New monoclonal antibody REGN727: more effective than statins?

Speaking of surrogate endpoints, I ran across the following headline in Daily Briefing, an e-newsletter I receive as part of my membership in the American Society of Health-System Pharmacists (ASHP): Experimental Drug May Be More Effective Than Statins.

The headline links to several published reports (including this one on theheart.org) about REGN727, an investigational human monoclonal antibody to proprotein convertase subtilisin/kexin 9 (PCSK9). According to the article, PCSK9 is a serum protease involved in the breakdown of hepatic low-density lipoprotein (LDL) receptors.  As a result of antibody-mediated inhibition of PCSK9 by REGN727, hepatic LDL receptors are spared, leading to subsequent reductions in serum LDL concentrations.  At the 2012 American College of Cardiology meeting earlier this week, lead investigators said REGN727 could be a potential "game changer" in the management of dyslipidemia, although a significant amount of research would still be required before the agent becomes available in the US.

In these early phase I trials, a subcutaneous injection of REGN727 was effective at reducing LDL concentrations by up to three-fourths, even in patients already taking maximally-tolerated doses of atorvastatin. Notably, the studies were conducted in healthy volunteers and were not powered to detect differences in clinical outcomes (e.g., cardiovascular morbidity and mortality).

While the drug may be effective at reducing serum LDL concentrations, questions remain as to whether these effects impart significant improvements in cardiovascular outcomes, as we have seen several recent examples where this correlation does not exist.  One investigation in particular is ARBITER 6-HALTS, which compared extended-release niacin (Niaspan^®) to ezetimibe (Zetia^®) and found that, despite being more effective at reducing LDL concentrations, ezetimibe was inferior to niacin at reducing cardiovascular events [1].

So, is this new agent promising? Yes. Is it worth further investigation? Of course.  Alternatives are limited for patients who continue to have progressive atherosclerosis despite maximally-tolerated doses of statins and other antidyslipidemic medications. But to say REGN727 "may be more effective" than statins is a bit of a stretch at this time. Statins do reduce serum LDL concentrations, but they also improve cardiovascular outcomes independently of their effects on LDL, even in patients with cholesterol in the accepted "normal" range.  Whether REGN727 is also able to do this -- independently of its effects on serum LDL concentrations -- is yet to be seen, but is what I think will determine its overall clinical utility in the management of atherosclerotic disease.

 References

1. Taylor AJ, Villines TC, Turco M, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26;361(22):2113-22.