Inclisiran Data in NEJM Prompt Talk of What Comes Next

Inclisiran’s performance in three large randomized trials is now detailed in two papers published in the New England Journal of Medicine—the previously reported data show LDL cholesterol levels slashed by around 40% in patients with heterozygous familial hypercholesterolemia (FH) and around 50% in those who have atherosclerotic cardiovascular disease (ASCVD) or are thought to be at elevated risk due to type 2 diabetes or another condition.

Each of the double-blind, phase III trials was presented in late 2019: ORION-9 and ORION-10 at the American Heart Association Scientific Sessions and ORION-11 at the European Society of Cardiology Congress.

The phase III results reassuringly echo the efficacy seen in phase II studies and show consistent safety through 18 months across thousands of patients, said Kausik K. Ray, MD (Imperial College London, England), lead author of the NEJM paper published this week on ORION-10 and -11. “With these data, it was so flat in terms of a lack of any adverse signal other than what one would predict, which is a small difference in injection-site adverse events,” he observed.

Inclisiran, an investigational, twice-yearly small interfering RNA (siRNA), was developed by The Medicines Company; soon after these ORION trial results became public, Novartis announced its plan to buy the company for $9.7 billion.

Now, the injectable is winding through the US Food and Drug Administration and European Medicines Agency approval processes, said Ray.

Inclisiran only requires injections every 6 months and many are hoping this will lead to better adherence, not only compared with statins but also with PCSK9 inhibitors alirocumab (Praluent; Sanofi/Regeneron) and evolocumab (Repatha; Amgen), both monoclonal antibodies (mAbs) that must be administered every 2 weeks.

“It’s much like trying to clean up a mess; it makes more sense to turn off the tap. What inclisiran does is it stops the liver from making PCSK9 [to begin with], so that means you can give injections much less frequently,” explained Frederick J. Raal, MD, PhD (University of the Witwatersrand, Johannesburg, South Africa), lead author of the ORION-9 paper.

Seth Martin, MD (Johns Hopkins University, Baltimore, MD), commenting on the NEJM papers for TCTMD, said that the advent of drugs aimed at the PCSK9 pathway is exciting, but emphasized that their uptake will rest on whether these drugs are accessible and affordable. Of note, manufacturers of the PCSK9 inhibitors cut prices following market launch after their high costs sparked controversy. Prior authorization requirements, at least in the United States, also have slowed uptake.

“The class of PCSK9 inhibitors has clearly fit an unmet need in clinical practice. But in reality of actually implementing on the front lines, it’s been hard to fill that unmet need due to all the access barriers to therapy,” Martin said, adding, “These ORION-9, -10, [and] -11 data look promising, so I’m excited to see the story continue.”

How inclisiran will play out in the real world remains unknown, as does its effects on hard outcomes. The latter question, said Ray, will be at least partially addressed at the virtual American College of Cardiology (ACC) 2020 Scientific Session, when researchers will present a pooled analysis of data from ORION-9, -10, and -11. But ultimately, the scientific community will have to wait a few years for results from the ongoing, large-scale, cardiovascular outcomes trial, ORION-4, to know for sure.

Inclisiran Data to Date

As previously reported by TCTMD, ORION-10 enrolled 1,561 patients with ASCVD, while ORION-11 enrolled 1,617 patients with either ASCVD or an ASCVD risk equivalent (type 2 diabetes, FH, or a 10-year CV event risk ≥ 20% as assessed by the Framingham Risk Score for Cardiovascular Disease or equivalent). Mean LDL cholesterol levels at baseline were 104.7 mg/dL and 105.5 mg/dL, respectively. ORION-10 was performed in the United States and ORION-11 in Europe and South Africa.

Both trials randomized participants to receive inclisiran (284 mg) or matching placebo, both given as a 1.5-mL subcutaneous injection at four time points: day 1, day 90, day 270, and day 450.

