Dr Rachel Bastiaenen, PhD, St George's University of London, St George's Hospital London, UK

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are monoclonal antibodies which lower LDL cholesterol by increasing availability of LDL receptors in the liver thus increasing LDL clearance from the bloodstream. The US Food and Drug Administration (FDA) has recently approved Evolocumab (Repatha) and Alirocumab (Praluent) for use in patients with hypercholesterolaemia who are unable to lower LDL cholesterol using diet and statins alone. Evolocumab is also approved for use in Europe.

Multiple clinical trials including patients with heterozygous and homozygous familial hypercholesterolaemia, patients unable to tolerate statins and patients at high risk of cardiovascular events who are inadequately controlled on statin therapy have demonstrated effective and dramatic lowering of LDL cholesterol using PCSK9 inhibitors.(1,2)

In the ODYSSEY trials 2341 patients at high risk of cardiovascular events with elevated LDL cholesterol despite maximum tolerated statin dose were randomised to receive alirocumab or placebo in a 2:1 ratio. At week 24 the LDL cholesterol level was 61% lower in the treatment group compared with 0.8% lower in the placebo group (p<0.001) and this effect was maintained over 78 weeks. Treatment related adverse events that were more prevalent in the alirocumab group included injection-site reactions, myalgia and neurocognitive events (amnesia and memory impairment).(1)

In the OSLER trials 4465 patients were randomised to receive evolocumab plus standard therapy or standard therapy alone in a 2:1 ratio. Patients were followed for 11 months with assessment of lipid levels, safety and cardiovascular events. Compared with standard therapy, evolocumab reduced LDL cholesterol by 61%. Neurocognitive events were more frequent in the treatment group but other adverse events were similar between groups. The rate of prespecified and ‘exploratory’ cardiovascular events at 1 year was reduced in the evolocumab group (HR 0.47; 95%CI 0.28-0.78; p=0.003).(2)

There are numerous controversies regarding the rapid approval of PCSK9 inhibitors for use in LDL cholesterol lowering. Outcome data is awaited in the form of the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) which has recruited 27500 patients randomised to evolocumab or placebo and will report on a composite primary endpoint of cardiovascular death, MI, hospitalisation for unstable angina, stroke or coronary revascularisation in 2017. Although many believe that LDL cholesterol level is a surrogate marker for cardiovascular risk, the outcome data for PCSK9 inhibitors is not yet available to back this up. In addition there are concerns regarding lack of long-term safety data and high costs. It is likely that initially these drugs will be reserved for patients with severe familial hypercholesterolaemia and recurrent cardiovascular events.

References

  1. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372(16):1489-99.
  2. Sabatine MS, Guigliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372(16):1500-9.
Cardio Debate Expert Comments

Monoclonal antibodies PCSK9 inhibitors have appeared as a new lipid-lowering therapeutic class with a different mechanism of action. Different phase 3 trials with these new compounds, including evolocumab, alirocumab and bococizumab, have shown a significant and substantial reduction of LDL-cholesterol levels on top of statins or standard of care in different populations, thus suggesting a role for these new compounds to treat patients at high risk of cardiovascular disease, patients with intolerance to (maximum doses of) statins or subjects with familial hypercholesterolaemia.

These results have led to the recent approval of some of these drugs by the FDA in USA (evolocumab and alirocumab) and by the EMEA in Europe (evolocumab). This approval has been based, however, on the surrogate end-point of LDL-cholesterol reduction, as trials showing a cardiovascular risk reduction are still lacking.

Preliminary data from safety analyses or post-hoc adjudicated events with alirocumab and evolocumab suggest a reduction of cardiovascular events associated to these new drugs compared with placebo or standard of care, respectively. These preliminary results, together with the significant reductions achieved in LDL-cholesterol levels and the data on cardiovascular events reported from genetic studies with gain- or loss-of function PCSK9 gene mutations suggest that PCSK9 inhibitors could effectively reduce cardiovascular risk. However, these results, though promising, are not sufficient to prove the cardiovascular benefit of these drugs and trials specifically designed to assess these outcomes are required. In this respect, different studies with evolocumab (FOURIER trial), alirocumab (ODYSSEY OUTCOMES) and bococizumab (SPIRE trials) are already ongoing and will help to shed light on this particular matter. Additionally, long-term safety of PCSK9 inhibitors should be further explored.

PCSK9 Inhibitors: A New Era In Lipid Management

The story is as short as it is breathtaking. Just over 10 years have elapsed since the discovery of the protein PCSK9, its role in the modulation of LDL receptor activity, and the availability of specific inhibitors for use in clinical practice.

The results of the efficacy and safety studies have also been impressive, and the monoclonal antibodies (mAbs) anti-PCSK9 have consistently shown a lowering of the level of LDL cholesterol by on average 50-60% in all clinical settings, including patients treated with statins at the maximum tolerated dose, in monotherapy, or in combination with ezetimibe.

Interestingly, PCSK9 inhibitors also significantly lower  Lipoprotein (a), which is now considered to be an important risk factor for cardiovascular (CV) disease with limited therapeutic options.

Patients with Familial Hypercholesterolemia, who fail to reach desired goals, as well as statin intolerant/resistant subjects, may clearly benefit from being administered a biweekly or monthly SC injection of these new therapeutic agents.

If the promising clinical outcome studies (Fourier, Odyssey and Spire I and II) currently under way finally confirm compelling CV event reduction -exploring much lower LDL levels than that ever achieved before with conventional therapy- then we will witness a huge shift in the treatment of atherosclerotic CV disease and high LDL cholesterol related pathologies.

Despite the beneficial effects of statins, many patients remain at a high residual risk of cardiovascular events either due to risk beyond intensity statin therapy or tolerance issues which preclude increasing statin doses. As a result, there continues to be interest in developing novel approaches to lowering LDL cholesterol. Proprotein convertase subtilisin kexin type 9 (PCSK9) has emerged as an attractive target, given its important role in regulating hepatic expression of the LDL receptor on the liver surface. This is further supported by the finding that PCSK9 levels increase with statin therapy and that genetic studies demonstrate that less PCSK9 activity associates not only with lower LDL cholesterol levels, but also less cardiovascular events.
The early experience with monoclonal antibodies against PCSK9 have been extraordinary. Administered either as mono therapy or in combination with statin therapy, subcutanenous administration of these agents every 2-4 weeks results in dose dependent lowering of LDL cholesterol up to 70%. This provides a great therapeutic opportunity to drive LDL cholesterol levels to much lower levels than can be achieved with statin therapy and will be an important adjunct to those who can only be treated with low doses and those with statin intolerance. Large outcome trials are currently in progress to evaluate the impact of PCSK9 inhibitors on cardiovascular events. Early pooled data from longer term phase 2 studies suggests that this is likely to be beneficial, although we wait to have definitive evidence from clinical trials.
These agents appear to be safe and well tolerated. Injection site reactions appear to be mild at most. While theoretical concerns have been raised with regard to the safety of achieving very low LDL cholesterol levels, there is currently no evidence to suggest that this should be a problem. Similarly, while there is immense interest in the neurocognitive effects of these agents, these effects are yet to be studied systematically in a cohort at risk for cognitive decline. Once the outcome data becomes available, systematic analyses will be able to inform with regard to cost effectiveness of these agents. Given the high cost or of production, it will be important to demonstrate cost effectiveness to justify widespread use. As PCSK9 inhibitors begin to be used in clinical practice, they give the clinician an important additional agent to further lower cardiovascular risk.