In this article from RGA's ReFlections newsletter, Dr. Heather Lund explores the mechanisms of action, indications, drug development, treatment outcomes, and possible impact of this new class of lipid-lowering agents on insurance.
Lowering cholesterol is consistent with better cardiovascular (CV) outcomes, including reductions in myocardial infarctions (MI) and strokes. While treatment with statins is the mainstay of lipid-lowering therapy, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK-9) have emerged as a powerful new targeted tool.
These treatments are enabling lower levels of cholesterol to be achieved and might improve CV outcomes further, especially in those at higher risk either because of established atherosclerotic cardiovascular disease (ASCVD) or because optimal levels of cholesterol cannot be achieved on statin therapy alone.
This article will address the mechanisms of action, indications, drug development, treatment outcomes, and possible impact of this new class of lipid-lowering agents on insurance.
Hepatocytes (liver cells) have low-density lipoprotein (LDL) receptors on their surfaces. Circulating LDL-cholesterol (LDL-C) binds to these receptors. The receptor-cholesterol complex is then taken into the hepatocyte and degraded, after which the LDL receptor recycles back to the cell surface to bind more circulating LDL-C. This process is rapidly and continuously repeated throughout the cell’s 20-hour lifespan, enabling clearance of approximately 100 to 150 LDL-C particles.
PCSK-9 is a protein produced primarily in the liver that regulates the number of LDL receptors. It binds to the LDL receptor part of the receptor-cholesterol complex and prevents LDL receptors from recycling back to the cell surface. This reduces the number of LDL receptors on the hepatocytes and increases serum levels of LDL-C. The more PCSK-9 is produced by the liver, the higher the serum LDL-C level.
PCSK-9 inhibitors block the activity of PCSK-9, thereby increasing clearance of LDL-C and lowering cholesterol levels by an average of 50% to 60% in patients on statin therapy.1
The PCSK-9 protein is encoded by the PCSK-9 gene on chromosome 1. Mutations alter the function of the gene. Twenty years ago, two breakthrough discoveries related to the gene occurred: A gain-of-function mutation was found to be the cause of familial hypercholesterolemia (FH), and loss-of-function mutations were found to be associated with very low cholesterol levels and associated reduction in the incidence of cardiovascular disease. These discoveries led to the identification of PCSK-9 as a potential drug target for cholesterol control.
While medical society guidelines for treatment using these inhibitors may differ slightly, most have been broadened to include specific LDL treatment targets.
For those without cardiovascular disease and where LDL-C targets are not met, despite taking medications such as statins and a second-line therapy such as ezetimibe (an inhibitor of intestinal cholesterol absorption). For adults heterozygous for FH, high-dose statin monotherapy will achieve a 55% to 60% LDL-C reduction. However, if after three months of compliant statin therapy the LDL-C target has not been reached, a second-line drug is generally needed. Options currently include either ezetimibe or a PCSK-9 inhibitor, or both. Ezetimibe, which is usually the preferred option, can lower LDL-C by an additional 20% to 30%. However, it may not be sufficient for patients with FH.
For those with known cardiovascular disease where LDL-C targets need to be even lower (i.e., secondary prevention of cardiovascular disease). While no trials specifically for heterozygous FH patients have yet demonstrated improved clinical outcomes, in the FOURIER trial of a cohort without FH (detailed below), PCSK-9 inhibition, despite not decreasing the risk of CV death, lowered the risk of non-fatal myocardial infarction (MI) and non-fatal stroke sufficiently so that its use by inference can be recommended.
For those considered either high-risk (due to previous MI, angioplasty or stent, stroke, or history of heart disease, hospitalization for unstable angina, or peripheral arterial disease [PAD]) or very high risk (due to multiple episodes of listed high-risk events) and where LDL-C targets have not been met despite optimal first-line medical therapy.
In the 10% to 20% of those who are statin intolerant, PCSK-9 inhibition may also be a treatment option.
PCSK-9 inhibitors are generally very well tolerated. Safety data is available for up to nearly five years. However, there are adverse effects, which can include flu-like symptoms with fatigue, back pain, and – rarely – myalgia. Elevated liver enzymes have not been seen. The most common side effect is redness, bruising, or pain at the injection site.
