Inclisiran Effectively Lowers LDL Across High-risk Settings

Liam Davenport

October 15, 2020

Inclisiran (The Medicines Company) sustainably reduces low-density-lipoprotein (LDL) cholesterol levels across genotypes in heterozygous familial hypercholesterolemia (HeFH) and in the primary prevention setting in high-risk patients, suggest the latest data from the ORION program.

The research was presented at the European Atherosclerosis Society (EAS) 2020 Virtual Congress on October 5, held online this year due to the COVID-19 pandemic.

In a substudy of the ORION-9 trial, 293 HeFH patients randomized to inclisiran, the novel small-interfering (si)RNA agent, or placebo were stratified by the number of FH-associated variants and then subdivided into eight genotypes.

The degree of LDL cholesterol lowering with inclisiran was similar across all subgroups, ranging from 37% to 56%, and between 72% and 82% of patients achieved their LDL cholesterol target with the drug.

These results confirm the top-line genotype data presented when the trial was published earlier this year.

"Upregulation of residual functional LDL receptors across HeFH genotypes by inclisiran is sufficient for cellular uptake of LDL cholesterol," said study presenter Frederick Raal, MD, PhD, University of the Witwatersrand, Johannesburg, South Africa.

"Significant reductions in LDL cholesterol across HeFH genotypes suggest that inclisiran may provide therapeutic benefit independent of the causative mutation."

ORION-11 compared the impact of inclisiran and placebo on LDL cholesterol levels in patients at high risk for a cardiovascular event, despite being on maximally tolerated statin therapy.

Presenting data on 203 primary prevention patients, Kausik Ray, MD, PhD, Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, showed that inclisiran reduced LDL cholesterol levels by 47% by day 510.

These were in line with the previously presented overall study data, which showed that inclisiran was associated with a 50% reduction in LDL cholesterol.

Ray said that the results demonstrate "that a 6-monthly dosing regimen with inclisiran is feasible, and represents a promising new add-on therapy for primary prevention patients who require additional LDL lowering."

Proportional Benefit

Alberico L. Catapano, MD, PhD, Professor of Pharmacology at the University of Milan, who is past president of the EAS, was not involved in either study. He told | Medscape Cardiology that "obviously," outcomes data are awaited for inclisiran but that he does not "expect much of a surprise."

He said that the "benefit will be proportional to the reduction of LDL cholesterol" and, if there continue to be no safety concerns, "I wouldn't expect anything different from what we have seen with other lipid-lowering drugs."

Asking to speculate on whether inclisiran could eventually move beyond being an add-on therapy to be used first-line, Catapano said that "statins are incredibly cheap, effective, and safe, whatever people say."

However, he added, "in some specific populations, [inclisiran] may be one of the things you might look at."

He explained that it could be considered for people who are intolerant to statins, but that "very much depends on the pricing."

Catapano added that the "fixed-dose combination of statins and ezetimibe [Nustendi] is available as a generic, so it's really very, very cheap nowadays, and so this will probably be the first approach."

"Then there will be a competition between antibodies, PCSK9 inhibitors, inclisiran, and other small interfering RNAs, and perhaps newer drugs."


Presenting the ORION-9 substudy, Raal explained that there is greater overlap between severe HeFH phenotypes and homozygous FH than previously thought, with some HeFH patients carrying two mutations.

These can be compound mutations, with mutations in both alleles of one gene, or double mutations, in which there are mutations in one allele of two different genes.

The mutations can severely affect residual LDL receptor function, and the response to other lipid-lowering therapies has been shown consequently to vary by FH genotype, Raal said.

To determine the effectiveness of inclisiran across a range of genotypes, the team studied patients with confirmed HeFH, a family history of FH, and a history of untreated LDL cholesterol above 4.9 mmol/L.

They were required to have a current LDL cholesterol level of at least 2.6 mmol/L despite maximally tolerated statins, with or without ezetimibe.

Raal reported that 482 patients were randomized 1:1 to inclisiran or placebo, given on days 1, 90, 270, and 450, with follow-up on days 30, 150, 330, and 510, and a final assessment on day 540, 90 days after the last dose.

This included 293 individuals with gene mutations. Thirty-seven had two variants: 18 with compound HeFH and 19 with a double mutation.

The remaining 256 had a single mutation, with 168 LDL receptor negative, 28 receptor defective, and 60 status unknown, and a further 231 receptor pathogenic, 17 likely pathogenic, and eight with a variant of uncertain significance.

More than 80% of all participants were receiving high-intensity statins, and more than half ezetimibe. Between 18.2% and 26.4% of participants had established atherosclerotic cardiovascular disease (ASCVD).

Inclisiran was associated with a substantial reduction in LDL cholesterol levels at day 510 over baseline, at 41.2%, or 1.5 mmol/L, in patients with two variants, and 46.0%, or 1.8 mmol/L, in patients with a single LDL receptor variant.

There were wide variations within groups, with the largest reduction in LDL cholesterol levels seen in LDL receptor unknown patients (56% or 2.1 mmol/L) and the lowest at 37.2%, or 1.4 mmol/L, in compound HeFH patients. All reductions were nevertheless significant (P < .05).

