Alirocumab Safely Lowers LDL Cholesterol in Nine Trials

PARIS, FRANCE and TARRYTOWN, NY – Alirocumab (Sanofi/Regeneron Pharmaceuticals), a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), effectively lowered LDL-cholesterol levels among patients who received the investigational drug in a number of clinical trials^[1].

Sanofi and Regeneron announced the topline results from nine ODYSSEY clinical trials today, stating that the hypercholesterolemic patients who received alirocumab had larger reductions in LDL cholesterol from baseline at 24 weeks compared with placebo or an active comparator, including ezetimibe (Zetia, Merck/Schering-Plough) and atorvastatin.

The phase 3 studies included different patient populations, such as those with familial hypercholesterolemia (FH), those at high or very high cardiovascular risk, and those intolerant to statin therapy.

In one trial, known as the ODYSSEY Long-Term study, investigators randomized 2341 patients at high cardiovascular risk treated with lipid-modifying therapy to either alirocumab or placebo. At 24 weeks, a secondary end point for the assessment of lipids, treatment with alirocumab resulted in significantly large reductions in LDL cholesterol compared with the placebo arm. Patients in the long-term study will be treated for 78 weeks (the change in LDL cholesterol from baseline at 78 weeks is the primary end point). The ODYSSEY Alternative trial, which included statin-intolerant patients, also met its primary end point, according to Sanofi and Regeneron.

Alirocumab was tested in two dosing regimens: 75-mg or 150-mg subcutaneous injection every two weeks. At the 75-mg dose, investigators had the option to increase the dose to 150 mg to achieve the protocol-specified LDL-cholesterol targets. Ongoing studies, which were not part of today's announcement, include the CHOICE I and CHOICE II trials, both of which are testing a monthly injection of alirocumab.

Regarding safety and tolerability, injection-site reactions were more common among those who received alirocumab vs those treated with placebo. The most commonly reported adverse events were nasopharyngitis and upper-respiratory-tract infection, but the companies say these events were balanced between treatment groups. There was no significantly increased risk of serious adverse events, such as liver- and muscle-related events.

In March, it was reported that the US Food and Drug Administration asked the companies to monitor the clinical-trial program for possible neurocognitive adverse events. In the nine ODYSSEY trials reported today, Sanofi and Regeneron said there was no observed increase in neurocognitive risk.

The companies said they plan to present some of the ODYSSEY trials making up today's announcement at the European Society of Cardiology 2014 Congress in Barcelona, Spain.

Alirocumab is currently being tested in patients with acute coronary syndrome receiving evidence-based medical therapy and dietary management for dyslipidemia. The large outcomes study will determine whether the addition of alirocumab reduces the recurrence of cardiovascular events. In ODYSSEY OUTCOMES , the primary end point is a composite end point of coronary heart disease death, nonfatal MI, fatal and nonfatal ischemic stroke, and unstable angina requiring hospitalization. Approximately 18 000 patients will be enrolled and full results are not expected until 2018.

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