Alirocumab (1) – Praluent®

• Clinical trials
  • The COMBO II trial was a randomised, controlled, double-blind trial conducted at study centres in Canada, Denmark, France, Hungary, Israel, Russia, South Africa, South Korea, the USA and Ukraine.
  • The ALTERNATIVE trial enrolled patients with statin intolerance and moderate to very high cardiovascular risk; during the 24-week treatment period, they were treated with lipid-lowering therapy (excluding statins and ezetimibe) with alirocumab (75 mg or 150 mg), ezetimibe (10 mg) or atorvastatin (20 mg).
  • The CHOICE II study investigated patients with moderate to very high cardiovascular risk who were being treated with lipid-lowering medicinal products other than statins.

a) For patients for whom statins are an option

• An additional benefit is not proven.
• Mortality – all-cause mortality
  • The patient-relevant endpoint of all-cause mortality is derived from the number of AEs that resulted in death during treatment. After 52 weeks, one death occurred in each of the treatment groups. This result is not statistically significant.
  • The COMBO II study was not prospectively designed to assess differences in mortality. Deaths were recorded only as safety endpoints. Consequently, no adjudication was carried out by an independent endpoint committee. Consequently, there is no hint of any additional benefit of alirocumab compared with ezetimibe.
• Morbidity – Cardiovascular events
  • Taken together, there is no hint of any additional benefit of alirocumab over ezetimibe for the endpoint of cardiovascular events; the additional benefit is not proven for this endpoint.
• Health-related quality of life
  • No relevant data were available for the assessment of the health-related quality of life endpoint. Consequently, an additional benefit of alirocumab compared with ezetimibe is not proven for the quality of life endpoint.
• Side effects – SAE
  • After 52 weeks, a serious AE occurred in 20.3% of patients in the alirocumab arm and in 21.8% of patients in the ezetimibe arm. These results do not differ to a statistically significant degree. An additional benefit of alirocumab over ezetimibe is not proven.
• Side effects – discontinuation due to AEs
  • Following 52 weeks of treatment with alirocumab or ezetimibe, 14 patients (8.1 per cent) and 7 patients (8.0 per cent), respectively, discontinued the study due to an AE. There were no statistically significant differences between the treatment groups, and the additional benefit of alirocumab over ezetimibe is not proven.
• Side effects – General allergic reactions at the injection site
  • After 52 weeks, the administration of alirocumab, compared with ezetimibe, was numerically associated with a higher frequency of general allergic reactions at the injection site among patients (18 (10.5%) vs. 3 (3.4%) patients). However, there were no statistically significant differences between the treatment groups. An additional benefit of alirocumab over ezetimibe is therefore not proven for this endpoint.
• Supplementary endpoint – change in LDL-C levels
  • After 52 weeks of treatment, administration of alirocumab reduced patients’ LDL-C levels by an average of 51.3%. By comparison, in the ezetimibe arm, LDL-C levels were reduced by an average of 12.1%. These results show a statistically significant difference in favour of alirocumab (MD −39.2; 95% CI [−48.4; −29.9]; p < 0.001).
  • The endpoint ‘change in LDL-C level’ is a surrogate parameter and is not, in itself, clinically relevant to patients. The statistically significant differences in LDL-C reduction achieved with alirocumab compared with ezetimibe are not reflected in patient-relevant endpoints, such as the prevention of cardiovascular events.
• Conclusion
  • Overall, no advantages of alirocumab were observed with regard to patient-relevant endpoints in patient population a). An additional benefit of alirocumab over ezetimibe in patients for whom statins are an option is not proven.

b) For patients for whom statin therapy is not an option due to contraindications or treatment-limiting side effects

• The additional benefit is not proven.
• Overall, neither the ALTERNATIVE study nor the CHOICE II study can be used for benefit assessment of alirocumab in patients for whom statin therapy is not an option due to statin intolerance or contraindications.
• Conclusion
  • Additional benefit is not proven for this patient population.

c) For patients in whom pharmacological and dietary options for lipid-lowering have been exhausted

• An additional benefit is not proven.
• In summary, particularly in light of the uncertainties regarding the operationalisation of the criterion ‘30% reduction in LDL-C’ for the endpoint ‘reduction in the frequency of LDL apheresis’, the ESCAPE study cannot be used to assess the additional benefit of alirocumab compared with the appropriate comparator therapy.
• Conclusion
  • An additional benefit is therefore not proven for patient population c).

Courtesy translation only, please refer to the German original.