at high risk for ASCVD also saw their LDL-cholesterol levels cut by more than half versus placebo over 18 months in ORION-11. The smaller-scale ORION-1 trial included 501 patients with or at high risk for ASCVD and showed an LDL-cholesterol reduction of 52.6% after 6 months and 30-40% at 1 year with good safety outcomes. ORION-4, the large-scale cardiovascular outcomes trial, is ongoing.

“The use of inclisiran achieved durable and potent reductions in LDL cholesterol using essentially a twice-yearly injection in patients with ASCVD who were already on appropriate, aggressive lipid-lowering therapies over 18 months of follow-up with a safety profile similar to placebo in this high-risk cardiovascular population,” said R. Scott Wright, MD (Mayo Clinic, Rochester, MN), who presented the data from ORION-10 here today in a late-breaking clinical trial session at the American Heart Association (AHA) Scientific Sessions 2019.

If approved by the US Food and Drug Administration, “twice-yearly administration will coincide with typical twice-yearly patients visits with US healthcare providers,” he pointed out, “and inclisiran will potentially offer a new novel treatment for LDL cholesterol using a method that's easy to use with a prefilled syringe. It's well tolerated. It’s safe, potent, and durable.”

Today, we don’t need to think about drug A versus B, we need to think about the optimal therapy to bring the LDL and other lipid variables into the right range for effective secondary prevention. R. Scott Wright

Karol Watson, MD, PhD (David Geffen School of Medicine at UCLA, Los Angeles, CA), who served as a discussant for the findings, told TCTMD that “there's a lot of excitement with this mechanism. It’s a new class, which is something that always excites us.”

But many unanswered questions remain regarding inclisiran, said Watson, including how the drug affects HDL cholesterol, triglycerides, and lipoprotein(a) levels, and also if there are any “important inter-individual differences in the inclisiran response.”

Additionally, “we saw a very, very safe profile over 18 months, but this is theoretically a lifelong therapy,” she noted. “And, frankly, we don’t really know what the impact of this infrequent dosing will be on patient adherence. I would love to say that most of my patients come to see me twice a year, but they don’t. I don’t know if it’s ‘out of sight out of mind’ or if patients will be encouraged to maintain therapy.”

ORION-10

For ORION-10, Wright and colleagues randomized 1,561 patients with ASCVD and elevated LDL cholesterol (≥ 70 mg/dL) already on maximally tolerated statins to receive placebo or four injections of inclisiran over 18 months (days 1, 90, 270, and 450). Of note, 10% of patients were taking concomitant ezetimibe over the course of the study.

At the end of the study, day 510, LDL cholesterol had been reduced by 56% (time-averaged) with inclisiran over placebo (P < 0.00001).

Treatment-emergent adverse event rates were similar between the placebo and inclisiran arms (75% vs 74%), as were the rates of serious adverse events (26.3% vs 22.4%), including those that led to drug discontinuation (2.2% vs 2.4%). There were only 20 instances of a protocol-defined skin event at the injection site (2.6%)—13 mild and seven moderate—in the study group, which fell after the protocol switched to a prefilled syringe midway through the study.

There were no other differences with regard to liver or kidney function or to the prespecified exploratory cardiovascular endpoint defined as cardiac death, any signs or symptoms of cardiac arrest, nonfatal MI, and/or stroke (10.2% vs 7.4%).

Unanswered Questions

Speaking during a media briefing, Watson said it remains to be seen whether inclisiran treatment will lead to improved long-term clinical outcomes above and beyond what is currently capable with statins. “In addition, the very, very impressive 58% lowering in LDL—there are some patients who will achieve that with statin therapy. What will be the impact of inclisiran versus statin therapy on the equivalent LDL-lowering?” she asked.

Wright argued that this might not be the “right question” to ask right now. “No one to date has suggested replacing statins with [inclisiran],” he told TCTMD. “At this stage, the drug is being tested in high-risk patients and [familial hypercholesterolemia] patients as an adjunct to statins. Today, we don’t need to think about drug A versus B, we need to think about the optimal therapy to bring the LDL and other lipid variables into the right range for effective secondary prevention.”

Overall, Watson said, “what we’re getting to is the idea that the lower we push LDL, the better the clinical outcomes will be. . . . Once we get the LDL low, if we get it even lower, we still see lower clinical events and we don’t know where that floor is. What we do know is that the long-term benefits of LDL-lowering therapy require that patients stay on therapy. It requires us to get the LDL low and keep it low, and therefore, theoretically seeing a therapy that can get LDL very lower and adherence improved would make clinical outcomes better.”

Theoretically seeing a therapy that can get LDL very lower and adherence improved would make clinical outcomes better. Karol Watson

Wright confirmed that the manufacturer aims to submit inclisiran for FDA approval before the end of the year and to the European regulatory authorities in early 2020.

“That’s very different from getting an endorsement, particularly a [class] Ia recommendation from guidelines, which will require the full outcomes studies and the long-term safety data as well,” noted Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who chaired the media briefing.

“If the outcomes trials validate what most of us think it will or hope it will, [inclisiran] will be more broadly used than just a niche, I think, because there is so much of a burden of atherosclerosis that remains that we’re not addressing that this could be a powerful tool,” according to Watson.

“If this drug is approved, it will be nice to have a second option to lower LDL in the PCSK9 pathway,” Wright said. “Then the question becomes: is it more convenient to take a drug twice a year versus 26 times a year and what's the value to patients?” He acknowledged not knowing how inclisiran will be priced but said “those are issues to be considered.”

“Inclisiran is the first cholesterol-lowering agent in the siRNA class that opens up a whole host of new and exciting possibilities, and definitely increasing the number and types of effective therapeutic options that our patients have available to them is good medicine,” Watson concluded.