Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study

Presented at ESC Congress 2014 by: Christopher Paul CANNON (Boston, US)

Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolaemia not adequately controlled with current lipid-lowering therapy: results of ODYSSEY FH I and FH II studies

Presented at ESC Congress 2014 by: Michel FARNIER (Dijon, FR)

Background

Statin treatment significantly reduces cardiovascular risk in people with high LDL cholesterol levels. An important question since a long time has been if this risk reduction is the result of the LDL-lowering, or of statins per se. Despite the great progress made with lipid-lowering agents, a significant residual cardiovascular risk however remains.
Alirocumab is a monoclonal antibody directed against PCSK9, which is tested for its ability to further lower LDL-C levels in addition to existing treatment. About 10 years ago, PCSK9 has been discovered as a gene that importantly influences the LDL level and CV. People with PCSK9 loss-of-function mutations have a very low CV risk, which is the rationale to develop PCSK9 inhibitors. The ODYSSEY clinical trial program evaluates alirocumab in addition to standard lipid-lowering therapy in patients with heterozygous familial hypercholesterolemia (HeFH, trials ODYSSEY FH I, FH II and HIGH FH) or patients with high or very high CV risk (trials ODYSSEY COMBO I, COMBO II OPTIONS I, II and LONG TERM OPTIONS). The ODYSSEY COMBO II, and FH I and FH II were presented immediately after each other and jointly discussed.
ODYSSEY COMBO II is a randomized, double-blind, parallel-group study comparing alirocumab with ezetimibe in patients at high cardiovascular risk with hypercholesterolemia not adequately controlled with statin therapy. Decrease in LDL-C levels was analyzed after 24 weeks of treatment with alirocumab or ezetimibe, in addition to statin therapy.
The ODYSSEY FH I and FH II evaluated the efficacy (LDL-C reduction) and safety of 24 weeks alirocumab vs. placebo in addition to lipid-lowering therapy in patients with heterozygous familial hypercholesterolemia (HeFH) not adequately controlled with lipid-lowering treatment.

Main results

ODYSSEY COMBO II

• After 24 weeks, a reduction in LDL-C of 50.6% was seen with alirocumab, and 20.7% with ezetimibe, both in addition to maximum tolerated statin treatment (LS mean difference (SE) vs. ezetimibe: -29.8% (2.3) P <0.001).
• 77% of the patients achieved LDL-C target levels, compared to 45% of the ezetimibe-treated patients.
• 18% of patients randomized to alirocumab needed dose adjustment based on their LDL-C levels at week 12.
• The LDL-C decrease achieved with alirocumab was stable during the 52-week follow-up.
• 77% of the alirocumab-treated patients achieved LDL-C target levels, as compared to 45.6% of the patients in the ezetimibegroup.
• Typical statin-related adverse events were equally seen in the treatment arms. Small numerical differences in relevant side effects were observed, like more verified CV events (4.8% vs. 3.7% in alirocumab vs. ezetimibe), more injection-site reactions (2.5% vs. 0.8% with placebo injection), less neurocognitive disorders (0.8 % vs. 1.2%), more often ALT> 3x ULN (1.7% vs. 0.4%) and creatine kinase> 3x ULN (2.8% vs. 2.5%). The alirocumab injections were generally well tolerated and compliance with self-injections was good.

ODYSSEY FH I and FH II

• FH I and FH II showed a LS mean difference (SE) in decline at week 24 relative to baseline LDL-C compared to placebo of -57.9% (2.7) and -51.4% (3.4), respectively.
• Approximately 40% of patients in FH I and FH II received a higher dose at week 12.
• At week 24, 72.2% of high-risk patients achieved the LDL target level <2:51 mmol/L (vs. 2.4% of patients on placebo), and 81.4% of patients with very high risk achieved LDL <1.81 mmol/L (vs. 11.3% on placebo).
• The achieved LDL-C reductions were consistent for 52 weeks follow-up.
• Adverse events were generally similar between treatment groups, with small numerical differences. 3.1% of patients on alirocumab and 3.7% of patients who received a placebo injection, discontinued treatment due to adverse events.

Conclusion

These ODYSSEY studies show that alirocumab results in a significant decrease in LDL-C compared to good standard therapy in patients with high CV risk because of inadequately controlled hypercholesterolemia (including HeFH patients). On alirocumab, more patients achieved LDL-C target.
Alirocumab was generally well tolerated and the number of patients who discontinued treatment due to adverse events was very low. The small numerical differences in adverse events between treatment groups are observed in different directions in the individual studies. When the four now presented studies are analyzed together, no significant differences are observed between treatment groups.
Given the effectiveness of alirocumab in addition to statins, the involved researchers consider alirocumab a promising means to further reduce the residual CV risk of statin-treated patients They recognize that LDL-C is a surrogate endpoint; but it is the best they have got at the moment. Of course we need to await the results with respect to clinical outcomes, but very likely the LDL level is also important: both aspects are important.

- Our reports are based on information made available at the ESC congress -