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Monthly alirocumab may provide additional treatment option for lowering LDL
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SAN DIEGO — A monthly regimen of alirocumab 150 mg or 300 mg was well tolerated and significantly reduced LDL levels at 24 weeks in patients with poorly controlled hypercholesterolemia in the ODYSSEY CHOICE I and II studies.
The ODYSSEY CHOICE I study assessed the efficacy and safety of alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) 300 mg every 4 weeks with or without statin therapy in patients with poorly controlled hypercholesterolemia and moderate-to-high CV risk. The ODYSSEY CHOICE II study evaluated the efficacy and safety of alirocumab 150 mg every 4 weeks without statin therapy in patients with hypercholesterolemia and muscle-related statin intolerance who were receiving ezetimibe (Zetia, Merck), fenofibrate or dietary intervention alone.
The primary efficacy point for both studies was change in calculated LDL from baseline to 24 weeks.
Michel Farnier
“This is the first evaluation of a new strategy with alirocumab,” Michel Farnier, MD, PhD, from Point Médical, Dijon, France, told Cardiology Today.
ODYSSEY CHOICE I
Patients were randomly assigned alirocumab 300 mg every 4 weeks, alirocumab 75 mg every 2 weeks (calibrator arm) or placebo. The dose regimen changed at 12 weeks in patients who did not achieve predetermined LDL treatment goals or did not have a 30% or greater reduction in LDL from baseline to 8 weeks.
“Very few patients needed dose titration to 150 mg every 2 weeks,” Farnier said.
The percent reduction in LDL from baseline to 24 weeks was significantly higher with monthly alirocumab 300 mg compared with placebo both in patients receiving concurrent statin therapy (least-square mean difference vs. placebo, –58.7%) and not receiving statin therapy (–52.4%; P <.0001 for both).
From 21 to 24 weeks, monthly alirocumab 300 mg was associated with a 55.2% reduction in the primary endpoint compared with placebo (65% reduction for the statin group, 55.2% reduction for the no-statin group; P < .0001)
Patients assigned monthly alirocumab 300 mg with possible dose adjustment who were receiving concurrent statin therapy had lower baseline LDL levels. This resulted in lower mean LDL levels at 24 weeks compared with patients not receiving concurrent statin therapy, Farnier said.
ODYSSEY CHOICE II
Patients were randomly assigned alirocumab 150 mg every 4 weeks, alirocumab 75 mg every 2 weeks (calibrator arm) or placebo, with possible dose reduction at 12 weeks.
The percent reduction in LDL from baseline to 24 weeks was also significantly higher with monthly alirocumab 150 mg compared with placebo (least-square mean difference, –56.4%; P < .0001).
From baseline to weeks 9 to 12, the mean reduction in LDL was 55.5% compared with placebo (P < .0001).
In both studies, patients who required dose adjustment at 12 weeks tended to have higher mean LDL levels at baseline. In ODYSSEY CHOICE I, one in five patients receiving concurrent statin therapy and one in seven patients not receiving statin therapy required dose adjustment to 150 mg every 2 weeks to achieve target LDL. In ODYSSEY CHOICE II, one in two patients required dose adjustment to 150 mg every 2 weeks to achieve target LDL. An additional 20% reduction in LDL was reported for patients in ODYSSEY CHOICE II who underwent dose adjustment to 150 mg every 2 weeks.
“A large proportion of patients with statin intolerance can be treated with alirocumab 150 mg every 4 weeks,” Farnier said.
Safety results
In ODYSSEY CHOICE I, the rate of treatment-emergent adverse events ranged from 71% to 78% for patients assigned monthly alirocumab 300 mg and 61% to 75% for patients assigned placebo. In ODYSSEY CHOICE II, the rate of treatment-emergent adverse events was 77.6% vs. 63.8%, respectively.
The alirocumab and placebo groups had a similar frequency of muscle-related symptoms. No deaths were reported. The rate of injection-site reactions was higher than that reported in other ODYSSEY studies, but the reactions were mostly mild and not associated with drug discontinuation.
“The higher injection-site reaction rate observed in CHOICE I and II vs. earlier ODYSSEY studies could potentially be a factor of two 1-mL injections at each administration (CHOICE I only; previous ODYSSEY studies had one 1-mL injection at each administration) and/or more frequent study visits,” the researchers wrote in the abstract. – by Rob Volansky
Reference:
Stroes ESG, et al. Poster 1107-105. Presented at: American College of Cardiology Scientific Sessions; March 14-16, 2015; San Diego.
Disclosure: Farnier reports associations with Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Kowa, Merck, Pfizer, Recordati, Roche, Sanofi and SMB.
Perspective
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Kim Eagle, MD
The excitement around PCSK9 inhibitors is immense, partly because of the magnitude of their effect on lipids and partly because moderate- and high-dose statin therapy is associated with a high rate of side effects. There is a substantial population that is unable to take a statin, so the whole class of PCSK9 is exciting for the notion of prevention. Also, for people who don’t like taking pills or have difficulty with compliance, this represents a whole new notion in terms of preventive care, regardless of whether it is every 2 weeks or every 4 weeks.
These two particular studies show that for some patients, a dose adjustment might be required.
The site reactions were not insignificant. They described about a threefold increase in injection-site inflammation after the injection, so that will have to be dealt with.
The studies are relatively small, so we have to be careful about getting too far ahead of ourselves. Also, while there is no doubt that the PCSK9 inhibitors have a profound effect on LDL cholesterol, we are still waiting for the pivotal trial that will absolutely show reduction in events. The early returns of moderate-size studies appear to be promising, but we are anxious to be sure that there are no major untoward but rare side effects that come in the back door. We have seen that before in drugs that impact the lipid system.
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