As expected, all groups also had "robust" reductions in PCSK9 levels, which is the target of inclisiran, and patients given the drug were substantially more likely to reach their LDL cholesterol target than those given placebo.

Raal reported that 82% of patients with two variants reached their LDL cholesterol target with inclisiran, compared with 7% with placebo, whereas 73% of single LDL receptor variant patients reached their target with the drug, compared with 13% of those given placebo.

There were, again, wide variations across subgroups, with substantially more patients reaching their LDL cholesterol target with inclisiran than with placebo, regardless of HeFH genotype.

Few patients experienced serious adverse events, and rates were approximately twice as high in the placebo group as in the inclisiran group.

Injection-site reactions were relatively common with inclisiran, at 22.7% in patients with two variants and 16.1% in those with one LDL receptor variant, but they were all mild to moderate.

"This safety profile for inclisiran remained consistent when stratified by heterozygous FH genotype," Raal said.

He acknowledged, however, that there are some limitations to the study, including that "potential bias from variability and subgroup samples cannot be excluded."

Catapano told | Medscape Cardiology that inclisiran worked "as expected" across the HeFH genotypes, and the variability in LDL cholesterol reductions between subgroups did not reveal any differences in terms of efficacy.

He emphasized that this is not surprising because, in HeFH, "the other allele is still working," so the efficacy of the drug should not be affected.

"It's not like in homozygous HF when you have LDL receptor negative patients; anything that upregulates LDL receptor will work very poorly," Catapano said. "But in this case, the other allele is fine, so it would compensate and allow higher expression of the LDL receptor."


Presenting ORION-11, Ray noted that statins are recommended as a first-line therapy in individuals at high risk of developing ASCVD, defined as patients with a single high-risk condition, such as diabetes or FH, or a combination of risk factors known to increase risk.

However, he highlighted that, despite the use of maximally tolerated statins, many will not reach their LDL cholesterol goals, "indicating that additional therapies are required."

The researchers therefore conducted a study with the same treatment and follow-up schedule as ORION-9, randomizing 203 primary prevention patients to inclisiran or placebo, alongside 1414 secondary prevention patients not included in this analysis.

In the primary prevention cohort, 65% of the patients had diabetes, 11.3% had FH, and 23.6% had a 10-year predicted cardiovascular risk of at least 20%.

Inclisiran was associated with substantial placebo-corrected reductions in LDL cholesterol levels, at an average of 47.2% from baseline to day 510, or a time-averaged change from baseline after day 90 to day 540 of 42.3%.

This translated into absolute reductions in LDL cholesterol of 1.55 mmol/L and 1.37 mmol/L, respectively.

Ray said the time-averaged assessment is "important because what we want to assess also is whether this infrequent dosing regimen provides coverage over a long period of time, like 15 months."

Moreover, almost half (49.4%) of primary prevention patients achieved an LDL cholesterol target below 1.8 mmol/L by day 510, compared with 1.1% of those in the placebo group, giving an odds ratio for achieving target of 91.8 (95% CI, 12.2 - 689.2).

Ray also showed that there were marked and significant reductions over baseline at day 510 with inclisiran for total cholesterol, non-high-density-lipoprotein (HDL) cholesterol, apolipoprotein B, and lipoprotein(a) levels (P < .0001 for all).

These were reflected in significant time-averaged reductions in total cholesterol, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) levels from baseline after day 90 to day 540 (P < .001), as well as a small but significant increase in HDL cholesterol levels (= .0198).

As with ORION-9, there were relatively few treatment-emergent serious adverse events with inclisiran (20.4% of the inclisiran group and 12.4% of the placebo group).

Ray said the safety profile is consistent with previous studies, "with no evidence of liver, kidney, or platelet toxicity."

"The one caveat is there is a small excess of injection-site adverse events which are mild to moderate in nature, none severe and persistent."

Catapano commented that the "good thing about this latest generation of small interfering RNAs is the way they are targeted to the liver…and that makes the dose...substantially lower than for the previous ones."

This is beneficial in terms of adverse events, and he said "safety, to date, appears to be not an issue" with inclisiran.

Both studies were sponsored by The Medicines Company. Raal reports being being on consulting/advisory boards for The Medicines Company, Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, and Novartis; receiving research funding from The Medicines Company, Amgen, and Regeneron Pharmaceuticals; receiving honoraria/expenses from Sanofi-Aventis, Regeneron Pharmaceuticals, and Novartis. Ray reports being on consulting/advisory boards for The Medicines Company, Novartis, Amgen, Regeneron Pharmaceuticals/Sanofi, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Kiowa, Bayer, Daiichi Sanyo, New Amsterdam, and Esperion; receiving research funding from Amgen, Regeneron Pharmaceuticals/Sanofi, Pfizer, and Daiichi Sanyo; and receiving honoraria/expenses from Amgen, Regeneron Pharmaceuticals/Sanofi, Boehringer Ingelheim, and Novo Nordisk.

European Atherosclerosis Society (EAS) Virtual Congress 2020: Late-breaker 1. Presented October 5, 2020.

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