Inclisiran Safe and Effective in Patients With Impaired Renal Function: ORION

MAASTRICHT, the Netherlands—Inclisiran, a small, interfering RNA (siRNA) that targets the synthesis of PCSK9 in the liver, can be safely given to patients with and without impaired renal function, as well as to patients with rare homozygous familial hypercholesterolemia (FH), according to new data presented last week.

In an analysis of the ORION-7 and ORION-1 studies, inclisiran (The Medicines Company), which is delivered as a subcutaneous injection twice per year, significantly lowered LDL cholesterol levels in patients with normal renal function and in those with varying degrees of kidney impairment.

At 60 days, inclisiran lowered LDL cholesterol by 47.4% in patients with normal renal function and by 52.2% and 49.8%, respectively, in patients with mild and moderate renal impairment in the ORION-7 study. In ORION-1, inclisiran lowered LDL cholesterol by 57.6% in those with normal renal function and by 35.1%, 53.1%, and 49.2%, respectively, in patients with mild, moderate, and severe renal impairment.

John Kastelein, MD, PhD (Academic Medical Center, Amsterdam, the Netherlands), one of the study’s investigators, told TCTMD that while there was no initial concern about using inclisiran in patients with kidney disease, “when you consider how common underlying renal impairment is in [atherosclerotic cardiovascular disease (ASCVD)] patients, along with the fact that inclisiran is renally cleared, it is important to have a robust data set in this patient population.”

Given every 6 months, inclisiran offers an advantage over the bimonthly and monthly injections of the now-approved PCSK9 inhibitors evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi-Aventis/Regeneron). Several studies testing inclisiran have been presented and published to date, but the drug is not yet approved for clinical use.

When you consider how common underlying renal impairment is in ASCVD patients, along with the fact that inclisiran is renally cleared, it is important to have a robust data set in this patient population. John Kastelein

The new analysis presented at the European Atherosclerosis Society (EAS) Congress 2019 also included data from ORION-7, a smaller pharmacokinetic study involving 31 patients with impaired renal function treated with inclisiran. ORION-1 was significantly larger, with investigators randomizing 501 patients at high risk of ASCVD and elevated LDL cholesterol levels despite treatment with statins to inclisiran or placebo. The ORION-1 investigators allowed patients with renal impairment to be included in the trial, and the main results were presented at the European Society of Cardiology Congress in 2017.

In this combined analysis, the researchers focused their attention on safety, tolerability, and efficacy in patients with differing degrees of renal impairment. In terms of safety, pooled data showed no difference in the adverse event profile among patients with normal or impaired renal function. There were no changes in laboratory parameters reflective of worsening renal failure in patients from either trial, as well as no detrimental changes in liver function. In both studies, PCSK9 levels were reduced by nearly 70% at 60 days regardless of renal function.

“From a clinical perspective, inclisiran’s LDL cholesterol-lowering effects are very strong regardless of patient’s renal function, in addition to demonstrating excellent consistency,” said Kastelein. “The tolerability, safety, and LDL cholesterol and PCSK9 reductions are not altered by renal impairment.”   

In general, Kastelein said the twice-a-year dosing regimen can help more patients reliably get to lower LDL cholesterol levels while overcoming the challenges of adherence. The reductions in LDL cholesterol are “robust and persistent,” he said, noting that the dosing regimen is 300 mg inclisiran given at day 1, day 90, and every 6 months thereafter. These new data suggest the dose won’t need to be adjusted in patients with impaired kidney function. 

During the session, moderator Tom Seijkens, MD, PhD (Academic Medical Center, Amsterdam), noted there were increases in several pharmacokinetic measurements, such as the maximum observed plasma concentration (Cmax) of inclisiran and the area under the curve (AUC) of the plasma concentration over 48 hours, across patients with worsening renal functioning. The researchers say the slow early clearance of inclisiran would be expected given the renal impairment and point out that by 48 hours there was no inclisiran detected in the plasma irrespective of the patient’s renal function.   

ORION-2 in Homozygous FH

Frederick Raal, MBBCh, PhD (University of the Witwatersrand, Johannesburg, South Africa), also presented new results at the EAS Congress. ORION-2, a pilot study, included just four patients with homozygous FH treated with inclisiran and showed that the therapy reduced LDL cholesterol levels in three of those individuals. In these three patients, LDL cholesterol levels were reduced by 17.5%, 32.7%, and 37.0%, respectively, by day 180 and the maximum reduction observed was 43.0% from baseline on day 120. In the nonresponder, LDL cholesterol levels were unchanged at day 180, although PCSK9 levels were reduced by roughly 60%.

“The lowering of LDL cholesterol was expected in terms of the type of mutations,” said Raal. “Importantly, we did not have to increase or escalate the dose. The reduction in PCSK9 was prolonged, but very interestingly, as we have seen with monoclonal antibody therapy, two of the patients who had an identical mutation had a very different response to this medication. So there must be other reasons why some patients don’t respond as well as others.”

Homozygous FH is extremely rare, difficult to treat, and associated with very early mortality from ASCVD, said Raal. In the ORION-2 patients, baseline LDL cholesterol levels ranged from 193 to 618 mg/dL. All were treated with high-dose statin therapy as well as ezetimibe, but Raal noted these agents are limited in their effectiveness in this population. Lomitapide (Juxtapid; Aegerion) and mipomersen (Kynamro; Kastle Therapeutics) provide larger reductions in LDL cholesterol, but they carry a risk of liver toxicity, he said.

Phase III studies testing inclisiran are ongoing, including the ORION-5 study with 45 homozygous FH patients and the ORION-9 study with 482 heterozygous FH patients. The large-scale, cardiovascular outcomes study known as ORION-4 is being conducted by researchers from the University of Oxford and will enroll approximately 15,000 patients. Results are expected in 2024.