Several innovations regarding drug development for PCSK-9 inhibition exist, and more advances in gene-based therapies and delivery modes are being explored.2
Monoclonal antibodies (mABs) are synthetic proteins (immunoglobulins) that have a defined specificity for a target antigen. This was the first type of PCSK-9 targeting therapeutic to be developed. These are administered through subcutaneous injections every two to four weeks. mABs have several advantages, including minimal drug interaction, as mABs bypass liver and kidney metabolism, as well as greater target specificity, which reduces potential off-site effects. Two mABs, alirocumab and evolocumab, are fully humanized mABs that bind free plasma PCSK-9, promoting PCSK-9 protein enzyme degradation. Early trials of both, which showed LDL reductions of approximately 50% to 60% compared with placebo, have been followed by Phase III cardiovascular outcome trials of FOURIER for evolocumab and ODYSSEY OUTCOMES for alirocumab.3, 4
The FOURIER trial involved participants with a history of MI, stroke, or symptomatic PAD, on maximum statin therapy followed up for 2.2 years, and showed a statistically significant reduction in cardiovascular events.3 A recently published 7.1-year follow-up study to FOURIER, FOURIER-OLE (participants were a subset of the FOURIER cohort), confirmed safety, tolerability, and a sustained 15% lower risk of major adverse cardiovascular events versus those who received a placebo.5 This is noteworthy, given concerns regarding possible harmful effects from very low LDL-C levels such as diabetes, stroke, cataracts, and neurocognitive impairment, and provides evidentiary support of the cumulative benefit of aggressive lowering of LDL-C.
The ODYSSEY OUTCOMES trial involved participants with recent acute coronary syndrome (ACS) episodes who had been on maximum statin therapy. The trial tested efficacy of alirocumab versus placebo, and participants, who were followed up for 2.8 years, showed a statistically significant reduction in recurrent major adverse CV events.4
Additional benefits of PCSK-9 antibodies include a reduction in triglyceride levels by 12% to 31% and an approximately 7% increase in high-density lipoprotein (HDL) cholesterol.
Interestingly, while the exact mechanism is not yet understood, sub-analysis of the above trials showed a lowering of lipoprotein(a) (Lp[a]) by approximately 25% and may explain some of the CV outcome benefits. Lp(a) is a genetically determined pro-inflammatory atherogenic LDL-like particle that is independently associated with atherosclerotic cardiovascular disease (ASCVD).6 As an aside, Lp(a) has also emerged as a potential additional new drug target due to recently published results of a phase 1 trial of muvalaplin, an oral formulation of a selective small molecule inhibitor of Lp(a). Muvalaplin has shown encouraging reduction in Lp(a) levels without modulating plasminogen activity.7 Another recent phase 1 safety and tolerability trial of lepodisiran, a small interfering RNA (siRNA) targeting Lp(a) production, showed positive results, supporting the need for further research.8
As mentioned above, another method of limiting PCSK-9 activity is to block its production, which is dependent on messenger RNA (mRNA). Inclisiran is an siRNA therapy which consists of a synthetic nucleotide sense strand as well as an antisense strand, which bind to and then degrade the PCSK-9 mRNA, silencing gene expression and preventing protein translation. Inclisiran, which is administered via subcutaneous injection, has been approved to treat individuals with primary hypercholesterolemia or mixed dyslipidemia as a second-line treatment when LDL-C goals are not met.
The many ORION trials of inclisiran have shown its effectiveness, with an average 50% reduction in LDL-C across different participant groups.9 While cardiovascular outcome benefits have not yet been shown with inclisiran, two randomized controlled trials, ORION-4 and VICTORION-2 PREVENT, are underway, with results due in 2026 and 2027, respectively.
