Evolocumab (2) – Repatha®

• Clinical trials
  • To demonstrate the additional benefit of evolocumab in combination with a statin, or a statin with other lipid-lowering therapies, in the patient group ‘adult patients with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, for whom statin therapy is an option’, the pharmaceutical manufacturer presents the double-blind, randomised controlled trial FOURIER.
  • The pharmaceutical manufacturer has submitted the APHERESE study as new scientific evidence to demonstrate additional benefit. The study is a two-phase trial, comprising a 6-week randomised phase and an 18-week single-arm follow-up phase with evolocumab treatment for all patients.

a1.1) Adult patients (without known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial occlusive 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

• The additional benefit is not proven.
• No new scientific evidence is available for this patient population. The assessment corresponds to that set out in the resolution of 9 March 2016.

a1.2) Adult patients (with known atherosclerotic cardiovascular disease (myocardial infarction, stroke or peripheral arterial occlusive 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

• An additional benefit is not proven.
• mortality
  • Overall mortality was described in the study protocol as death from any cause and was defined as the time from the start of the study to the date of death, regardless of the cause of death. The endpoint included deaths from both cardiovascular and non-cardiovascular causes, as well as events whose cause could not be clearly attributed. No significant difference was observed between the study arms.
  • The time to cardiovascular death was defined as the period from the start of the study to the date of death due to one of the following cardiovascular events: acute myocardial infarction, sudden cardiac death, stroke, death due to cardiovascular procedures, cardiovascular haemorrhage, other causes with a specific cardiovascular aetiology (e.g. pulmonary embolism or peripheral arterial disease). No statistically significant difference was observed between the study arms.
  • In the mortality category, no statistically significant differences were observed in the overall population. However, opposite effect estimates were observed for both the cardiovascular death endpoint and the all-cause mortality endpoint in the North America and Europe patient populations.
• Morbidity – fatal myocardial infarction and non-fatal myocardial infarction
  • The endpoint was defined as the time to the first myocardial infarction (MI) from the start of the study until the day of death from a myocardial infarction or the occurrence of a non-fatal myocardial infarction (spontaneous myocardial infarction, myocardial infarction following ischaemic compromise, fatal myocardial infarction (without biomarkers), myocardial infarction caused by PCI, stent thrombosis, restenosis or coronary artery bypass). Statistically significant differences were observed between the treatment arms for the composite endpoint, in favour of evolocumab in combination with statins.
  • No statistically significant differences were observed for fatal myocardial infarctions, whilst a statistically significant advantage of evolocumab over the comparator arm was observed for non-fatal myocardial infarctions. In the overall population, there were statistically significantly fewer non-fatal myocardial infarctions in the evolocumab group than in the comparator group (3.3% vs. 4.5%; HR: 0.72 [0.64; 0.82]; p = <0.001).
• Morbidity – fatal and non-fatal stroke
  • The endpoint was defined as the time to the first stroke (haemorrhagic or non-haemorrhagic) from the start of the study until the day of death from a stroke or the occurrence of a non-fatal stroke.
  • No statistically significant differences were observed for fatal strokes, whilst a statistically significant advantage of evolocumab over the comparator arm was observed for non-fatal strokes. There were statistically significantly fewer non-fatal strokes in the evolocumab group than in the comparator arm (1.3% vs. 1.5%; HR: 0.76 [0.62; 0.92]; p=0.006).
• Morbidity – Transient ischaemic attack (TIA)
  • The occurrence of TIAs was also assessed as a secondary endpoint in the study. No statistically significant differences were observed between the treatment groups.
• Morbidity – LDL-C at week 120 (mg/dl)
  • The change in LDL-C levels from the start of the study to week 120 following the start of lipid-lowering treatment was described in terms of the absolute and percentage change in LDL-C levels. There was a statistically significant greater reduction in LDL-C levels – by an average of 52.2 mg/dl – in the evolocumab group compared with the control arm.
  • The LDL-C levels are shown for reference. This is a laboratory value which is not considered, in itself, to be a patient-relevant endpoint, but rather a surrogate parameter.
• Side effects – severe adverse events (SAEs); discontinuation due to adverse events (AEs)
  • No statistically significant differences were observed between the treatment groups.
• Side effects – Specific adverse events (AEs)/AEs of particular interest
  • In its dossier, the pharmaceutical manufacturer reports statistically significant differences for the AEs of particular interest ‘hypersensitivity-related events’ and ‘injection site AEs’, which occurred more frequently in the intervention arm than in the control arm. With regard to ‘demyelination-related events’, a statistically significant difference was observed in favour of the evolocumab arm.
• Overall assessment
  • To demonstrate the additional benefit of evolocumab in combination with a statin (with or without other lipid-lowering therapies), the pharmaceutical manufacturer presents the FOURIER study as new scientific evidence. The study exhibits major methodological limitations with regard to the benefit assessment question.
  • In summary, it can be stated that, due to the conditions for the use of evolocumab, the patient population included in the study only partially corresponds to the marketing authorisation for evolocumab, and that the appropriate comparator therapy was only incompletely implemented in the comparator arm. Furthermore, the effects observed in the study vary so markedly depending on the geographical region that, regardless of the aforementioned limitations regarding prior therapy and the implementation of the appropriate comparator therapy (ZVT), the results cannot be uncritically extrapolated to German clinical practice. On balance, therefore, no additional benefit can be validly inferred.
  • An additional benefit of evolocumab compared with maximally tolerated lipid-lowering therapy is therefore not proven.

a3) Adult patients with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, in whom pharmacological and dietary options for lipid-lowering have been exhausted

• An additional benefit is not proven.
• To demonstrate additional benefit, the pharmaceutical manufacturer has submitted the APHERESE study. This is a 6-week comparative study in which evolocumab was investigated in comparison with LDL apheresis, with the primary objective of avoiding the need for apheresis.
• Given the chronic nature of hypercholesterolaemia and the associated need for long-term, continuous administration of evolocumab, or the patients’ ongoing need for LDL apheresis, the 6-week study duration is considered too short to draw conclusions from the study regarding the additional benefit of evolocumab versus LDL apheresis.
• Consequently, no data relevant to the benefit assessment are available. An additional benefit of evolocumab over LDL apheresis is therefore not proven.

Courtesy translation only, please refer to the German original.