PCSK9 Inhibitors: Who Could Need More than a Statin?

By Rhodes Hambrick

Peer Reviewed

The atherosclerotic cardiovascular disease (ASCVD) risk associated with hyperlipidemia (HLD), readily apparent from the Framingham Heart Study¹ of the mid-20^th century, has been the target of innumerable attempted pharmacologic interventions ever since. One class of agents, the HMG-CoA reductase inhibitors, or statins, became – and have remained² – the gold standard for managing HLD-associated ASCVD risk in the setting of the remarkably favorable findings of multiple studies in the 1990s.^3-5 While other agents, including niacin, fish oil, and fibrates, have been demonstrated to have favorable effects on some combination of LDL, HDL, and triglycerides, only statins have been conclusively proven to be of consistent, predictable benefit in reducing ASCVD-related morbidity and mortality.

That said, IMPROVE-IT, a 2014 trial⁶ in which ezetimibe, an inhibitor of intestinal cholesterol absorption, was added to statin monotherapy, demonstrated that reductions in LDL cholesterol levels below those achievable with statins alone resulted in further decreases cardiovascular events; this generated renewed interest in therapies targeted specifically at LDL. Meanwhile, research into cholesterol metabolism uncovered a protein known as proprotein convertase subtilisin/kexin type 9, or PCSK9, responsible for degrading the hepatic LDL receptor. Interestingly, individuals bearing loss-of-function mutations in the PCSK9 gene were found⁷ to have significantly lower (> 40%) average plasma LDL concentration when compared with those with wild-type PCSK9, with corresponding decreases in ASCVD-related events – and no discernible sequelae. This prompted investigation into the possibility of mimicking this biologic effect in the form of a novel biologic agent directed against PCSK9, ideally increasing the concentration of LDL receptor, decreasing the serum LDL concentration, and decreasing cardiovascular events.

This research was fruitful: 2015 brought the publication of two Phase III trials of alirocumab⁸ and evolocumab,⁹ fully human monoclonal antibodies directed against PCSK9. Each was shown to result in dramatic decreases in serum LDL compared to patients on standard therapy, of decreases of over 50% for final serum LDL values in the range of 45-60 mg/dL. Both were well tolerated, with rates of serious adverse events similar to those of placebo, though a non-significant increase in neurocognitive events was noted in both cohorts, including amnesia, memory impairment, and a confusional state; the reasons for the development of these events is uncertain, with no clear pathologic relationship to LDL physiology, though are reportedly similar to those that have been observed in other trials of monoclonal antibodies.^8-9

While these data are impressive, neither of the above trials individually demonstrated a significant decrease in ASCVD-related morbidity or mortality. That said, a 2015 meta-analysis¹⁰ of multiple trials of PCSK9 inhibitors used in patients with familial hypercholesterolemia suggested that use of a PCSK9 inhibitor is associated with a statistically significant decrease in all-cause mortality and myocardial infarction. Regardless, when evaluating a novel therapy, it is critical to recognize the danger in examining only surrogate endpoints, such as serum LDL, ejection fraction, or glycated hemoglobin, without simultaneously examining hard, patient-relevant clinical outcomes, such as myocardial infarction, stroke, and mortality. The 2008 ACCORD trial,¹¹ which demonstrated increased mortality for patients with type 2 diabetes mellitus treated to a more intensive hemoglobin A1C target, serves as a potent proof of principle.

Nevertheless, the observed efficacy and safety of alirocumab and evolocumab in the aforementioned trials prompted the FDA to grant each agent approval^12-13 for the treatment of elevated LDL in patients with familial hypercholesterolemia and those with clinically apparent ASCVD incapable of reaching goal reductions in LDL with high-intensity statin therapy alone. In the meantime, studies of each agent continue, with the goal of demonstrating conclusive clinical benefit beyond statin monotherapy alone: “ODYSSEY Outcomes” for alirocumab¹⁴ and “FOURIER” for evolocumab.¹⁵

All the same, even if ODYSSEY Outcomes and FOURIER demonstrate that PCSK9 inhibitors result in a significant reduction in ASCVD-related morbidity and mortality, a crucial question remains: whom should receive one? Given the tremendous research effort necessary to bring these biologics to market, it is perhaps unsurprising that Regeneron and Amgen, the pharmaceutical companies responsible for alirocumab and evolocumab, respectively, have both attached hefty price tags to their products – over $14,000 for a year’s supply of either drug.¹⁶ A cost-benefit argument favoring their use is most plausible for patients with homozygous familial hypercholesterolemia, for whom LDL apheresis is an effective method to reduce LDL in the statin-intolerant – at a cost of close to $100,000 per year.^17-18

Given that these are agents designed for prevention of future disease rather than treatment of extant disease, their efficacy in reducing ASCVD-related events will have to be considerable to justify such a high price in all but the most high-risk patients – who, given the systemic nature of metabolic derangements, often have significant comorbidities and other pressing medical concerns. Indeed, a recent analysis by the Boston-based Institute for Clinical and Economic Review¹⁶ employing current estimates at the efficacy of these agents suggested that a cost-effective price would be $2400 – less than one-fifth their current cost. It thus remains an open question what role these agents will come to occupy in the world of cardiovascular risk management; regardless, their successful development and safe implementation is a testament to the power of modern biomedicine to translate basic scientific discoveries to the bedside.

Dr. Rhodes Hambrick is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Donnino, MD, cardiologist, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

 

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