Experiments in mice followed by non-human primates using CRISPR/Cas-based treatment to precisely edit the PCSK-9 gene or specific nucleases (bases) have been carried out, the latter allowing for safer and even more precise gene silencing.10 This essentially results in a loss-of-function mutation that permanently silences hepatic PCSK-9 production. To date, initial results show durable LDL-C reductions.11
Advantages of using CRISPR/Cas include reduced usage of standard cholesterol-lowering medications and their associated side effects, thereby enhancing cardiovascular disease prevention. In mid-November 2022, Verve Therapeutics announced an exciting finding from its VERVE 101 trial, where CRISPR technology was used to turn off the PCSK-9 gene in people with heterozygous FH. The results showed successful and substantially lowered cholesterol in study participants and appears to be safe.12
Genetic alterations on somatic cells such as liver cells will not affect the next generation, but if germline cells are edited, the changes could pass to offspring. Notwithstanding the significant ethical considerations, safety, tolerability, and possible off-target effects of gene therapy that need to be assessed in longer-term studies, this development is certainly noteworthy. Not only in terms of using CRISPR technology as a potential “one and done” treatment for dyslipidemia, but also for the management of more common conditions.
mABs can also provide immunity against PCSK-9, as they can act as passive vaccines. Active immunity in the form of a PCSK-9 vaccine, however, while technically challenging, has inherent appeal as a way to potentially reduce the overall cost of treatment and improve adherence. Early safely and efficacy trials of several PCSK-9 vaccine approaches are currently underway.
Several oral PCSK-9 inhibitors are currently in phase I and II clinical trials, which is exciting as, if successful, they would help reduce overall costs of therapy as well as the need for subcutaneous injections.
Of interest as well, but outside of the scope of this article, as these are very uncommon, are third-line treatments for LDL-C reduction which include ileal bypass surgery, portacaval anastomosis, and liver transplantation.
While PCSK-9 inhibition is incredibly effective at reducing LDL-C levels, most people will achieve LDL-C goals with statin monotherapy. As such, statins are unlikely to be replaced as first-line therapy in the immediate future, particularly because they are both efficacious and cost effective and have significant cardiovascular outcome trials to support their use.
Since their approval in the late 1980s, statins have been and remain the mainstay for effective lowering of cholesterol following the discovery of the relationship between lipids and atherosclerosis in the 1960s. Still, there remains a need for alternative potent lipid-lowering therapies.
PCSK-9 inhibition is, therefore, another tool in the cholesterol and cardiovascular outcome-reduction toolkit. Interestingly, circulating levels of PCSK-9 are upregulated in the presence of statins, so inhibiting PCSK-9 seems to complement the LDL-C lowering effect of statins.
PCSK-9 inhibition is not usually a first-line cholesterol-lowering therapy. From an underwriting perspective, while laboratory results would be used to risk-assess an applicant, it is important to initially ensure a thorough understanding of the reasons and comorbidities associated with the need for PCSK-9 inhibition.
There are also barriers to access to consider, and cost is certainly one of them. The cost of mABs has decreased significantly, to around USD 6,000 a year (from USD 14,000 per year). Cost-benefit studies have shown that mABs are cost-effective for those at greatest risk. The cost-effectiveness of inclisiran, for example, at around USD 6,500 a year, is yet to be established. Use and reimbursement would need to be managed according to recognized guidelines. But at the same time, insurance access could be broadened to those who would benefit most from using mABs or other approved therapies.
The most significant question might be: What will the likely impact of PCSK-9 inhibition be on future mortality and morbidity trends?
Substantial gains in longevity because of improvements in cardiovascular mortality, driven by better management of vascular risk factors and reduction in smoking rates, were seen in the latter half of the past century. But mortality improvements have slowed and lifestyle diseases such as diabetes and obesity have skyrocketed. The role of the insurer in enabling more proactive management of these lifestyle-related trends – and not just through access to medication – cannot be underestimated.
Many factors drive future mortality trends, but PCSK-9 inhibition, through reducing cardiovascular events, could potentially generate improvements in the future. Although reported only at study-level and not patient-level, a meta-analysis of 24 randomized trials of PCSK-9 inhibitors across a diverse range of baseline cardiovascular disease risks and clinical profiles (as was seen with the benefits of statins), found a reduction in all-cause mortality of 55%, cardiovascular mortality of 50%, and MI of 51%.13
Despite the significant impact of available lipid-lowering agents on improved cardiovascular outcomes, and while lifestyle modification remains a cornerstone of control, the identification of new pathways and drug targets continues to push the boundaries of what might be possible. PCSK-9 inhibition, through various current and potential modes of delivery, appears to be well tolerated and has become a noteworthy evolution. These treatments are a fascinating tale of medical advances and outcome improvements at their best, with potential sequels to follow. Hopefully a tailwind for mortality improvements and positive medical advances will continue for years to come.
