ORION-11: 50% Reduction in LDL With Twice-Yearly Injection

September 11, 2019

PARIS — Phase 3 trial results show a 50% reduction in low-density lipoprotein cholesterol (LDL) levels with a twice-yearly subcutaneous injection of the novel RNA agent inclisiran (The Medicines Company).

Results of the first of three phase 3 trials, ORION-11, which were presented at the recent European Society of Cardiology (ESC) Congress 2019, World Congress of Cardiology, show a 54% reduction in LDL vs placebo over an 18-month treatment period, with no obvious signs of toxicity.

Topline results of ORION-11 were released a few days before the conference. The Medicines Company reported that primary and secondary endpoints had been met, with efficacy consistent with findings from phase 1 and 2 studies.

Two additional phase 3 trials will report soon, and a filing for approval by the US Food and Drug Administration for an LDL-lowering indication is planned for the year's end. Filings in the rest of the world will be made early next year. A cardiovascular outcome trial is underway.

Inclisiran is the first of a new class of cholesterol-lowering agents known as small interfering RNA. It is a double-stranded RNA molecule that harnesses a natural process called RNA interference, which has the ability to switch off specific genes — in this case, the gene for PCSK9.

"Chemical modification has allowed inclisiran to be selectively taken up by the liver and specifically inhibit the synthesis of the PCSK9 protein, which interferes with the clearance of LDL," ORION lead investigator Kausik Ray, MD, Imperial College London, United Kingdom, told an ESC press conference on the ORION-11 study results.

"So inclisiran has the same target as the PCSK9 monoclonal antibodies already available but represents a different approach to its inhibition and has the benefit of a very long duration of action, resulting in dosing being required just twice a year," he commented.

The ORION-11 study enrolled 1617 patients with atherosclerotic cardiovascular disease whose LDL levels were higher than 70 mg/dL (90%) or who were at high risk for cardiovascular disease with LDL levels higher than 100 mg/dL (10%). Patients were already taking statins at maximum tolerated doses; 95% of patients were taking high-dose statins, and 7% were taking ezetimibe (multiple brands).

Baseline LDL level was 107 mg/dL in the patients who received inclisiran and 104 mg/dL in the placebo group.

The primary endpoint was mean LDL reduction at day 510 (18 months). Results showed that mean LDL levels had risen by 4% in the placebo group but had fallen by 49% in the inclisiran group, a between-group difference of –54%.

"As the drug is long acting with an infrequent dosing schedule, it is probably more important to look at the average LDL reduction over the whole treatment period," Ray said. The average level of LDL over the period from day 90 to day 540 was reduced by 50% in the inclisiran group vs the placebo group, he reported.

"We have shown durable, potent, and consistent effects over 18 months of treatment," he stated.

Safety Promising So Far

Safety results also look good as of now, he indicated. "So far, the safety results are virtually indistinguishable in the treatment and placebo groups," Ray noted.

There was an increase in injection site reactions (4.69% with inclisiran vs 0.5% with placebo). Thirty-eight patients experienced injection site reactions while taking inclisiran; these were classified as mild in two patients and as moderate in 15 patients. All reactions were transient.

Laboratory tests have shown no evidence of liver, kidney, muscle, or platelet toxicity. Results from liver function tests, kidney function tests, creatine kinase measurements, and platelet counts were "virtually indistinguishable" between the treatment and the placebo groups.

Rates of serious adverse events, including all-cause death and new and worsening malignancy, were almost identical in the two groups; if anything, they were numerically lower in the treatment group, Ray reported.

The prespecified exploratory cardiovascular endpoint — rate of cardiac death/cardiac arrest/myocardial infarction (MI)/stroke — was numerically lower in the inclisiran group (7.8% vs 10.3%).

The endpoints of rates of fatal or nonfatal MI (1.2% vs 2.7%) and fatal and nonfatal stroke (0.2% vs 1.0%) were also lower in the inclisiran group.

