Alirocumab (2) – Praluent®

• Clinical trials
  • The multicentre, double-blind, randomised controlled trial ODYSSEY OUTCOMES enrolled approximately 19,000 patients aged ≥ 40 years who had suffered an acute coronary syndrome (STEMI, NSTEMI or unstable angina with a high risk of myocardial infarction) between 4 and 52 weeks prior to the start of the study.
  • The COMBO II study is a multicentre, randomised, controlled, double-blind trial.

a1) Adult patients (without known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial disease)) with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, who do not achieve LDL-C targets with the maximum tolerated dose of statins and for whom statins are an option

• The additional benefit is not proven.
• However, as these studies did not include patients without known atherosclerotic cardiovascular disease, no assessment of the patient population a1) can be made on the basis of these studies.
• There are therefore no data available to establish any additional benefit of alirocumab for this patient population.

a2) Adult patients (with known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial disease)) with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, who do not achieve LDL-C targets with the maximum tolerated statin dose and for whom statins are an option

• In its overall assessment of the results of the COMBO II study, the G-BA therefore concludes, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV and taking into account the severity of the condition, the written submissions and the oral hearing, that alirocumab provides additional benefit over the appropriate comparator therapy in adult patients (with known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial occlusive disease) and primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, who do not achieve LDL-C targets with the maximum tolerated statin dose and for whom statins are an option, is not proven.
• mortality
  • Overall mortality In the ODYSSEY OUTCOMES trial, 3.0% of patients in the alirocumab arm and 3.7% of patients in the control arm died. This result shows a statistically significant difference in favour of alirocumab (HR = 0.79, 95% CI [0.63; 1.00], p = 0.046).
  • All-cause mortality In the COMBO II study, approximately 2% of patients in both study arms died. This result is not statistically significantly different.
• Morbidity – Major Adverse Cardiovascular Endpoint (MACE)
  • The combined cardiovascular endpoint MACE comprises the individual components ‘death from CHD’, ‘non-fatal myocardial infarction’, ‘fatal/non-fatal ischaemic stroke’ and ‘hospitalisation for unstable angina’. For the combined endpoint, statistically significant advantages were observed with alirocumab in the relevant patient population (9.2% vs. 11.2%, HR = 0.78, 95% CI [0.68; 0.89], p < 0.001). With regard to the individual components, statistically significant advantages were also observed with alirocumab for the endpoints ‘non-fatal myocardial infarction’ (6.8% vs. 8.0%, HR = 0.83, 95% CI [0.71; 0.97], p = 0.017) and ‘fatal/non-fatal ischaemic stroke’ (1.1% vs. 1.6%, HR = 0.67, 95% CI [0.47; 0.97], p = 0.033).
  • The composite cardiovascular endpoint MACE comprises the individual components ‘death due to coronary heart disease’, ‘non-fatal myocardial infarction’, ‘fatal/non-fatal ischaemic stroke’, ‘hospitalisation due to unstable angina’. The dossier did not contain any usable data for the relevant patient population; the data from the pharmaceutical manufacturer’s written statement show no statistically significant difference between the treatment groups.
• Morbidity – Hospitalisation due to heart failure
  • For the endpoint ‘hospitalisation due to heart failure’, there were no statistically significant differences between the treatment groups.
  • In both study arms, only three patients in total had to be hospitalised due to heart failure. There is no statistically significant difference between the treatment groups.
• Health-related quality of life
  • Quality of life was not assessed in the ODYSSEY OUTCOMES study.
  • Quality of life was not assessed in the COMBO II study.
• Side effects – Serious adverse events (SAEs)
  • Serious adverse events (SAEs) In the ODYSSEY OUTCOMES trial, a SAE occurred in 23.8% of patients in the alirocumab arm and in 26.2% of patients in the control arm. These results show a statistically significant difference in favour of alirocumab (HR = 0.91, 95% CI [0.85; 0.98], p = 0.010).
  • Serious adverse events (SAEs) In the COMBO II study, SAEs occurred in 27.5% of patients in the alirocumab arm and in 26.4% of patients in the ezetimibe arm. These results are not statistically significantly different.
• Side effects – discontinuation due to adverse events (AEs)
  • Discontinuation due to adverse events (AEs) In the study, 3.5% of patients in the alirocumab arm and 3.7% of patients in the control arm discontinued the study due to anAE. There was no statistically significant difference in this outcome between the treatment arms.
  • Discontinuation due to adverse events (AEs) During the 104-week treatment period, 10.3% of patients in the alirocumab arm and 9.3% of patients in the ezetimibe arm discontinued the study due to anAE. There were no statistically significant differences between the treatment groups.
• Side effects – allergic reactions and local reactions at the injection site
  • In the ODYSSEY OUTCOMES study, there were numerically more ‘allergic reactions’ in the alirocumab arm compared with the control arm (8.0% vs. 7.1%). With regard to the adverse event ‘local reactions at the injection site’, there were statistically significantly more local reactions with alirocumab compared with placebo (4.2% vs. 2.5%, HR = 1.68, 95% CI [1.33; 2.12], p < 0.001).
  • After 104 weeks, treatment with alirocumab led to allergic reactions in 8.4% of patients (7.1% in the ezetimibe arm) and to local reactions at the injection site in 3.4% of patients (1.4% in the ezetimibe arm). However, there were no statistically significant differences between the treatment groups.
• Overall review
  • An overall review of the results of the COMBO II study therefore shows no additional benefit of alirocumab compared with appropriate comparator therapy in adult patients (with known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial disease) with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, who do not achieve LDL-C targets with the maximum tolerated statin dose and for whom statins are an option.

