Inclisiran Effective Across FH Genotypes, as Well as in Primary Prevention

Inclisiran, an investigational small interfering RNA (siRNA) that inhibits production of the PCSK9 protein in the liver, significantly lowers LDL-cholesterol levels across a range of different genotypes of heterozygous familial hypercholesterolemia (HeFH), including patients with the severest forms of the disease, according to a new analysis of the ORION-9 trial.

For a second study, an analysis of ORION-11, researchers reported that inclisiran was effective in lowering LDL cholesterol in patients without atherosclerotic cardiovascular disease (ASCVD). Kausik Ray, MD (Imperial College London, England), said that while statins are first-line medical therapy for primary prevention after diet and lifestyle changes, “many of these individuals fail to attain the goals required for their level of risk.”

Both analyses were presented as late-breaking clinical trials this week at the virtual European Atherosclerosis Society Congress 2020.

Frederick Raal, MBBCh, PhD (University of the Witwatersrand, Johannesburg, South Africa), who presented the genetic analysis from ORION-9, appeared fairly optimistic that inclisiran, which is given just twice per year as a subcutaneous injection, will be a transformative treatment for patients with and without ASCVD.

“This is a really disruptive therapy,” he said in a discussion following both presentations. “You’re guaranteeing about a 50% reduction in LDL cholesterol. The patients who would benefit most would be the highest-risk patients, and that would be patients with familial hypercholesterolemia, those with established cardiovascular disease, and those with multiple risk factors. But potentially, because we’re getting nearly a 50% reduction with really only two injections a year, [inclisiran] could have a place in type 2 diabetics who have an overall increased cardiovascular risk. I think the range, particularly if it’s safe in the long term—we haven’t seen any major side effects to date—will be much broader than currently where we’re just using this agent in the very high-risk patients and those with FH.”

Ray agreed, noting that the agent would likely receive an indication in the patients studied in the different ORION clinical trials where maximally tolerated statin therapy doesn’t provide sufficient reduction in LDL-cholesterol levels commiserate with the patient’s risk. “And maximally tolerated might include no statins if they were statin intolerant,” said Ray.     

ORION-9, Inclisiran by Genotype

Inclisiran was developed by The Medicines Company, which was then purchased by Novartis for nearly $10 billion early in 2020 largely on the strength of the inclisiran data. Multiple phase III trials to date have shown that the siRNA lowers LDL levels in a broad range of patients, including those with HeFH, those with established ASCVD, as well as those at high risk for ASCVD. ORION-4, the large-scale cardiovascular outcomes trial being led by the University of Oxford is underway, but European and US regulators are currently reviewing the drug for potential approval based on its ability to lower LDL cholesterol.  

Speaking about the genetic analysis from ORION-9, Raal said there is more overlap between the severe genotypes of HeFH and homozygous familial hypercholesterolemia (HoFH) than previously thought, noting that some HeFH patients may carry two mutations. Normally, HeFH patients carry a single variant in the LDLR, APOB, or PCSK9 genes, with the LDLR gene variant the most common cause of HeFH. However, with compound HeFH, a patient carries different mutations in both alleles of one gene, such as LDLR, while double HeFH is characterized by mutations in one allele of two different genes.

In previous studies, the treatment response of other lipid-lowering therapies has been shown to vary by FH genotype, said Raal, and for that reason they wanted to confirm that treatment with inclisiran was effective across a range of patients.

Based on the genetic testing in ORION-9, mutations in LDLR were identified in 293 patients, with 37 found to have two variants, including 18 with compound HeFH and 19 with double HeFH. This left 256 patients with a single mutation in LDLR, who were further stratified into different groups based on LDL-receptor function: negative (n =168), defective (n = 28), or unknown (n = 60).

Among those with compound or double HeFH, inclisiran reduced LDL cholesterol by 37.2% and 46.3%, respectively. Even when stratified by LDL-receptor function, inclisiran lowered LDL cholesterol levels 43.0% in those who were receptor-negative, 48.6% in those who were receptor-defective, and by 56.1% in those with unknown LDL-receptor function. For the patients with a known pathogenic LDLR mutation, LDL-cholesterol levels were lowered 46.3% with inclisiran.

“The absolute reduction in LDL cholesterol was also similar across all the different genotypes and was quite impressive in those with two variants,” said Raal.

Overall, more than 80% of patients with two variants achieved the LDL-cholesterol target of less than 70 mg/dL for secondary prevention and less than 100 mg/dL for primary prevention. Similarly, 73% of patients with a single mutation in LDLR achieved the LDL targets. For those with a known pathogenic LDLR mutation, 72% of the inclisiran-treated patients got to goal.  

Primary Prevention

For the primary-prevention analysis, Ray focused on 203 high-risk patients without ASCVD in ORION-11 who had LDL-cholesterol levels 100 mg/dL or higher and type 2 diabetes, familial hypercholesterolemia, or a 10-year cardiovascular risk score ≥ 20%.

From baseline to day 510, the placebo-corrected percentage reduction in LDL cholesterol with inclisiran was 47.2% in the primary-prevention cohort, a relative reduction was not statistically different from the 53.3% observed in the secondary-prevention group. In terms of absolute numbers, LDL cholesterol was reduced by 60 mg/dL in those without preexisting ASCVD. Total and non-HDL cholesterol levels were reduced by 28.4% and 39.5%, respectively. Apolipoprotein B and lipoprotein(a) were also significantly reduced with inclisiran. With respect to targets, 78% of inclisiran-treated patients had LDL levels of less than 100 mg/dL at day 510 while 53% had a 50% or greater reduction from baseline.

When reported as the time-averaged change in LDL cholesterol from baseline after day 90 to day 540, an analysis necessary to establish the efficacy of a drug given just twice per year, LDL levels were reduced 42.3%, or 53.0 mg/dL, in the primary prevention population.

Asked about the potential strengths of inclisiran stack up against the PCSK9 inhibitors or bempedoic acid, Ray said such comparisons are difficult without head-to-head studies. Even without such studies, inclisiran could be a welcome addition for physicians and patients. “We know for our patients one size doesn’t fit all and there are going to be different needs,” he said. “We’ve clearly shown that with monotherapy, ie, with statins, many patients won’t get to the LDL level needed for their level of risk, particularly when you’re aiming for below 1.4 mmol/L, or 55 mg/dL.” 

Moreover, the addition of twice-yearly inclisiran would provide convenience in terms of dosing, said Ray.

The safety profile of the drug was consistent by FH genotype, with adverse events being similar between inclisiran and placebo as in the overall ORION-9 population. In ORION-11, there were also similar rates of adverse events between inclisiran and placebo, “with no evidence of liver, kidney, or platelet toxicity,” say Ray. He added there are data out to 3 or 4 years from the open-label ORION 3 study now showing any harms. “As much as what we can comment on right now, the only thing we see is a small excess of injection-site reactions, and even in people that get them, when they get the next [injection], those sites don’t flare up again,” said Ray.