However, the addition of a mAb targeting PCSK9 to existing LLT may help those patients at high cardiovascular risk to achieve the recommended truly LDL C levels or percentage lowering. The ODYSSEY COMBO studies are designed to assess the efficacy and safety of alirocumab as add on therapy to stable, max imally tolerated daily statin therapy in patients with hypercholesterolemia at high cardiovascular risk versus placebo or ezetimibe. These patients, at high cardiovascular risk, are recommended for intensive lowering of LDL C. COMBO II will also allow a comparison of the efficacy and safety of alirocumab versus ezetimibe, both given on top of maximally tolerated doses of statin. Ezetimibe is frequently added to statins to provide greater reductions in LDL C, particularly where patients are unable to tol erate titration to a higher potency.

However, while generally well tolerated, ezetimibe lowers LDL C levels only modestly. As an add on to statin therapy, a 15. 1% greater reduction in LDL C was observed with statin ezetimibe combination therapy when compared with sta tin monotherapy in a meta analysis of 27 double blind, placebo controlled, or active comparative studies of over 21,000 subjects with a mean treatment duration of 9 weeks. In this meta analysis, only 10. 3% of patients with established CHD who received statin monotherapy achieved the pre defined LDL C goal of 70 mg dL. Even with the addition of ezetimibe, only 32. 1% of patients achieved this LDL C goal, suggesting the need for more effective LLT.

The trials within the ODYSSEY program use a treat to goal approach and are designed to address unmet needs of patient populations on current standard of care unable to achieve LDL C goals, using a flexible dosing strategy for individualized therapy based on degree of LDL lowering needed to achieve an adequate treatment response. A key aspect of the COMBO studies is the po tential to up titrate alirocumab treated patients based on their LDL C levels after 8 weeks of treatment. The start ing dose of 75 mg Q2W was selected to provide an ap proximate 50% decrease in LDL C from baseline when added to statin therapy, as determined by a dose response model. As such, all patients were initially treated with 75 mg Q2W. However, those selleck kinase inhibitor patients whose LDL C levels remain 70 mg dL after 8 weeks of treatment were dose up titrated in a blinded manner at week 12 to 150 mg Q2W without a need to increase the injection volume. With this flexible treatment scheme, most patients can be expected to achieve an LDL C level of 70 mg dL without reaching very low LDL C levels.