Meeting News CoveragePerspective

ODYSSEY ALTERNATIVE: Alirocumab superior to ezetimibe for LDL lowering in statin-intolerant patients

CHICAGO — In statin-intolerant patients with very high LDL, those assigned alirocumab had lower LDL levels at 24 weeks compared with those assigned ezetimibe, according to findings presented at the American Heart Association Scientific Sessions.

In addition, alirocumab, a PCSK9 inhibitor in development by Sanofi and Regeneron, was better tolerated than atorvastatin in that patient population, researchers found.

In the ODYSSEY ALTERNATIVE trial, researchers randomly assigned 314 patients to receive subcutaneous alirocumab 75 mg or 150 mg every 2 weeks plus oral placebo, oral ezetimibe (Zetia, Merck) 10 mg/day plus subcutaneous placebo, or oral atorvastatin 20 mg/day plus subcutaneous placebo.

All patients were statin intolerant due to muscle-related symptoms and had LDL ≥70 mg/dL if at very high CV risk and LDL ≥100 mg/dL if at moderate or high CV risk.

The primary endpoint was percentage change in LDL at 24 weeks in the intention-to-treat population. The key secondary endpoint was percentage change in LDL at 24 weeks in the on-treatment population.

Patrick M. Moriarty, MD, said at a press conference that the least squares mean change in LDL at 24 weeks in the intention-to-treat population was –45% for those assigned alirocumab vs. –14.6% for those assigned ezetimibe (mean difference, –30.4; P<.0001).

Patrick M. Moriarty, MD

Patrick M. Moriarty

The least squares mean change in LDL at 24 weeks in the on-treatment population was –52.2% for those assigned alirocumab vs. –17.1% for those assigned ezetimibe (mean difference, –35.1; P<.0001), he said.

Moriarty, from the University of Kansas Medical Center, Kansas City, said that the curves separated at 4 weeks and maintained separation through 24 weeks.

The goal of LDL <70 mg/dL for very high-risk patients and LDL <100 mg/dL for moderate- and high-risk patients was achieved by 42% of those assigned alirocumab vs. 4% of those assigned ezetimibe, while the goal of LDL <100 mg/dL for all was achieved by 61% of those assigned alirocumab vs. 10% of those assigned ezetimibe (P<.0001 for both), he said.

In both the intention-to-treat and on-treatment analyses, those assigned alirocumab demonstrated greater reduction in non-HDL, apolipoprotein B and lipoprotein(a) compared with those assigned ezetimibe, Moriarty said.

Those assigned atorvastatin were more likely to have a skeletal-muscle related treatment-related adverse event compared with those assigned alirocumab (HR=1.63; 95% CI, 1.01-2.62), the researchers found. All groups had high rates of adverse events and study drug discontinuation, Moriarty said.

Moriarty told Cardiology Today that another interesting finding is that “the complexity of these statin-intolerant patients is demonstrated by their history of 100% intolerance, but only 25% of the patients were unable to tolerate atorvastatin in the 24-week blind group.” 

At the end of the trial, all patients were allowed to enter into a 3-year, open-label phase of the trial in which all received alirocumab, Moriarty said. Only 2.8% of patients needed to discontinue alirocumab in this phase, he said. “In patients 100% intolerant to statin, 97% were able to tolerate alirocumab,” Moriarty said, – by Erik Swain and Brian Ellis

For more information:

Moriarty PM. LBCT.02: Anti-Lipid Therapy and Prevention of CAD. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Disclosure: The study was funded by Sanofi and Regeneron. Moriarty reports receiving research grants from Amgen, B. Braun, Catabasis, Eli Lilly, Esperion, Genzyme, Kaneka, Kowa Pharmaceuticals, Novartis, Pfizer, Regeneron and Sanofi; honoraria from Amarin and Kowa Pharmaceuticals; and consulting or advisory board fees from B. Braun, Catabasis, Duke Clinical Research Institute, Eli Lilly, Kaneka and Regeneron.

CHICAGO — In statin-intolerant patients with very high LDL, those assigned alirocumab had lower LDL levels at 24 weeks compared with those assigned ezetimibe, according to findings presented at the American Heart Association Scientific Sessions.

In addition, alirocumab, a PCSK9 inhibitor in development by Sanofi and Regeneron, was better tolerated than atorvastatin in that patient population, researchers found.

