ORION-10: 58% Reduction in LDL With Inclisiran

PHILADELPHIA — A second phase 3 trial with the novel lipid-lowering agent inclisiran (The Medicines Company), which is administered just twice yearly as a subcutaneous injection, have shown impressive reductions in patients already taking statins.

The ORION-10 study was presented today here at the American Heart Association (AHA) Scientific Sessions 2019.

The trial showed a 58% reduction in low-density lipoprotein (LDL) cholesterol over the 18-month study period, with no difference in safety compared with placebo in patients with established atherosclerotic cardiovascular disease already taking statins.

The results are similar to those seen in the ORION-11 study — the first phase 3 trial of inclisiran to be reported — which was presented a few weeks ago at the European Society of Cardiology meeting.

"Our results show that inclisiran is a new novel treatment for lowering LDL," lead investigator, R. Scott Wright, MD, concluded. "It is easy to use in prefilled syringes, safe, and its effects are potent and durable."

Wright, from Mayo Clinic, Rochester, Minnesota, noted that LDL lowering is the most effective intervention to change the course of atherosclerotic cardiovascular disease, yet substantial residual risk remains despite aggressive treatment with statins and other agents.

"There is a compelling need for novel therapies to further lower LDL on top of current LDL-lowering treatments," he said. "Inclisiran one such therapy."

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

The agent has been designed to be selectively taken up by the liver and specifically inhibit the synthesis of the PCSK9 protein, which interferes with the clearance of LDL.

The ORION-10 study enrolled 1561 patients with atherosclerotic cardiovascular disease already on statins and randomly assigned them to inclisiran 300 mg or placebo given by subcutaneous injection at day 1 and day 30, then every 6 months thereafter for 18 months.

Of the enrolled population, 95% were taking effective lipid-lowering therapy: 90% were on statins, 79% were on high intensity statins, and 9% were on ezetimibe. Mean baseline LDL level was 105 mg/dL.

Results showed that at the end of the study (day 510), LDL was reduced in the inclisiran group by 58% vs placebo. The time-averaged reduction in LDL from day 90 to day 540 was 56% (P for both endpoints < .00001).

In terms of safety, treatment emergent adverse events did not differ between the inclisiran and placebo groups.

Injection site reactions occurred in 2.6% of inclisiran recipients vs 0.9% of placebo recipients.

Wright noted that this was less than seen in prior studies and similar to or less than that seen with the PCSK9 monoclonal antibodies. Most injection site reactions were mild, a few were moderate, and none were severe or persistent, he reported.

Injection pain occurred in 2.1% of the inclisiran group vs 0.4% of the placebo group with the vial and syringe method of administration but was reduced to 1.0% with inclisiran vs 0.1% with placebo when prefilled syringes were introduced in the second half of the study.

In terms of laboratory measures, liver, kidney, and muscle enzymes did not differ between the two groups. One patient in the inclisiran group had a low platelet count, but Wright noted that this was lowest at the time of randomization and rose during the study.

There were also no difference in serious adverse events, overall mortality, cardiovascular mortality, or cancer mortality between the two groups. New or worsening malignancy occurred in 3.3% of both groups. Adverse events leading to drug discontinuation occurred in 2.4% of inclisiran recipients vs 2.2% of placebo recipients.

A prospective exploratory cardiovascular endpoint (MedDRA-defined cardiovascular nonadjudicated terms, including cardiac death, and any signs or symptoms of cardiac arrest, nonfatal myocardial infarction (MI), and/or stroke) occurred in 7.4% of the inclisiran group vs 10.2% of the placebo group.

Cardiovascular death occurred in 0.9% of the inclisiran group vs 0.6% of the placebo group, and fatal/nonfatal MI or stroke in 4.1% vs 3.3%, respectively.

"New and Exciting Possibilities"

Designated discussant of the study, Karol E. Watson, MD, said that inclisiran was opening up "new and exciting possibilities" for LDL lowering.

Watson is professor of medicine/cardiology at the David Geffen School of Medicine at University of California, Los Angeles.

She said the ORION-10 results showed "very impressive and durable lowering in LDL with inclisiran, but I would also like to see what effect it has on HDL, triglycerides, and Lp(a)."

"It looks safe over 18 months, but we don't yet have safety data beyond that point, and this will likely be a lifelong therapy. I would also like to know if there any important inter-individual differences in inclisiran responses," she commented.

Wright responded, "There is always concern about safety with any new drug and that is appropriate. There is a very long phase 3 cardiovascular outcomes trial ongoing — ORION 4 — which will provide additional data on safety. In addition, all of the patients from earlier and current trials are being followed up for longer-term safety. So far we have not seen any difference to placebo."

Infrequent Dosing: Friend or Foe?

Wright suggested that the twice-yearly administration of inclisiran would coincide with patients' twice-yearly visits to their healthcare provider.

But Watson countered: "We don't know what the impact will be of the infrequent dosing. I would love to say that all my patients come to see me twice a year, but they don't. And I don't know if it will be a case of 'out of sight, out of mind,' or if patients will be encouraged to maintain therapy themselves."

She also pointed out that it is not yet known whether treatment with inclisiran will lead to improved clinical outcomes over the long term over and above what is seen with statins.

"While the 58% reduction in LDL seen here is very impressive, there are some patients who can achieve this on statins," she said. "What will be the impact of inclisiran vs statins on equivalent LDL lowering?"

Wright replied that how inclisiran compares to statins is not the right question to ask. "No one has suggested replacing statins with a drug like this. It is being tested at present as an add-on to statins in high-risk patients and those with familial hypercholesterolemia."

Noting that all the evidence so far shows that lower LDL levels give better outcomes and long-term benefits require patients to stay on their therapy so that the LDL is reduced as low as possible for as long as possible, Watson concluded that "a therapy that can get LDL down to lower levels and improve adherence should lead to improved outcomes."

Asked how much excitement there was in the cardiology community about this new agent, Watson said, "There is a lot of excitement," adding, "there will be much more if the results of ORION-4 show a substantial in reduction in cardiovascular outcomes."

She suggested that how the drug will eventually be used will depend largely on the results of ORION-4. "If the results are good, I think it will be used broadly on top of statins. There is so much more burden of atherosclerotic disease remaining even with use of statins so I think this will be a powerful pathway."

But she noted that inclisiran would not be used with a PCSK9 inhibitor monoclonal antibody because they are both drugs targeting a similar pathway. "It would be one or the other."

Wright added that the options for lowering LDL via the PCSK9 pathway could come down to "what is more convenient — a drug that is given twice a year or one that is given 26 times a year."

He noted that approval applications for inclisiran for an LDL reduction indication are expected before the year end in the United States and in early 2020 in Europe. "So, it should be on the market long before the outcome trial results are available like all other lipid-lowering therapies were."

The ORION-10 trial was funded by The Medicines Company. Wright reports research support from the company.

American Heart Association (AHA) Scientific Sessions 2019. Presented November 16.

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