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Alirocumab bests ezetimibe for LDL reduction in ODYSSEY studies
BARCELONA, Spain — New data from the ODYSSEY clinical trials program demonstrate significant LDL reductions with the investigational PCSK9 inhibitor alirocumab compared with ezetimibe and placebo.
The ODYSSEY FH I and II trials were designed to evaluate the effect of alirocumab (Sanofi/Regeneron) in patients with heterozygous familial hypercholesterolemia (HeFH) whose LDL levels were inadequately controlled on a current statin and other lipid-lowering regimen. The researchers noted that patients were well-treated at the start of the study; more than 80% were taking maximum doses of statins and 55% to 65% were taking combination therapy with ezetimibe. All participants with prior CVD had LDL cholesterol >70 mg/dL, while those without prior CVD had LDL >100 mg/dL.
Michel Farnier
“HeFH is one of the most common inherited diseases, characterized by extremely high LDL levels and premature atherosclerosis and CVD. In the real world, about 80% do not reach the LDL goal of less than 2.5 mmol/L, or 100 mg/dL. Despite intensive lipid-lowering therapy, HeFH patients require new options,” Michel Farnier, MD, PhD, from Point Médical, Dijon, France, said during a presentation.
The double blind, placebo-controlled trials included 735 patients with HeFH who were randomly assigned to receive a subcutaneous injection of alirocumab 75 to 150 mg every 2 weeks (n=490 across both studies) or matching placebo (n=245 across both studies) for 78 weeks, in addition to their current therapy.
At 24 weeks, alirocumab significantly reduced LDL from baseline by a mean of 48.8% in the FH I study and 48.7% in the FH II study, compared with increases of 9.1% and 2.8% among patients assigned placebo in both studies (P<.0001). Also at 24 weeks, significantly more patients assigned alirocumab reached the LDL target of ≤100 mg/dL in high-risk patients or <70 mg/dL in very-high-risk patients (72.2% vs. 2.4% in FH I; 81.4% vs. 11.3% in FH II; P<.0001). To reach the prespecified LDL level <70 mg/dL, up-titration to 150 mg every 2 weeks was necessary in 40% of patients assigned alirocumab.
Pooled data from FH I and II indicated that treatment-emergent adverse events were similar between the alirocumab and placebo groups (74.8% vs. 75.4%). Study discontinuation related to treatment-emergent adverse effects was reported in 3.1% of the alirocumab group vs. 3.7% of the placebo group.
Christopher P. Cannon
Christopher P. Cannon, MD, physician at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and executive director of cardiometabolic trials at Harvard Clinical Research Institute, presented new data from the ODYSSEY COMBO II trial at the ESC Congress. This trial compared alirocumab with ezetimibe (Zetia, Merck) when added to regular statin therapy in patients with hypercholesterolemia and elevated risk for CVD.
The trial enrolled 720 patients who were already receiving a maximally tolerated daily statin dose. Patients were randomly assigned to receive a subcutaneous injection of alirocumab 75 mg to 150 mg every 2 weeks (n=479) or oral ezetimibe 10 mg daily (n=241) for 104 weeks. All patients were also assigned a placebo treatment, either a pill in the active alirocumab group or an injection in the active ezetimibe group to maintain blinding.
Compared with ezetimibe, alirocumab significantly lowered LDL by week 24 (50.6% vs. 20.7%; P<.0001). A similar trend was observed by week 52 — a 49.5% reduction with alirocumab vs. 18.3% reduction with ezetimibe (P<.001).
Seventy-seven percent of patients assigned alirocumab achieved LDL levels <70 mg/dL by week 24 compared with 45.6% of patients assigned ezetimibe (P<.0001).
“This trial evaluated a 75-mg initial dose of alirocumab, which could be increased to 150 mg if needed. However, more than three-quarters of patients were able to reach target LDL levels at the initial dose without the need to up-titrate,” Cannon said in a press release.
“The adverse events were generally comparable with ezetimibe,” he said during a press conference. Treatment-emergent adverse events occurred in 71.2% of the alirocumab group vs. 67.2% of the ezetimibe group, leading to discontinuation in 7.5% and 5.4%, respectively. The most common adverse events were upper respiratory tract infection, accidental overdose, dizziness and myalgia. – by Katie Kalvaitis
For more information:
Cannon CP. Hot Line II. Coronary Artery Disease and Lipids.
Farnier M. Hot Line II. Coronary Artery Disease and Lipids. Both presented at: the European Society of Cardiology Congress; Aug. 30-Sept. 3, 2014; Barcelona, Spain.
Disclosure: The studies were funded by Sanofi and Regeneron. Cannon reports receiving grants from Accumetrics, Arisaph, AstraZeneca, Boehringer Ingelheim and Janssen Pharmaceuticals; grants and consulting fees from GlaxoSmithKline, Merck and Takeda; and consulting fees from Bristol-Myers Squibb, CSL Behring, Essentialis, Lipimedix, Pfizer, Regeneron and Sanofi Aventis. Farnier reports receiving grants, consulting fees and/or honoraria, and delivering lectures for Abbott, Amgen, Boehringer Ingelheim, Eli Lilly, Genzyme, Kowa Pharmaceuticals, Merck and Co., Novartis, Pfizer, Recordati, Roche, Sanofi and Regeneron, and SMB.
Perspective
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PCSK9 inhibition holds great promise for treatment of patients with hyperlipidemia, perhaps particularly for those who are statin intolerant or have genetically mediated diseases that are typically associated with very high levels of cholesterol and for which statin therapy may be only partially effective. From a biologic point of view, it is interesting that, for treatment of patients with CV disorders, agents of this class are moving into potentially front-line therapies. For example, oncologists and rheumatologists are well ahead of us in the use of biologic agents to modify disease. For this to present itself within CV medicine is very exciting.
So far, alirocumab seems to be well tolerated, and it is attractive to consider a future where you only need to dose yourself maybe once every 2 weeks. I think many patients would find that to be attractive; others might have trouble with giving themselves a subcutaneous injection. In addition, the safety profile is quite acceptable. A lot of studies have been looking at extending therapy for increasingly longer periods of time, making sure [it] remains safe and effective. It seems that over the last couple of years at major meetings — ACC, AHA and now ESC — we have had a litany of PCSK9 inhibitor trials and, directionally, the results seem to be quite similar, and everyone is waiting for the clinical event trials to be completed.