In the ODYSSEY ALTERNATIVE trial, researchers randomly assigned 314 patients to receive subcutaneous alirocumab 75 mg or 150 mg every 2 weeks plus oral placebo, oral ezetimibe (Zetia, Merck) 10 mg/day plus subcutaneous placebo, or oral atorvastatin 20 mg/day plus subcutaneous placebo.

All patients were statin intolerant due to muscle-related symptoms and had LDL ≥70 mg/dL if at very high CV risk and LDL ≥100 mg/dL if at moderate or high CV risk.

The primary endpoint was percentage change in LDL at 24 weeks in the intention-to-treat population. The key secondary endpoint was percentage change in LDL at 24 weeks in the on-treatment population.

Patrick M. Moriarty, MD, said at a press conference that the least squares mean change in LDL at 24 weeks in the intention-to-treat population was –45% for those assigned alirocumab vs. –14.6% for those assigned ezetimibe (mean difference, –30.4; P<.0001).

Patrick M. Moriarty, MD

Patrick M. Moriarty

The least squares mean change in LDL at 24 weeks in the on-treatment population was –52.2% for those assigned alirocumab vs. –17.1% for those assigned ezetimibe (mean difference, –35.1; P<.0001), he said.

Moriarty, from the University of Kansas Medical Center, Kansas City, said that the curves separated at 4 weeks and maintained separation through 24 weeks.

The goal of LDL <70 mg/dL for very high-risk patients and LDL <100 mg/dL for moderate- and high-risk patients was achieved by 42% of those assigned alirocumab vs. 4% of those assigned ezetimibe, while the goal of LDL <100 mg/dL for all was achieved by 61% of those assigned alirocumab vs. 10% of those assigned ezetimibe (P<.0001 for both), he said.

In both the intention-to-treat and on-treatment analyses, those assigned alirocumab demonstrated greater reduction in non-HDL, apolipoprotein B and lipoprotein(a) compared with those assigned ezetimibe, Moriarty said.

Those assigned atorvastatin were more likely to have a skeletal-muscle related treatment-related adverse event compared with those assigned alirocumab (HR=1.63; 95% CI, 1.01-2.62), the researchers found. All groups had high rates of adverse events and study drug discontinuation, Moriarty said.

Moriarty told Cardiology Today that another interesting finding is that “the complexity of these statin-intolerant patients is demonstrated by their history of 100% intolerance, but only 25% of the patients were unable to tolerate atorvastatin in the 24-week blind group.” 

At the end of the trial, all patients were allowed to enter into a 3-year, open-label phase of the trial in which all received alirocumab, Moriarty said. Only 2.8% of patients needed to discontinue alirocumab in this phase, he said. “In patients 100% intolerant to statin, 97% were able to tolerate alirocumab,” Moriarty said, – by Erik Swain and Brian Ellis

For more information:

Moriarty PM. LBCT.02: Anti-Lipid Therapy and Prevention of CAD. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Disclosure: The study was funded by Sanofi and Regeneron. Moriarty reports receiving research grants from Amgen, B. Braun, Catabasis, Eli Lilly, Esperion, Genzyme, Kaneka, Kowa Pharmaceuticals, Novartis, Pfizer, Regeneron and Sanofi; honoraria from Amarin and Kowa Pharmaceuticals; and consulting or advisory board fees from B. Braun, Catabasis, Duke Clinical Research Institute, Eli Lilly, Kaneka and Regeneron.

    Perspective
    Robert P. Giugliano

    Robert P. Giugliano

    This study is very good news, because we not uncommonly find patients who don’t tolerate high-dose statins, and less frequently find patients who don’t tolerate statins at any dose. That is a real challenge. They often have very high levels of cholesterol and have tried a number of therapies that do not work. Until today, we didn’t know whether anything other than a statin was worth trying with respect to reducing CV outcomes, but here you see a therapy with fantastic potential. Alirocumab had some really good data presented that suggest even in patients who don’t tolerate statins, it appears to be a very promising alternative.

    • Robert P. Giugliano, MD, SM
    • Physician Associate Professor in Medicine Harvard Medical School

    Disclosures: Giugliano reports research involvement for novel cholesterol-lowering therapies, including the IMPROVE-IT and FOURIER studies.

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