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3 October 2014
PCSK9 inhibition in the corner: new data on safety and efficacy

PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has been the focus of much attention for its potential for reducing lipid-related residual cardiovascular risk, given evidence of substantial lowering of low-density lipoprotein (LDL) cholesterol. Indeed, at the European Society of Cardiology Congress, Barcelona 30 August-3 September, 2014 a post hoc analysis of ODYSSEY LONG TERM gave a hint in line with this expectation. However, the safety of very low LDL cholesterol levels is a concern, in particular, the risk of ischaemic complications after stroke. Results from an animal model, however, suggest that very low LDL cholesterol levels associated with PCSK9 inhibition should not increase haemorrhagic complications after acute ischemic stroke.

Robinson JG, Farnier M, Krempf M et al. Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: first results from the ODYSSEY LONG TERM study in 2,341 patients. Reported at ESC Congress Hotline 2, 31 August 2014.
Tran-Dinh A, Levoye A, Lambert G, Louedec L, Journé C, Meilhac O, Amarenco P. Low levels of low-density lipoprotein-C associated with proprotein convertase subtilisin kexin 9 inhibition do not increase the risk of hemorrhagic transformation. Stroke 2014 Aug 14. pii: STROKEAHA.114.005958. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25123222
Summary
Comments & References
STUDY SUMMARY: ODYSSEY LONG TERM
Objective To assess the safety, tolerability and efficacy of treatment with a monoclonal antibody to PCSK9 (alirocumab) in patients at high risk of cardiovascular disease (CVD) on maximally tolerated lipid-lowering therapy (including statin)
Study design Randomised, double-blind, placebo-controlled study. Patients were allocated 2:1 to alirocumab (150 mg subcutaneously every 2 weeks) or placebo for 78 weeks. The mean duration of treatment was 65 weeks (both arms).
Study population 2,341 patients at high risk of CVD (including patients with heterozygous familial hypercholesterolaemia) with LDL cholesterol levels ≥1.81 mmol/L (70 mg/dL) on maximally tolerated statin therapy; 1,553 were randomised to treatment with alirocumab and 788 received placebo.
Primary variables
  • Efficacy: percent change from baseline to week 24 in LDL cholesterol
  • Safety: adverse events, cardiovascular treatment-emergent adverse events
Methods
  • Intention-to-treat analysis for percent change in LDL cholesterol
  • post hoc Kaplan Meier analysis for time to first adjudicated major CV event, based on the primary endpoint of the ODYSSEY OUTCOMES trial (coronary heart disease [CHD] death, non-fatal myocardial infarction [MI], fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalisation)
Main results
  • Alirocumab treatment resulted in significant reduction from baseline in LDL cholesterol, by 61.9% (p<0.0001) versus placebo at week 24. 81% of alirocumab-treated patients reached LDL cholesterol goals according to their level of CV risk.
  • Treatment-emergent adverse events (TEAEs) occurred in 79% (1,218 of 1,550) alirocumab and 81% (635 of 788) of placebo patients. Discontinuation due to TEAEs was similar in each group (6.2% and 5.5%, respectively).  There was no imbalance in the frequency of TEAEs.
  • For patients who completed at least 52 weeks on study treatment, there was a significant reduction in cardiovascular outcomes: absolute event rates were 1.4% with alirocumab versus 3% with placebo, Hazard ratio 0.46, 95% confidence interval [CI] 0.26-0.82, p<0.01. 
Author's conclusion

Alirocumab is the first non-statin treatment that appears to reduce additional CV events on top of statin therapy, and this is very encouraging since previous trials of various lipid-lowering drugs have failed to find this.

STUDY SUMMARY: Tran-Dinh et al.
Objective To evaluate the potential for risk of haemorrhagic complications after cerebral ischaemia/reperfusion at very low levels of LDL cholesterol, using an experimental model (mice with PCSK9 deficiency).
Study design Experimental animal model
Study population Mice with genetic PCSK9 deficiency (PCSK9 −/−) and wild type mice (PCSK9 +/+). The PCSK9 deficient mice had significantly lower LDL cholesterol levels (mean 0.2 g/L) compared with controls; these levels are in the same range as those observed in patients treated with PCSK9 inhibitors.
Primary variables
  • Haemoglobin concentration in the ischaemic cerebral tissue
  • Infarct volume
Methods Both groups of mice were fed a high-fat/high-cholesterol (21%/0.15%) diet for 1 month and were then subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous haemorrhagic transformation was assessed by quantification of haemoglobin in ischaemic tissue.
Main results

Haemoglobin concentration in ischaemic cerebral tissue did not differ between PCSK9 deficient and wild type mice (31.5 [18.9–60.1] versus 32.8 [14.7–69.9] ng/mg protein, p=0.81). There was also no difference in infarct volume between the two groups.

In addition, using a validated in vitro model of the blood–brain barrier, there was no difference in endothelial barrier integrity at decreasing LDL cholesterol levels under ischaemia/reperfusion conditions.

Author's conclusion These observations suggest that PCSK9 inhibition, leading to LDL cholesterol lowering, should not increase haemorrhagic complications after acute ischaemic stroke.

COMMENT

PCSK9 plays a critical role in regulating cholesterol homeostasis. Although its mechanism of action remains to be fully elucidated, it is thought that binding of PCSK9 to the surface of the cell leads to conformational changes, in turn enhancing intracellular degradation of hepatic LDL receptors, resulting in an increase in plasma LDL cholesterol levels.1  On this basis, therefore, inhibition of PCSK9 has emerged as a novel target for further lowering of LDL cholesterol levels, in patients at high CV risk inadequately treated by statins or intolerant to statins. However, it is also relevant that inhibitors of PCSK9 also have important effects on other lipids, notably lipoprotein(a),2 which is a potential contributor to lipid-related residual CV risk.3 Certainly, the clinical development of monoclonal antibody therapies to PCSK9 has gathered pace, with three of these agents now in large prospective outcomes studies.4-7

Given the pitfalls of recent trials of novel lipid-modifying therapies which attempted to address the issue of residual CV risk, there has been much interest in foretelling the results. Hence this post hoc analysis from ODYSSEY LONG TERM. These findings provide reassuring safety data for treatment up to 78 weeks, as well as a hint in the right direction for potential clinical benefits. However, we need to bear in mind that this study was not powered for analysis of CV outcomes, as well as the limitations inherent in post hoc analyses.

A second question associated with PCSK9 inhibition concerns the safety of very low LDL cholesterol levels, specifically in relation to the risk of haemorrhagic complications after ischaemic stroke.8,9 However, the results from this experimental model by Tran-Dinh et al (2014) suggest that lowering of LDL cholesterol levels with PCSK9 inhibition should not increase the risk of haemorrhagic complications after acute ischemic stroke, albeit with the caveat that this is an animal model which does not account for the cumulative LDL-lowering effects associated with PCSK9 inhibition on top of statin therapy.

Despite these reservations, these studies do suggest promise for this novel therapy to address lipid-related residual CV risk.

References

1. Petrides F, Shearston K, Chatelais M et al. The promises of PCSK9 inhibition. Curr Opin Lipidol 2013;24:307–12.
2. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278-88.
3. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
4. NCT01663402. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727). Available at: https://clinicaltrials.gov/ct2/show/NCT01663402.
5. NCT01764633. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). Available at: https://clinicaltrials.gov/ct2/show/NCT01764633
6. NCT01975376. The Evaluation Of PF-04950615 (RN316), In Reducing The Occurrence Of Major Cardiovascular Events In High Risk Subjects (SPIRE-1). Available at: https://clinicaltrials.gov/ct2/show/NCT01975376.