Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events

Robinson JP, Farnier M, Krempf M, et al.
NEMJ, published March 15, 2015, at NEJM.org; DOI: 10.1056/NEJMoa1501031

Background

Alirocumab is a monoclonal antibody inhibiting proprotein convertase subtilisin–kexin type 9 (PCSK9),and  has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in addition to statin therapy [1-3].
The present study aimed to obtain additional safety data and enrolled  2341 patients (mean age of 60 years) at high risk for cardiovascular events with LDL cholesterol levels of minimally 70 mg per deciliter (1.8 mmol/L) despite treatment with statins at the maximum tolerated dose. Patients were randomly assigned to treatment with alirocumab (150 mg; n=1553) or subcutaneous placebo (n=788) every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.

Main results

• At week 24, alirocumab-treated patients had a mean LDL-c level of 48 mg/dL (1.2 mmol/L), and the placebo group had 119 mg/dL (3.1 mmol/L). The difference in mean % change from baseline between the alirocumab and placebo groups was −62 % (P<0.001).
• 79.3% of alirocumab-treated patients reached the LDL-c target of <70 mg/dL, as opposed to 8.0% in the placebo group (P<0.001).  
• The treatment effect was consistent over a period of 78 weeks.
• The number of adverse events was comparable for treatment with alirocumab (81.0%) and placebo (82.5%) and was reason for discontinuation of the study drug in 7.2% and 5.8% of patients respectively.
  Alirocumab treatment (relative to the placebo group) produced higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (including amnesia, memory impairment, and confusional state) (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).
• The rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was 48% lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P = 0.02).
• The cumulative incidence curves progressively separated over time.
• The efficacy of alirocumab was similar across various clinically relevant subgroups.

Conclusions

The ODYSSEY LONG TERM trial showed that the PCSK9 inhibitor alirocumab, as compared with placebo, reduced LDL cholesterol levels by an additional 62 percentage points at week 24 in high-risk patients on top of statin therapy at the maximum tolerated dose. The effect was stable over 78 weeks of therapy. In a post-hoc analysis of the in the ODYSSEY OUTCOMES trial prespecified primary endpoint (but not prespecified in LONG TERM), a reduction of the occurrence of CV events was seen with treatment with alirocumab. Studies with longer follow-up periods are needed as the present duration was still relatively short for a treatment of a chronic disease.

Editorial comment [4]

Stone and Lloyd-Jones evaluate the ODYSSEY LONG TERM and the OSLER (evolocumab) trials [4] and state that “[…] Because PCSK9 inhibitors allow the achievement of lower LDL cholesterol levels than those achieved to date with statins, a close look at safety is a paramount consideration”. […] “The ODYSSEY LONG TERM and OSLER studies whet our appetites for further results that show cardiovascular benefit and documented safety, even at substantially lower LDL cholesterol ranges than achieved before. However, it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary endpoint analysis and safety assessment, are available” […]
“[…] results, including the current ones, fit well into the framework established by the 2013 cholesterol guidelines of the American College of Cardiology and the American HeartAssociation, which recommended that nonstatins could be used in higher-risk patients in
whom statin therapy did not lower LDL cholesterol levels sufficiently or in patients with unacceptable side effects from statin therapy, with a strong preference for use of non-statins thathave been determined to be safe and effective in randomized, controlled trials [5]. The evidence-driven cholesterol guidelines did not endorse the concept that lower LDL cholesterol levels are better at all costs. They  emphasized that, while lower is better, it matters how you get there andwhether the benefits outweigh the risks for that patient. Much work remains to be done, but PCSK9inhibitors appear on track to become important arrows in our quiver for targeting reduction ofcardiovascular events among higher-risk patients when statins are not enough”.

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References

1. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody
to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-53.
2. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367:1891-900.
3. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29-36.
4. Stone NJ, Lloyd-Jones DM. Lowering LDL Cholesterol Is Good, but How and in Whom? NEMJ March 15, 2015DOI: 10.1056/NEJMe1502192