Momentum Builds for PCSK9 Inhibition at ACC.17: Even Lower LDL-C is Even Better

Evidence has strongly established low-density lipoprotein cholesterol (LDL-C) as a causal risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). Biologic interventions that decrease LDL-C reduce the rates of ASCVD events.1,2 Unfortunately, a sizeable number of patients either show inadequate responses or intolerance to statins and other existing agents.3,4

Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease that targets the hepatic LDL receptor for degradation.5 Inhibition of PCSK9, a novel strategy for lowering LDL-C, represents an exciting addition to traditional therapies. This article will review five important clinical trials of PCSK9 inhibition that were presented at the ACC.17 Scientific Sessions: FOURIER, EBBINGHAUS, SPIRE-1, SPIRE-2, and ORION-1.


The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial was the first randomized clinical trial presented at ACC.17 and was the first reporting clinical trial of PCSK9 inhibition designed to primarily assess hard clinical endpoints.6 The trial studied evolocumab, a fully human monoclonal antibody against PCSK9, which is administered as a subcutaneous injection. More than 27,500 patients with established ASCVD and LDL-C levels ≥70 mg/dL who were treated with maximally tolerated statin therapy were enrolled.

Participants were randomized to evolocumab 140 mg every 2 weeks or 420 mg monthly versus placebo. The primary composite endpoint was the rate of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization.

Evolocumab lowered LDL-C levels from a median of 92 mg/dL to a median of 30 mg/dL, representing a 59% reduction compared with placebo, and patients receiving evolocumab had a 15% relative reduction and 1.5% absolute reduction in the composite primary endpoint (9.8% vs. 11.3%). Compatible with other secondary prevention trials in modern times (e.g., Treating to New Targets [TNT], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]), there was no significant effect on cardiovascular or all-cause mortality. However, the magnitude of risk reduction increased over the second year compared to the first year, suggesting that longer follow-up might show even more impressive results.

From a safety perspective, injection-site reactions were experienced by 2.1% of patients in the evolocumab group versus 1.6% in the control group. The rate of drug discontinuation was 0.1% and was due to discomfort at the injection site. There were no differences between study groups in muscle-related events, cataracts, diabetes, or cognitive decline. Furthermore, there were no neutralizing antibodies.


The Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in high cardiovascUlar risk Subjects (EBBINGHAUS) trial was a safety-centered substudy of FOURIER.7 The motivation for this analysis was the theoretical concern for accelerated cognitive decline among patients with very low LDL-C levels, as well as previous reports that PCSK9 inhibitor therapy may be associated with neurocognitive adverse events in a small percentage of individuals.8

The study used the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognitive status. This is a well-validated computerized test that assesses memory, learning, and executive function. At the completion of 48 weeks, cognitive scores in the evolocumab and the placebo groups were not detectably different.

The EBBINGHAUS data suggest that even blood levels of LDL-C as low as 20 mg/dL or even lower may be safe from a neurologic perspective, which is in line with evidence that the brain synthesizes its own cholesterol. Although longer-term follow-up is certainly needed, these data provide additional reassurance on top of the observation that PCSK9 monoclonal antibodies may be too large to cross the blood brain barrier.

SPIRE 1, 2

The Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE-1 and SPIRE-2) investigated bococizumab, a partially-human, partially-murine monoclonal antibody to PCSK9.9 The studies included approximately 27,000 patients at high risk for a cardiovascular event. Enrolled participants had LDL-C levels of 70 mg/dL and above (for SPIRE-1) and 100 mg/dL and above (for SPIRE-2) after at least four weeks of statin therapy.

Study participants were randomized to either bococizumab 150 mg by subcutaneous injection every two weeks or placebo. The primary composite endpoint was myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, and cardiovascular death.

At 14 weeks, LDL-C levels decreased by 59% more in bococizumab treated patients. However, a clear trend of attenuation in LDL-C reduction was apparent over time, with the mean percent change in LDL-C among patients in the bococizumab group decreasing to -42% at 52 weeks and -38% at 104 weeks. SPIRE-2 showed lower cardiovascular event rates in the bococizumab arm (hazard ratio of 0.79 at 12 months), but SPIRE-1 (which enrolled patients with lower LDL-C) revealed no difference in cardiovascular events between the groups.

In a combined analysis, no difference was observed in the rates of cardiovascular death or all-cause mortality. In addition, high-titer anti-drug antibodies developed in almost half of the patients receiving bococizumab, and neutralizing antibodies developed in almost one-third. These antibodies were thought to be responsible for the attenuation in LDL-C reduction and likely accounted in part for the substantial variability in clinical efficacy that was observed among patients.