"These results on cardiovascular endpoints are a good start — cardiovascular events are going in the right direction, but of course we need larger numbers to know for sure, and we are conducting a cardiovascular outcomes trial to look at this further," Ray said.

"In summary, ORION-11 met all the primary and secondary endpoints, with a potent and sustained reduction in LDL. Safety data are very similar to placebo, with a small excess of injection site reactions, none of which were persistent," he concluded.

"This drug really opens up the field quite considerably," Ray commented. "The possibility of two injections a year with an excellent safety profile in a high-risk cardiovascular disease population gives us the additional reduction in LDL that so many patients need, but it also overcomes the problem of adherence and the problem of patients forgetting to take their statin pills every day or needing an injection every 2 weeks, as is the case with the PCSK9 inhibitor antibodies. It will give patients choices."

Ray pointed out that the reduction LDL with inclisiran is similar to that achieved with high-dose statins or the PCSK9 inhibitor monoclonal antibodies.

"It doesn't matter how you lower LDL," he added, "whether it is with a high-intensity statin taken every day or a PCSK9 MAb injection every 2 weeks, and now this RNA molecule. They can all give a 50% reduction in LDL. But the responsibility of taking regular medication for chronic disease management over lifetime is difficult, so the average reduction in LDL won't be as much as you think as adherence drops off, and over a 50-year time horizon, that will make a big difference."

More Safety Data Needed

Commenting on the results for the press, Francois Schiele, MD, University Hospital, Besancon, France, who is not involved with any studies of inclisiran, said the results were impressive so far but that more safety data are needed.

"We have to look very closely at safety, as this is a long-acting agent," Schiele said. "If there is a problem, then we cannot stop the activity of the drug for several months, so we have to be extra sure about adverse effects. Eighteen months is not enough."

But he agreed that there is a need to treat more consistently and aggressively with LDL-lowering therapy, especially in light of the fact that new guidelines recommend even lower LDL targets. "These new goals will be very difficult to achieve," he said.

Schiele noted that a twice-yearly injection would be particularly attractive for some patient groups, such as young patients with familial hypercholesterolemia. "It can be difficult to convince them that they have to take statins every day and injections twice a month forever. But an injection just a twice a year would be much easier," he said.

Ray reported that ORION-11 is one of three phase 3 trials that will be reported this year, with a total of 3600 patients.

"We also have 3-year data from open-label extension of earlier studies, and this safety data looks absolutely identical to what we are seeing in ORION-11. The treatment effect on LDL is maintained, and it appears to be safe. The safety profile so far looks to be excellent," Ray said.

Patients from the phase 3 trials are going to be followed in open-label extensions, he added.

Enrollment has begun for the ORION-4 cardiovascular outcomes trial, which will involve 15,000 patients in North America and the Unied Kingdom. Results are expected in 2024.

Ray is hoping to conduct a primary prevention study of inclisiran administered in a once-yearly dose. "In lower-risk patients, we perhaps don't need so much reduction in LDL, and so we are thinking of going with a once-a-year dosing schedule, but sticking with the 300-mg dose," he said.

What About Cost?

Asked about the cost of the drug, The Medicines Company CEO, Mark Timney, hinted that inclisiran may be priced lower than the PCSK9 inhibitors.

"We haven't said anything about price yet, and we won't until shortly before launch, but we are focused on patient affordability," he stated. "We are working with payors on identifying the population initially suitable for this drug — which will be the high-risk patients. And then we will work backwards to calculate a cost and figure out how we can get patients to afford it. In my view, there's no point in bringing such an innovation forward if patients can't get access to it.

"In the longer term, there are possibilities to think about using this type of drug in a population health framework, and then there would be larger populations who would could have access to this product, but it would have to be affordable," Timney added.

The ORION-11 trial was funded by The Medicines Company. Ray has received consulting fees and royalities from and holds shares in several companies, including The Medicines Company.

European Society of Cardiology (ESC) Congress 2019, World Congress of Cardiology: Presented September 2, 2019.

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