LDL-C reduction with PCSK9 inhibitors: An update on the latest evidence

PCSK9 inhibitors are novel agents that target proprotein convertase subtilisin-kexin type 9, a protein involved in the degradation of the LDL receptor in the liver. Inhibiting PCSK9 results in increased expression of the LDL-C receptor, and therefore increased clearance of cholesterol through hepatic metabolism. Three agents have been developed in this class so far: the humanised monoclonal antibody Bococizumab that retains a 3% murine sequence, and the two fully human antibodies Alirocumab and Evolocumab. Pfizer halted the development of Bococizumab after phase 2 studies revealed unacceptably high rates of attenuation of the lipid lowering effect due to the development of neutralising antibodies, as well as a significant incidence of injection site reactions.

On the other hand, data on Evolocumab from the OSLER programme of trials[1] already demonstrated the high efficacy of the drug in decreasing LDL-C to levels significantly below what is achieved with standard therapy. There was a signal toward possible increased incidence of neurocognitive deficits in the PCSK9 arm, but this was not significant at one year. On the basis of these data the FOURIER trial was launched to look at the effect of lowering LDL-C with Evolocumab on hard outcomes. Alirocumab is yet to report the results of its ongoing ODYSSEY outcomes trial[2].

FOURIER Study design

The FOURIER trial[3] enrolled 27,564 patients for a median follow-up of 26months. To be eligible patients had to have atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/dL (1.8 mmol/L) or higher who were receiving statin therapy. This was a randomised, double blind, placebo controlled trial conducted all across the globe. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke.

Results

The 61% reduction in LDL-C levels seen in the OSLER studies was confirmed in FOURIER with a 59% reduction in LDL-C levels to a mean on treatment level of 30 mg/dl (0.78 mmol/l). The primary endpoint was significantly lower in the PCSK9 arm with a relative risk reduction of 15% (HR 0.85, 95% CI 0.79 – 0.92, p<0.0001) which equates to an absolute reduction of 2% of the primary endpoint. The same was true for the key secondary endpoint of CV death, MI or CVA (HR 0.8, 95%CI 0.73 – 0.88, p<0.00001). A breakdown of the composite reveals that the drivers of outcome were CVA, TIA, MI and coronary revascularisation, with no significant difference in the rates of CV death or all-cause mortality in this study. Indeed a trend – albeit non-significant – toward higher rates of all-cause mortality was seen in the Evolocumab arm (4.8% vs. 4.3%, HR 1.04, 95%CI 0.91 – 1.19). These results, as report by the trial investigators, equate to a number needed to treat of 74 patients over a period of 2 years to prevent one cardiovascular death, myocardial infarction, or stroke.

The incidence of adverse events was not different between groups across the spectrum of adjudicated events, in particular the rates of adverse neurocognitive events (flagged as a possible drawback to PCSK9 therapy in the OSLER studies) was 1.6% in the Evolocumab arm vs. 1.5% in the placebo arm. The only adverse event that was higher in the Evolocumab arm was injection site reactions (2.1% vs. 1.6%, p,0.001) but 90% of these were mild and only 0.1% of patients required study drug discontinuation due to injection site reactions.

Spotlight on Neurocognitive effects

The EBBINGHAUS trial[4] was a substudy of the FOURIER trial which reported on the safety of Evolocumab with regards to neurocognitive function. It included 1974 patients enrolled in the main FOURIER study, and subjected them to a battery of neurocognitive tests at baseline and during therapy with Evolocumab. The primary endpoint was the spatial working memory strategy index of executive function performed as part of the Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessments (a standardized, well validated computer tablet-based testing platform). The trial was designed as a non-inferiority study (NI margin of 20%). The results revealed no difference between treatment and placebo arms with a change in scores from baseline to follow-up of -0.21 and -0.29 respectively (p<0.001 for non-inferiority) for the primary endpoint. In addition patient self-reported scores of neurocognitive function, and investigator reported neurocognitive effects were also not statistically different between the two groups. Crucially, an analysis of the group of patients with the lowest levels of LDL-C (<25mg/dL, 0.65mmol/L) did not reveal detrimental effects in the Evolocumab group either.

Discussion

The FOURIER trial has given us an unprecedented look at the effects of extremely low levels of LDL on cardiovascular health. Some people may suggest that the results largely support the theory that lower is better when it comes to LDL levels, although this study failed to actually show any reduction in mortality.

It is likely that the effects of low LDL-C levels, both positive and negative, will become more obvious as time goes on, and the results of longer term follow-up beyond the 26 months reported in this analysis will hopefully go a long way to shed light on the issue. Will the adverse mortality trend seen in the Evolocumab arm become significant or will therapy ultimately result in a reduction in deaths? Similarly, will a decade (or more) of extremely low levels of LDL have a more pronounced effect on neurocognitive function than that seen in the EBBINGHAUS study?

In addition to the clinical impact of the drug, cost considerations need to be taken into account due to the high price of these drugs. In the USA Evolocumab is reportedly marketed at $14000/year/patient. Given an NNT of 74 to prevent one non-fatal event over 2 years this results in a cost of over $2’000’000 to prevent one event. In this age of tight budgets a discussion around affordability of such drugs will inevitably be required before widespread use becomes the norm.

References

1.         Sabatine, M.S., et al., Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med, 2015. 372(16): p. 1500-9.

2.         Schwartz, G.G., et al., Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J, 2014. 168(5): p. 682-9.

3.         Sabatine, M.S., et al., Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med, 2017.

4.         Giugliano, R.P., et al., Design and rationale of the EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER trial. Clin Cardiol, 2017. 40(2): p. 59-65.