New LDL-lowering agent is consistently effective and safe in hypercholesterolemia

Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: first results from the ODYSSEY LONG TERM study in 2,341 patients

Presented at ESC Congress 2014 by: Jennifer ROBINSON (Iowa City, US)

Background

Alirocumab is a monoclonal antibody directed against PCSK9, which is tested for its ability to decrease LDL-c levels. The ODYSSEY LONG TERM study is part of the ODYSSEY clinical trial program to evaluate alirocumab in addition to standard lipid-lowering therapy in patients with high cardiovascular risk.
The ODYSSEY LONG TERM study evaluated the safety and tolerability of alirocumab in the longer term in high-risk patients with hypercholesterolemia (incl. heterozygous familial hypercholesterolemia HeHF)) not adequately controlled with standard lipid-lowering therapy. Approximately 1250 patients were randomized (2:1) to alirocumab 150 mg Q2W SC or placebo Q2W SC, in addition to maximally tolerated statin therapy and possibly additional lipid-lowering treatment. Safety parameters and changes in LDL-C levels were measured up to 20 months. The data presented here relate to analysis of the primary endpoint at 24 weeks, and a pre-specified analysis at 52 weeks, after a mean treatment duration of 65 weeks in both treatment arms (86% of patients had completed 52 weeks of treatment).

Main resultso) achieved the corresponding LDL-C target (<1.8 mmol/L for very high risk and <2.6 mmol/L for high risk patients ). Regardless of the risk level, 79% of patients on alirocumab reached LDL <1.8 mmol/L, compared to 8% for placebo.

• The number of relevant adverse events was generally similar between alirocumab- and placebo-treated patients. Small numerical differences were observed, such as more neurocognitive disorders with alirocumab (1.2%) than with placebo (0.5%).
• A post-hoc analysis of verified cardiovascular treatment-induced side effects, which corresponds to the primary endpoint of the ongoing ODYSSEY OUTCOMES trial, shows a consistently lower incidence of events seen with alirocumab versus placebo for at least 52 weeks of follow-up (Cox analysis model: HR 0.46, 95% CI: 0.26-0.82, nominal P <0.01).

• Alirocumab showed a significant decrease in LDL-C at week 24 compared to baseline (LS mean difference (SE) versus placebo: -61.9% (13), P<0.0001).
• 81% of patients with a high or very high CV risk randomized to alirocumab (vs. 9% in placeb

Conclusion

The ODYSSEY LONG TERM study is so far the largest and longest evaluation of a PCSK9 inhibitor. The study shows that alirocumab in addition to standard lipid-lowering therapy gives an effective reduction in LDL-C in high risk patients, and that a large majority of patients achieved LDL-C targets. Alirocumab is well tolerated and side effects are similar to placebo treatment.
Slightly more neurocognitive disorders were documented in alirocumab-treated patients than in the placebo group. In the ODYSSEY COMBO II, FH I and FH II studies, a numerical difference was seen in the opposite direction, thus fewer neurocognitive disorders with alirocumab. When all data from these four presented studies are combined, there is no safety signal that alirocumab leads to neurocognitive disorders.
In the discussion during a press conference, the heterogeneity of the LDL-response between patients was noted, and there were questions about any risks of a decrease of the LDL level to minimal quantities. The IQR in one of the studies has a lower limit of about 0.7 mmol/L, according to one of the researchers, and these patients appear to have no problems. These very low LDL levels seem to be safe. Because these can now be reached more often with available resources, low cholesterol levels are the subject of growing interest.
As an advance on the ongoing ODYSSEY OUTCOMES trial, a post-hoc analysis already showed a reduction in CV events with alirocumab compared to placebo. This should be confirmed in the outcomes study.

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