Costs and Benefits: How a New Cholesterol-Lowering Drug Compares to Others

Dr Kevin Cowart, assistant professor at the University of South Florida College of Pharmacy, discusses inclisiran, a new non-statin treatment for high cholesterol. Inclisiran works by increasing LDL recycling and expression, leading to increased uptake of LDL in the liver. It is indicated for adults with heterozygous familial hypercholesterolemia or clinical ASCVD who require additional LDL lowering. Clinical trials have shown that inclisiran significantly lowers LDL by about 50% compared to placebo. The dosing regimen involves a subcutaneous injection every three months for two doses, and then every six months thereafter. Inclisiran is typically used in combination with other lipid-lowering therapies. The cost of inclisiran is initially higher than PCSK9 inhibitors, but the long-term cost-effectiveness is still being evaluated. Ongoing research includes cardiovascular outcomes trials to further understand the role of inclisiran in managing cardiovascular disease risk.

Transcript:

My name is Dr. Kevin Cowart. I'm an assistant professor at the University of South Florida College of Pharmacy, and I practice as a clinical pharmacy specialist in ambulatory care in the Department of Family Medicine.

So today, I'll be talking about the inclisiran, which is one of the newest [00:00:30] non-statin treatments.

Yeah, so inclisiran is one of our newest non-statin medications. It works differently in compared to the statins and other non-statins such as PCSK9 inhibitors like ezetimibe, bempedoic acid, or icosapent ethyl or Vascepa.

It's a small interfering ribonucleic acid, which clinically increases LDL recycling and expression, which increases uptake of LDL in the liver. So it sort of works similarly to our PCSK9 inhibitors, although primary difference between and inclisiran and the available PCSK9 inhibitors is inclisiran works intracellularly to upregulate LDL receptors, whereas PCSK9 inhibitors work more extracellularly to bind and block the circulating PCSK9 protein.

At the present time, inclisiran is indicated to primarily treat two patient populations. So it's an adjunct to diet and maximally-tolerated statin therapy in adults with either heterozygous familial hypercholesterolemia or in adults with clinical ASCVD who require additional LDL lowering.

Yes. So there are three randomized, double-blind placebo-controlled trials that have evaluated the efficacy of inclisiran, and these were in the ORION clinical trials program, the ORION-9, 10, and 11 trials, which the co-primary endpoints in these studies were the placebo-corrected percentage of change in LDL from baseline to day 510, and the time-adjusted percentage change in LDL from baseline after day 90 through day 540.

Baseline LDL in the trials varied between about 100 to [00:04:30] 150. And across these trials, inclisiran significantly lowered LDL by about 50% as compared to placebo. The trials included patients with either heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease, or ASCVD, or in patients that had an elevated ASCVD risk.

And so in addition to the above randomized controlled trials, there have been some meta-analyses published on inclisiran as well, some of which also included the PCSK9 inhibitors since inclisiran [00:05:00] targets PCSK9. And the results were essentially confirmatory from the original ORION-9, 10, and 11 trials in that inclisiran provided superior LDL lowering over placebo, as well as compared to bempedoic acid, ezetimibe individually, or when combined with bempedoic acid and ezetimibe.

Now in regards to the differences between available PCSK9 inhibitors, in some of these metas, there was no significant difference in the treatment effect size between either alirocumab or evolocumab when compared to inclisiran. And we would expect that given that the LDL reductions were similar. However, inclisiran does appear to lower LDL about 10% less versus the available PCSK9 inhibitors.

I also wanted to mention the safety which was evaluated in these trials and drug discontinuation due to what we call treatment-emergent adverse effects. And serious adverse events occurred slightly more in patients taking inclisiran as compared with placebo but the overall incidence was still low. And most [00:06:00] of these were mild reactions at the injection site, which were reported more frequently in the inclisiran group, and this is what we have seen in most of the PCSK9 inhibitor trials. But importantly, no patients reported severe or persistent injection risk reactions.

Yes. So there is a unique difference with inclisiran [00:06:30] as compared to other non-statin that clinicians do need to be made aware of. It is a subcutaneous injection that's administered every three months for two doses, and then every six months thereafter.

So the key difference regarding an inclisiran is that it is not intended for self-injection. So the medication has to be administered by a healthcare provider but does not require any monitoring after administration. So some institutions have had to build new practice models around how this drug is administered, such as using an infusion center or administering it within [00:07:00] a clinic at a doctor's appointment.

Yeah. In 2022, the ACC published an expert consensus document on the role of non-statin therapies for LDL lowering in the management of atherosclerotic cardiovascular disease. And the level of evidence for PCSK9 inhibitors and ezetimibe have remained unchanged. [00:07:30] And in this consensus document, inclisiran received a 2B recommendation since the ORION-4 trial, which is evaluating clinical outcomes in people with the existing ASCVD, is still ongoing.

So at this time, inclisiran should be considered in patients who are not meeting their LDL goal with lifestyle modifications and other lipid-lowering therapies such as maximally-tolerated statin therapy, plus ezetimibe or a PCSK9 inhibitor.

Alternatively, inclisiran may also be considered for those with allergic reactions [00:08:00] to PCSK9 inhibitors or in people who may have difficulty self-administering a PCSK9 inhibitor, such as those with arthritis or in those with adherence concerns to a PCSK9 inhibitor.

Well, in the initial year, the cost appears to be higher than the annual cost for [00:08:30] the PCSK9 inhibitors, but that cost difference is less in subsequent years. And there really just isn't enough long-term outcomes data that's currently available to evaluate the long-term cost-effectiveness.

One important point to make regarding cost is that inclisiran is bill through the patient's medical insurance and not the pharmacy benefits coverage, and so clinicians do need to be made aware of that. And then there is copay assistance programs that are available, although that cost [00:09:00] is going to vary from patient to patient.

Yes. In the past, we have not had really good cardiovascular outcomes data for several of the older non-statin drugs. And with the newer non-statin drugs and therapies, we will likely see a shift in managing high cholesterol [00:09:30] and cardiovascular disease risks, similar to how we manage other chronic diseases like hypertension or heart failure, where we're not just using one medication but multiple medications to help the patient achieve their goals. And so in this case, that would be lowering cardiovascular risk and LDL.

Well, we're anticipating two of the [00:10:00] cardiovascular outcomes trials, which are the ORION-4 trial and the VICTORION-2P trial.

So in the ORION-4 trial, which I briefly already mentioned, it's enrolling people with preexisting ASCVD and an LDL over 100 who are on maximally-tolerated statin therapy, and that trial is planned for a median duration of about five years. The primary endpoint is a composite of coronary heart disease, death, non-fatal MI, and fatal or [00:10:30] non-fatal ischemic stroke or urgent coronary revascularizations.

And then the additional CV outcomes trial of the VICTORION-2P trial is enrolling adults age 40 or older who have established ASCVD, are on high-intensity statin therapy with or without ezetimibe, and have an LDL over 70. And the primary endpoint in that trial is the major adverse cardiovascular events including CV, death, non-fatal MI, and non-fatal ischemic stroke.

So the results of these two trials [00:11:00] will certainly help us understand the place in therapy for inclisiran and lowering cardiovascular disease risk.

Well, as one of the newest non-statin therapies, inclisiran, as I already mentioned, has the benefit on helping patients who are not meeting treatment goals, [00:11:30] maybe because of adherence or for whatever other issues, an alternative option. And so one more medication that can potentially lower cardiovascular disease and significantly lower LDL has a large impact in helping to manage LDL and cardiovascular risk reduction.