Small interfering RNAs (siRNA) provide yet another avenue for LDL-C lowering. While monoclonal antibodies act by sequestering PCSK9, siRNAs like inclisiran work by silencing the translation of the PCSK9 messenger RNA in the hepatocyte. Inclisiran could offer the advantage of more sustained LDL-C reduction and therefore less frequent dosing.

This trial assessed the LDL-C lowering effect of inclisiran in high-risk patients.10 A phase II, multi-center, double-blind trial, patients included in ORION-1 either had ASCVD or were at high risk of developing it. In this dose-finding trial, patients were randomized to a single dose or a two dose regimen. The primary endpoint was percentage of LDL-C lowering at 180 days, calculated as the least-squares mean percentage change in LDL-C.

A total of 501 patients were included in the analysis. Among those receiving inclisiran, LDL-C levels began to diverge from baseline at 14 days, achieving a nadir value at 60 and 150 days in the one dose and two dose groups, respectively. Levels then remained significantly divergent through 240 days.

At 180 days, the LDL-C reduction ranged from 28 to 53% across different inclisiran doses, with the greatest effect observed in the group receiving two doses of 300 mg of inclisiran. In this group, the mean reduction in LDL-C concentration was 64 mg/dL at 180 days and 59 mg/dL at 240 days. In contrast, LDL-C levels in the placebo groups had increased slightly at 180 days.

These results show significant and sustained LDL-C lowering with inclisiran, with persistent effect on LDL-C levels measured at up to 240 days. What remains to be seen is the extent to which patients prefer less frequent dosing and whether inclisiran, like evolocumab, improves hard cardiovascular endpoints.


In summary, lowering LDL-C via antibody-mediated antagonism of PCSK9 translated into an improved cardiovascular event rate with evolocumab in the large, very well-executed FOURIER trial. It appears that achieving sustained LDL-C reductions by upregulating the number of clearance receptors in the liver indeed holds clinically-meaningful cardio-protective potential. Moreover, the absolute LDL-C levels that were attained with evolocumab are unprecedented, and were remarkably well tolerated, including in a dedicated neurocognitive substudy, EBBINGHAUS. Building on IMPROVE-IT, these new results support the idea that even lower LDL-C is even better.

The findings from the SPIRE program reinforce the FOURIER results in documenting clinically meaningful event reduction with PCSK9 inhibition. This is important in that we now have multiple clinical trials showing hard outcome reduction. Disappointingly, there were neutralizing antibodies to bococizumab, highlighting the importance of manufacturing a fully human monoclonal antibody.

The future may be even brighter. Longer follow-up may reveal even greater benefits of PCSK9 inhibition and maintenance of very low LDL-C. Moreover, other approaches to PCSK9 inhibition are in the pipeline and may further expand our armamentarium. As shown in ORION-1, RNA interference targeting PCSK9 messenger RNA similarly leads to sustained reductions in LDL-C and offers ease-of-administration with no significant off-target effects.

To cement our understanding of the cardiovascular benefit of these novel classes of lipid-lowering agents, longer efficacy and careful post-marketing surveillance are needed. Meanwhile, in high risk patients who do not achieve adequate lipid control (e.g., LDL-C <70 mg/dL) with diet, maximal statin therapy, and ezetimibe, clinicians should discuss PCSK9 inhibition as an option to further improve outcomes.


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  2. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
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  6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017. [Epub ahead of print]
  7. Giugliano RP, Mach F, Zavitz K, et al. Primary results of EBBINGHAUS, a cognitive study of patients enrolled in the FOURIER trial. American College of Cardiology 2017 Scientific Sessions; March 18, 2017; Washington, DC. Abstract 17-LB-16161-AC.
  8. Swiger KJ, Martin SS. PCSK9 inhibitors and neurocognitive adverse events: exploring the FDA directive and a proposal for N-of-1 trials. Drug Saf 2015;38:519-26.
  9. Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527-39.
  10. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430-40.

Keywords: ACC Annual Scientific Session, ACC17, Angina, Unstable, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Biological Products, Cardiovascular Diseases, Cholesterol, LDL, Cognition, Diabetes Mellitus, Hepatocytes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver, Myocardial Infarction, Proprotein Convertases, RNA Interference, RNA, Messenger, RNA, Small Interfering, Receptors, LDL, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Stroke, Subtilisins, Treatment Outcome, Trinitrotoluene, Dyslipidemias

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