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The fascinating story of PCSK9 inhibition: Insights and perspective from ACC
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As health care providers who focus on risk-factor management, it is difficult not to be excited about the potential of PCSK9 inhibition. Indeed, some of the most highly attended sessions at the American College of Cardiology Scientific Sessions revolved around these new PCSK9 inhibitors under development. The substantial interest in the variety of data presented at this year’s meeting reflects that the development of PCSK9 inhibitors is coming along at a unique point in the realm of preventive cardiology from multiple perspectives.
The discovery of PCSK9
Parag H. Joshi
Seth S. Martin
Roger S.
Blumenthal
From a scientific perspective, there is justified pride in the rapid progress since the discovery of PCSK9 only about a decade ago. PCSK9, or proprotein convertase subtilisin/kexin type 9, is an enzyme that binds to the LDL receptor after it has received an LDL particle from the serum. When bound to PCSK9, the LDL receptor gets degraded along with the LDL particle that it contains. However, in the absence of PCSK9, or through PCSK9 inhibition, the LDL receptor recycles to the surface of the liver to collect another LDL particle while the initially collected LDL particle gets degraded, leading to dramatic reductions in LDL cholesterol.
Findings from laboratories around the world converged to form the origins of the PCSK9 story. Genetic mutations that increased PCSK9 activity were found to be the source of extremely elevated LDL levels in French families with high cholesterol in Montreal and Paris. Then, a research team at University of Texas Southwestern Medical Center, led by Helen Hobbs, MD, and Jonathan Cohen, PhD, identified participants with very low levels of LDL from the Dallas Heart Study. They found that a different genetic mutation causing PCSK9 deficiency led to lifelong reductions in serum LDL, which translated to a reduced risk for heart disease. A participant with LDL <20 mg/dL had two mutant copies of PCSK9 that essentially led to lifelong absence of PCSK9 altogether. Discovery of this healthy mother of two children served as proof that absence of PCSK9 and extremely low LDL levels were safe.
A busy drug pipeline
From a drug-development perspective, there is incredible optimism over PCSK9 inhibition. At ACC 2014, investigators presented the latest trial data in various phases of development from several pharmaceutical companies. This included five oral presentations of phase 3 data on evolocumab (Amgen), two posters of alirocumab (Sanofi/Regeneron) and one poster of phase 2 data on bococizumab (Pfizer).
During a featured oral session, results from the long-term, 52-week DESCARTES study evaluating the efficacy and safety of evolocumab in addition to multiple other combinations of lipid-lowering therapy were presented. Researchers found that a monthly subcutaneous injection of evolocumab 420 mg consistently led to approximately 50% more LDL reduction compared with placebo when added to a range of background therapies (diet alone, atorvastatin 10 mg daily, atorvastatin 80 mg daily and atorvastatin 80 mg plus ezetimibe 10 mg daily). LDL reduction persisted during the course of the 1-year trial, representing some of the longest-term data on this class so far. Importantly, adverse events were similar between placebo and evolocumab.
The same session included presentation of the MENDEL-2 and RUTHERFORD-2 studies, which showed similar LDL reductions of 50% to 60% with evolocumab 140 mg biweekly and 420 mg monthly during 12 weeks, with no major adverse event concerns compared with placebo or ezetimibe. Among patients with heterozygous familial hypercholesterolemia on statin therapy in RUTHERFORD-2, up to 80% achieved LDL <70 mg/dL at 12 weeks on monthly evolocumab vs. just 2% of placebo-treated patients.
The Late-Breaking Clinical Trials session delivered equally striking results on LDL reduction in statin-intolerant patients, a group that is prone to myalgias and other adverse effects. Inclusion in the GAUSS-2 trial required intolerance to at least two statin therapies, and reported adverse effects were few, particularly myalgias. In the LAPLACE-2 trial, evolocumab demonstrated impressive LDL reduction compared with ezetimibe in participants on high- and moderate-intensity statin treatment at baseline at 12 weeks. Compared with placebo, evolocumab led to 63% to 75% reductions in LDL, whereas the addition of ezetimibe only led to about a 20% reduction in LDL vs. placebo.
Similarly impressive LDL reductions were shown in presentations from the alirocumab and bococizumab programs. Importantly, there do not appear to be significant adverse event signals in any of these trials.
Interpretation of therapies in the context of new guidelines
Excitement aside, there may also be confusion as to how to interpret these therapies in the context of the 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults released by the ACC and American Heart Association in November. The new guidelines take a fresh approach to evaluating existing cholesterol-reduction data. Although statins were developed and used as LDL-reducing agents in numerous trials proving their efficacy in reducing CV events, the guidelines committee recognized the pleiotropic effects of statins as a possible explanation for their risk–benefit.
As a result, the guidelines rightly emphasize the use of statins as the means to reduce LDL, and they relegated other LDL-directed therapies to second-line therapies due to the lack of randomized trials demonstrating benefits in outcomes when added to baseline statin therapies. The committee also could not find randomized controlled trial evidence of a specific LDL target to endorse and therefore shifted the paradigm from a LDL target-based approach to an approach that relies more strongly than prior guidelines on the degree of risk for CV events with the intensity of statin therapy.
The new data provide consistent evidence of robust reductions in LDL by this novel mechanism, but the last few years have reminded us that improvement in surrogate endpoints, such as HbA1c or HDL cholesterol, do not necessarily translate to improvements in outcomes. Although LDL may be more reliable, trials examining CV and mortality outcomes when adding PCSK9 inhibitors to baseline statin therapy are crucial to guiding providers for the care of a broad population. We look forward to results from the ongoing FOURIER, ODYSSEY OUTCOMES, and SPIRE 1 and 2 trials, which will test CV outcomes with evolocumab, alirocumab and bococizumab, respectively.
Appropriate patient populations
From a patient perspective, there also is reason for hope. The FDA may eventually approve PCSK9 inhibitors for patients who currently have limited options for LDL reduction due to statin intolerance or who have residually high risk despite statin therapy. One of the main factors to consider from the patient perspective is the nature of delivery of this therapy; currently, as a monoclonal antibody, it is only in an injectable form. Compliance with oral medications is already suboptimal, suggesting that compliance with an injection may be less consistent in the primary-prevention setting. However, the once-monthly or biweekly schedule may mitigate some of the issues with compliance. Certainly, many patients are able to comply with multiple times-daily subcutaneous insulin in current clinical practice.
To gain approval for particular high-risk subgroups, adverse events are being carefully monitored. Despite a lack of any publically available evidence of neurocognitive effects, the FDA requested that these adverse events specifically be collected. There have been biological concerns about the effects of extremely low LDL levels on neurocognition; however, current data do not suggest a signal.
In conclusion, ACC 2014 generated tremendous enthusiasm and buzz over PCSK9 inhibitors. Unfortunately, it seems that we will have to wait until at least 2017 before outcomes data are available validating use in the majority of our patients. In the meantime, the safety and efficacy data are encouraging, and we eagerly anticipate further developments.
Disclosure: The authors report no relevant financial disclosures.