Large LDL Drops on Top of Max Statin With Anti-PCSK9 Antibody

November 01, 2012

CINCINNATI — New data on the anti-PCSK9 monoclonal antibody REGN727/SAR236553 (Regeneron Pharmaceuticals/Sanofi) show impressive reductions in LDL levels even when the agent is added on top of high-dose atorvastatin in people with primary dyslipidemia [1].

The latest phase 2 study with the product, published online October 31, 2012 in the New England Journal of Medicine, was conducted by a team led by Dr Eli Roth (Sterling Research Group, Cincinnati, OH).

Roth commented to heartwire : "There was still a 50% to 60% extra lowering of LDL when REGN727/SAR236553 was given on top of atorvastatin 80 mg."

The study involved 92 patients with LDL levels of 100 mg/dL or higher after receiving atorvastatin 10 mg for at least seven weeks. They were randomized to eight weeks of treatment with atorvastatin 80 mg daily plus REGN727/SAR236553; atorvastatin 10 mg daily plus REGN727/SAR236553; or atorvastatin 80 mg daily plus placebo. REGN727/SAR236553 was given once every two weeks by subcutaneous injection.

Results showed a much greater reduction in LDL in the two groups receiving the anti-PCSK9 antibody than in those receiving atorvastatin 80 mg alone.

LDL Lowering With Atorvastatin Alone or Plus REGN727/SAR236553

Group Lowering of LDL from baseline (%) p (vs atorvastatin 80 mg plus placebo)
Atorvastatin 80 mg plus antibody 73.2 <0.001
Atorvastatin 10 mg plus antibody 66.2 <0.001
Atorvastatin 80 mg plus placebo 17.3 --

 

All patients who received the antibody achieved an LDL below 100 mg/dL, compared with 52% of those who received atorvastatin 80 mg alone. And 90% of those who received the antibody achieved an LDL below 70 mg/dL, compared with 17% of those who received atorvastatin 80 mg alone.

As in previous studies with REGN727/SAR236553, there was a reduction of nearly one-third in levels of Lp(a) in patients given the antibody.

Addressing the observation that there was not a great difference between the LDL lowering in patients taking atorvastatin 10 mg plus REGN727/SAR236553 and those taking atorvastatin 80 mg plus REGN727/SAR236553, Roth said, "This may suggest that there is a maximal effect when the antibody is on board and additional amounts of statin then won't make much difference."

He explained that PCSK9 binds to the LDL receptor, stopping it from releasing its LDL to be cleared. By binding to the PCSK9, the antibody prevents this from happening, so the LDL receptors can be recycled and more LDL can be cleared. "Statins interfere with cholesterol production and stimulate the production of LDL receptors, while this antibody enables more LDL receptors to be available. But here may be a limit to how many LDL receptors you can have. Perhaps that is what we are seeing here," Roth suggested.

But he stressed that despite this observation, high-dose statins will remain the mainstay of treatment. "Statins have been proven to reduce events and so must be the basis of lipid-lowering therapy. While we do believe that further lowering of LDL should translate into clinical benefit, we don't know this for sure with these antibodies yet, and so until outcome data are available, they can be viewed only as add-ons to statin therapy. However, many patients can't take high-dose statins, and even if they can, there appear to be more benefits from adding in this antibody."

In terms of side effects, Roth says the antibody seems to have a good profile, with only a few minor injection-site reactions and some minor elevations in liver enzymes.

Roth noted that there are at least four anti-PCSK9 antibodies in development, but REGN727/SAR236553 appears to have the most data. "They could be the next big thing in the lipid-lowering field. It will depend on whether any new adverse events are seen and if the outcome studies are positive. But they certainly look very promising," he said.

Almost an entire late-breaking clinical-trial session at next week's AHA 2012 meeting is devoted to studies looking at PCSK9 inhibition in the treatment of hyperlipidemia.

The study was funded by Sanofi and Regeneron Pharmaceuticals. Roth has received consulting fees from Regeneron. Disclosures for the coauthors are listed on www.nejm.org .

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