b1) Adult patients (without known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial disease)) with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed dyslipidaemia, for whom statin therapy is not an option due to contraindications or treatment-limiting side effects

• The additional benefit is not proven.
• However, as patients without known atherosclerotic cardiovascular disease were not included in this study, no assessment of the patient population b1) can be made on the basis of this study.
• There are therefore no data available to demonstrate any additional benefit of alirocumab for this patient population.

b2) Adult patients (with known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial occlusive disease)) with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed dyslipidaemia, for whom statin therapy is not an option due to contraindications or treatment-limiting side effects

• The additional benefit is not proven.
• Overall, for this reason, no conclusions can be drawn from the ODYSSEY OUTCOMES study regarding the additional benefit of alirocumab.
• mortality
  • Overall mortality In the ODYSSEY OUTCOMES trial, 5.6% of patients in the alirocumab arm and 5.3% of patients in the control arm died. This difference between the treatment groups is not statistically significant.
• Morbidity – Major Adverse Cardiovascular Event (MACE)
  • The combined cardiovascular endpoint MACE comprises the individual components ‘death from coronary heart disease’, ‘non-fatal myocardial infarction’, ‘fatal/non-fatal ischaemic stroke’ and ‘hospitalisation for unstable angina’. For the combined endpoint, statistically significant advantages were observed with alirocumab in the relevant patient population (18.0% vs. 26.0%, HR = 0.65, 95% CI [0.43; 0.96], p = 0.036). With regard to the individual components, statistically significant advantages were observed with alirocumab only for the endpoint ‘non-fatal myocardial infarction’ (14.6% vs. 22.5%, HR = 0.62, 95% CI [0.40; 0.95], p = 0.030).
• Morbidity – Hospitalisation for heart failure
  • No statistically significant differences were observed between the treatment groups for the endpoint ‘hospitalisation for heart failure’.
• Health-related quality of life
  • Quality of life was not assessed in the ODYSSEY OUTCOMES study.
• Side effects – Serious adverse events (SAEs)
  • Serious adverse events (SAE) In the ODYSSEY OUTCOMES study, aSAEoccurred in 38.6% of patients in the alirocumab arm and in 34.4% of patients in the control arm. The difference between the treatment groups is not statistically significant.
• Side effects – Discontinuation due to adverse events (AE)
  • Discontinuation due to adverse events (AEs) In the ODYSSEY OUTCOMES study, 6.4% of patients in the alirocumab arm and 8.8% of patients in the control arm discontinued the study due to anAE. There is no statistically significant difference in this result between the treatment groups.
• Side effects – Allergic reactions and local reactions at the injection site
  • No data are available in the dossier for the relevant patient population.
• Conclusion
  • Given that the patient population studied in the ODYSSEY OUTCOMES trial consisted of patients at very high cardiovascular risk due to a known history of atherosclerotic cardiovascular disease who were not achieving their LDL-C targets, the decision not to administer further lipid-lowering agents in the control arm should be viewed critically and does not appear appropriate.

Courtesy translation only, please refer to the German original.