PHILADELPHIA – A second phase 3 trial of the new lipid-lowering agent inclisiran (The Medicines Company), administered only twice a year as a subcutaneous injection, has shown impressive reductions in patients already taking statins.
ORION -10 study was presented today at the American Heart Association (AHA) Scientific Sessions 2019.
The study showed a 58% reduction in low-density lipoprotein (LDL) cholesterol over the 18-month study period, with no difference in safety compared to placebo in patients with established atherosclerotic cardiovascular disease who were already taking statins.
The results are similar to those seen in the ORION-11 study ̵
"Our results show that inclisiran is another novel treatment for lowering LDL," concluded lead investigator R. Scott Wright, MD. "It's easy to use in pre-filled syringes, safely, and the effects of this are potent and durable."
Wright, of the Mayo Clinic, Rochester, Minnesota, noted that LDL lowering is the most effective intervention to alter the course of atherosclerotic cardiovascular. disease, but still significant residual risk despite aggressive treatment with statins and other agents.
"There is a great need for new therapies to lower LDL further on top of today's LDL-lowering treatments," he said. "Inclisiran such therapy."
Inclisiran is the first of a new class of cholesterol-lowering agents known as low interfering RNA (siRNA). This double-stranded RNA molecule utilizes a natural process called RNA interference, which has the ability to turn off specific genes – in this case, the gene for is PCSK9 .
The agent is designed to be selectively absorbed by the liver and specifically inhibits 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 by subcutaneous injection on day 1 and day 30, then every six months for 18 months.
Of the enrolled population, 95% were taking effective lipid-lowering therapy: 90% were on statins, 79% had high-intensity statins, and 9% were on ezetimibe. Mean baseline LDL level was 105 mg / dl.
The results showed that at the end of the study (day 510), LDL in the inclisiran group was reduced by 58% versus placebo. The mean reduction in LDL from day 90 to day 540 was 56% ( P for both endpoints <.00001).
In terms of safety, the resulting side effects of treatment did not differ between the inclisiran and placebo groups.
Injection site reactions occurred in 2.6% of inclisiran recipients versus 0.9% of placebo recipients.
Wright noted that this was less than seen in previous studies and equal or less than that seen with 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 inclisiran vs 0.4% of placebo with vial and syringe method of administration but was reduced to 1.0% with inclisiran vs 0.1% with placebo when pre-filled syringes were introduced in the second half of the study.
As regards laboratory measures, the liver, kidney and muscle enzymes did not separate 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 increased during the study.
There was also no difference in serious adverse events, general mortality, cardiovascular mortality or cancer mortality between the two groups. New or worsening malignancy occurred in 3.3% of both groups. Side effects that led to drug withdrawal occurred in 2.4% of inclisiran recipients versus 2.2% of placebo recipients.
A potentially exploratory cardiac and endpoint (MedDRA-defined cardiovascular non-judgmental term, including cardiac death, and any signs or symptoms of cardiac arrest, non-fatal myocardial infarction (MI) and / or stroke occurred in 7.4% of the inclisiran group against
Cardiovascular death occurred in 0.9% of inclisiran group vs 0.6% of placebo group, and fatal / non-fatal MI or stroke in 4.1% and 3.3%, respectively.  "New and exciting opportunities"
Designated discusser of the study, Karol E. Watson, MD, said that inclisiran opened for "new and exciting opportunities" for LDL lowering.
Watson is a professor of medicine / cardiology at David Geffen School of Medicine at the University of California, Los Angeles.
She said that the ORION-10 results showed "very impressive and durable lowering of LDL with inclisiran, but I also want to see what effect it has on HDL, triglycerides and Lp (a). "
" It looks safe ov is 18 months, but we do not have any safety data beyond this point and this is likely to be a lifelong therapy. I would also like to know if there are important differences between the individuals in the inclisiran response, "she commented.
Wright replied," There is always concern about safety with any new drug, and it is appropriate. A very long phase 3 cardiovascular outcome study – ORION 4 – is under way that will provide further data on safety. In addition, all patients from previous and current studies are followed up for long-term safety. So far, we have not seen any difference with placebo. "
Rare Dose: Friend or Enemy?
Wright suggested that the twice-yearly administration of inclisiran should coincide with patients' twice-yearly visits to health care.  But Watson countered:" We do not know what the effect of it is rare dosage will have. I would like to say that all my patients come to me twice a year, but they do not. And I don't know if it will be a case of & # 39; out of sight, out of mind & # 39; or whether patients will be encouraged to maintain therapy themselves. "
She also pointed out that it is not yet known whether treatment with inclisiran will result in improved long-term clinical outcomes beyond that seen with statins.
" Although the 58% reduction in LDL seen here is very impressive, are there any patients who can achieve this on statins, "she said." What will be the effect of inclisiran vs statins on equivalent LDL lowering? "
Wright responded that how inclisiran is compared to statins is not the right question." suggested replacing statins with a drug like this. . It is currently being tested as an adjunct to statins in high-risk patients and those with familial hypercholesterolemia. "
Note that all the evidence so far shows that lower LDL levels provide better outcomes and long-term benefits require patients to continue with their therapy so that LDL is reduced as low as possible for as long as possible," Watson concluded, "a therapy that can lower LDL to lower levels and improve compliance should lead to improved results. "
There was a lot of excitement in the cardiology community about this new agent, Watson said," there is a lot of excitement, "he adds," it will be much more if the results of ORION-4 show a significant reduction in cardiovascular outcomes. "
She suggested that how the drug will eventually be used will largely depend on the results of ORION-4." If the results are good, I think that it will be used widely on top of statins. There is so much more burden of atherosclerotic disease that remains even with the use of statins, so I think this will be a powerful way. "
But she noted that inclisiran would not be used with a PCSK9 inhibitor monoclonal antibody because they are both drugs targeting a similar pathway." That would be one or the other. "
Wright added that the alternatives to lower LDL via the PCSK9 path may come down to "what's more convenient – a drug given twice a year or one given 26 times a year. "
He noted that approval applications for inclisiran for an indication of LDL reduction are expected before the turn of the year in the United States and in early 2020 in Europe." So it should be on the market long before the results are available like all other lipid lowering therapies were. "
The ORION-10 study was funded by The Medicines Company. Wright reports research support from the company.  American Hear t Association (AHA) Scientific Sessions 2019. Presented November 16.
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