Robust LDL-Cholesterol Reduction With Alirocumab on Top of Maximally Tolerated Statins

March 24, 2015

GLASGOW, SCOTLAND — Background statin therapy, even the use of high-dose statin therapy, did not affect the ability of alirocumab (Sanofi/Regeneron) to reduce LDL-cholesterol levels in patients at high cardiovascular risk, according to a new analysis of the investigational inhibitor of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor[1].

The study was presented this week at EAS 2015: the European Atherosclerosis Society 2015 Congress. The researchers, led by Dr Michel Krempf (University Hospital, Nantes, France), reported that alirocumab reduced LDL-cholesterol levels 47% to 62% among patients also treated with a high-dose statin. For those not treated with a high dose of statin, the reduction in LDL cholesterol achieved with alirocumab ranged from 35% to 61%.

"Alirocumab is a monoclonal antibody for PCSK9 that has been shown to provide an additional LDL reduction, roughly a 50% decrease," said Krempf during his EAS presentation. "We also know that statins are known to increase the concentration of PCSK9, which is one of the paradoxes of statin therapy."

Krempf said that high-dose atorvastatin, for example, is known to increase PCSK9 plasma concentration approximately 35%. Fibrates and ezetimibe (Zetia, Merck/Schering-Plough) are also known to increase plasma concentrations of PCSK9, although to a lesser extent.

Given that high-intensity statin therapy might increase the amount of PCSK9, there was some concern that adding alirocumab to high-intensity statin therapy might result in diminished efficacy of the investigational drug. With that in mind, the group wanted to determine the efficacy of alirocumab among patients treated with a background of high-dose statin therapy vs lipid lowering with nonintensive statin therapy in the various clinical trials.

The six clinical trials were all part of the ODYSSEY investigational program testing alirocumab in 4166 patients with inadequately controlled LDL-cholesterol levels. The studies, including the COMBO 1 and 2 trials, the Familial Hypercholesterolemia (FH)1 and 2 studies, the HIGH-FH study, and the ODYSSEY-Long Term study, included patients taking a maximally tolerated statin and other lipid-lowering therapy (which included lower-dose statins). The high-intensity statin used was either atorvastatin 40 mg to 80 mg or rosuvastatin (Crestor, AstraZeneca) 20 mg to 40 mg.

In the six trials, there was no statistically significant difference in LDL reduction achieved with alirocumab on top of the high-intensity statin compared with individuals who received alirocumab on top of a lower-dose statin. In the ODYSSEY-Long Term study, which included more than 2300 of the 4166 patients, alirocumab on top of high-dose statin therapy reduced LDL-cholesterol levels an additional 62%, vs 61% among those treated with alirocumab and a lower-dose statin.

"Overall, the reduction with alirocumab is about 50% for all the studies, and there was no difference based on the intensity of the statin treatment," said Krempf.

When ezetimibe served as the comparator drug in the COMBO 2 study, alirocumab further reduced LDL-cholesterol levels by approximately 30%. Overall, there was still no difference in the LDL-cholesterol reductions achieved with alirocumab among patients who received concomitant therapy with ezetimibe and a high-dose statin and those who received ezetimibe and lower-dose statin with alirocumab.

Regarding adverse events, Krempf said there was no difference in any reported neurocognitive side effects among those who received alirocumab and those treated with placebo/ezetimibe. The most commonly reported adverse events were injection-site reactions, itchy skin, and influenza.

Longer-term efficacy results for alirocumab and evolocumab (Amgen, Thousand Oaks, CA) were presented at the American College of Cardiology (ACC) 2015 Scientific Sessions last week. The PCSK9 inhibitors are one of the most anticipated drug-class developments in cardiovascular medicine in many years. Both drugs hinted at reductions in cardiovascular end points, although those analyses were from pooled studies and postanalyses.

Although they are being closely monitored, especially for any potential neurocognitive side effects, alirocumab and evolocumab appear to be on track for possible US Food and Drug Administration (FDA) approval later this year. Clinical-outcomes studies are ongoing, including the large-scale morbidity and mortality trial ODYSSEY OUTCOMES, testing alirocumab in patients with acute coronary syndrome, and FOURIER, testing evolocumab in patients with cardiovascular disease.

Krempf reports consulting fees and/or honoraria from Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche, and Sanofi. Sanofi and Regeneron paid for his travel to the EAS meeting.

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