At day 510, inclisiran had reduced LDL cholesterol by 52.3% in ORION-10 and 49.9% in ORION-11 versus placebo, with time-adjusted reductions of 53.8% and 49.2%, respectively (P < 0.001 for all). Most adverse events were similar in the two study arms, apart from injection-site adverse events being more frequent with inclisiran than with placebo (2.6% vs 0.9% and 4.7% vs 0.5% in ORION-10 and -11, respectively), though most were deemed mild and none were severe or persistent.

In ORION-9, meanwhile, investigators enrolled 482 adults with heterozygous FH and a mean baseline LDL cholesterol level of 153 mg/dL, randomly assigning them to receive inclisiran (300 mg) or matching placebo, again at days 1, 90, 270, and 450. By day 510, LDL cholesterol was reduced by 39.7% in the inclisiran group and increased by 8.2% in the placebo group, a between-group difference of -47.9%. The time-averaged change between days 90 and 540 was a 38.1% reduction with inclisiran and a 6.2% increase with placebo, a between-group difference of -44.3% (P < 0.001).

Adverse events did not differ, and notably, Raal pointed out, LDL reductions were seen across all genotypes of FH.

In all three trials, around 90% of patients were on statins and more than two-thirds received high-intensity statins. In ORION-9, more than half of the heterozygous FH patients took ezetimibe.

For Raal, patients with heterozygous FH pose a particularly acute clinical need. The condition affects one in 250 individuals, amounting to around 30 million people worldwide, he said.

Unlike people who develop high cholesterol later in life, individuals with FH are exposed to high LDL levels from birth and have trouble controlling their LDL cholesterol with previously available therapies. With the combination of statin, ezetimibe, and one of the PCSK9-pathway drugs, “you can get the vast majority to a very acceptable level,” Raal said.

At even higher risk are the one in a million individuals with homozygous FH, a group that’s the focus of ORION-5. Raal also highlighted an ACC presentation likely to be of interest: on March 30, he will report data from a randomized trial of evinacumab, an ANGPTL3 inhibitor, in homozygous FH patients.

What’s Next

FDA approval is expected long before the results of ORION-4 are available in 2024, Ray noted, since other agents have also been approved on the basis of safety and lipid-lowering efficacy, prior to hard outcomes data.  

For Martin, it seems logical that inclisiran would prove beneficial. “I would say that yes, to some extent, we fully expect these LDL reductions to translate into clinical benefit. But it does need to be proven,” he cautioned, especially since trials for the mAb-based PCSK9 inhibitors on the market already have this level of evidence.

What will drive choice among the three drugs, Martin predicted, will not only be their price tags but also payer preference.

It will also be interesting to see if, in reality, the twice-yearly injection schedule improves adherence, he noted. “The challenges I see with adherence with [mAbs], often it’s the logistical issue of insurance reauthorization when patients are switching insurances or they’re moving . . . to another state and trying to have continuation of their care. It’s those kind of changes that lead to gaps in coverage for their therapy,” Martin commented. “The clinical trials don’t address the real-world challenges that come up with our patients. So there are going to be other barriers to adherence that still need to be thought of and addressed.”

Some of these barriers may be worked out in the United Kingdom, where the National Health Service (NHS) and Novartis have teamed up with the goal of bringing inclisiran to thousands of high-risk patients with ASCVD.

Ray said he hasn’t yet heard any numbers for cost. The NHS project, though, makes him optimistic. “If it was at the current cost of the mAbs, you wouldn’t be able to afford it for that number [of people]. So it’s got to be considerably less than the mAbs,” he conjectured. Having spent years researching these agents, he hopes that they will ultimately make it into the hands of the people who need them most.

“You do all this great work,” Ray said, “but if you can’t help the people out there, what’s the point?”

Another issue yet to be resolved is how inclisiran will be delivered, said Ray, who suggested it could be injected by a nurse or pharmacist, not necessarily a physician; it could even happen at a pharmacy instead of the doctor’s office. With two injections, “it’s like your flu shot essentially,” he said.