National Lipid Association
National Lipid Association
May 01, 2018
4 min read
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Inclisiran reduces LDL in variety of populations

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LAS VEGAS — Inclisiran, an RNA interference therapeutic targeting PCSK9, safely reduced LDL in various patient populations and subgroups, according to a late-breaking clinical trial presented at the National Lipid Association Scientific Sessions.

David Kallend, MBBS, chief medical officer of The Medicines Company, discussed analyses of the ORION trials.

As Cardiology Today previously reported, the phase 2 ORION-1 trial found that inclisiran (The Medicines Company) was associated with reduced LDL and PCSK9 and that the greatest LDL reductions were observed in patients assigned two 300-mg doses of inclisiran, with 48% having LDL levels reduced to less than 50 mg/dL.

Inclisiran doses greater than 300 mg had the same efficacy and duration of effect compared with the 300-mg dose, according to the presentation.

“There were some considerations previously that higher doses may sit in the liver and produce prolonged duration of effect,” Kallend said. “That isn’t the case. Any dose above 300 mg is cleared in the same way and has no greater efficacy.”

During the trials, researchers expect to see an average LDL reduction of 51% between the second injection in the ORION-1 trial and subsequent injections in the current program, according to the presentation. Injections of inclisiran 300 mg will be administered at 90, 270 and 450 days.

“It’s interesting that you need that second dose at day 90 to boost the starting efficacy of around 50% to around 55%, but however you give this drug, the return to baseline was consistently around 3% per month,” Kallend said.

It would take an estimated 18 months to wash out the effect of inclisiran on patients who had a peak reduction of around 55% at 150 days, according to the presentation.

At 180 days, an LDL reduction of at least 50% was achieved in various subgroups such as patients with diabetes, statin or nonstatin use, those older and younger than 65 years, men and women, and normal, mild or moderate renal function. There was also no difference in safety in any of the subgroups, including platelet counts, liver function and adverse events.

ORION-2 is a pilot study on patients with homozygous familial hypercholesterolemia to assess whether the dose or frequency of inclisiran would need to be adjusted. Five or six patients are currently enrolled in the study, and researchers are aiming for six to eight patients total before moving to phase 3, according to the presentation. Patients were given 300 mg inclisiran at day 1 and day 90.

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One patient who did not respond to monoclonal antibodies did not have a reduction in LDL or lipoprotein(a) despite durable and consistent PCSK9 reduction of greater than 60%, Kallend said, noting another patient had a 32.8% reduction in LDL at day 120 and 19.6% at day 300.

“What we see here, as we see in the patients without [familial hypercholesterolemia], is a similar — around 3% per month return back to baseline, so a prolonged and durable effect on LDL cholesterol and on PCSK9,” Kallend said.

Another patient with a similar variant as the patient who did not respond to inclisiran had a 44.3% reduction in LDL at day 120 and an estimated 25% reduction in lipoprotein(a). At day 300, there was a 24.9% reduction in LDL, according to the presentation.

The ORION-7 trial is analyzing the effects of inclisiran on patients with renal impairment.

“Thirty percent of our drug is excreted through the kidneys,” Kallend said. “It’s important to look at very closely.”

In patients with severe renal impairment, there was a fourfold increase in the maximum concentration of inclisiran between 2 to 4 hours after subcutaneous injection, according to the presentation. There was also a two- to threefold increase in exposure in patients with severe renal impairment.

“You may think that sounds like a lot,” Kallend said. “These are the first 48 hours. After 48 hours, no more drug is detected with the plasma and has either been excreted through the kidney or is sitting in the liver, having its effect in terms of PCSK9 suppression,” Kallend said.

Pharmacokinetics were the same in patients with severe renal impairment compared with a single 500-mg dose of inclisiran given to a patient without renal impairment.

At baseline, patients with renal impairment had LDL levels greater than 60 mg/dL. Several patients achieved LDL in the single digits and returned to baseline over time, similar to what was seen in other studies, according to the presentation.

Other ongoing trials include ORION-10 and ORION-11, which focus on lipid-lowering in the United States and Europe. ORION-5 includes patients with homozygous familial hypercholesterolemia, and ORION-9 featured patients with heterozygous familial hypercholesterolemia.

“These are fairly standard trials that are recruiting very quickly,” Kallend said. “They’re due to complete sometime around the third quarter of 2019.”

Another trial that will start in the next few months will compare the effects of inclisiran on patients with hepatic impairment vs. normal hepatic function, according to the presentation.

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Researchers will assess CV outcomes in the ORION-4 trial, which will include more than 15,000 patients older than 55 years with pre-existing CVD. Patients will be assigned 300 mg inclisiran sodium or placebo for a median of 5 years. The primary endpoint will be a composite of major adverse CV events, defined as MI, CHD death, fatal or nonfatal ischemic stroke or urgent coronary revascularization.

Throughout all the trials that are being conducted, researchers are accumulating 5 patient-years of safety data on inclisiran per day, which will potentially equate to 2,360 patient-years by the end of 2018.

“Inclisiran is emerging as a new class of drug to interact with PCSK9 with a one-size-fits-all dosing regimen of 300 mg subcutaneously, 1.5 mL, given on day 1, day 90 and every 180 days thereafter,” Kallend said. – by Darlene Dobkowski

Reference:

Kallend D, et al. Late Breakers. Presented at: National Lipid Association Scientific Sessions; April 26-29, 2018; Las Vegas.

Disclosure: The studies were funded by The Medicines Company. Kallend reports he is a full-time employee of The Medicines Company and receives salary and stock options.