Evolocumab (1) – Repatha®

• Clinical trials
  • To demonstrate the additional benefit in the patient population of ‘homozygous familial hypercholesterolaemia (HoFH), in whom pharmacological and dietary options for lowering lipids have not been exhausted’, the pharmaceutical manufacturer presents the 12-week randomised, placebo-controlled, double-blind TESLA trial.

a1) Hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia – patients for whom statin therapy is an option

• The additional benefit is not proven.
• On the one hand, the appropriate comparator therapy – “maximum tolerated drug and dietary therapy for lipid-lowering” – was not adequately implemented; on the other hand, the study duration of 12 weeks is insufficient for assessing additional benefit given the chronic nature of the condition.
• In the study, patients in the comparator arm were assigned fixed-dose regimens for statins and ezetimibe; it was not possible to adjust the dosage during the study.
• Furthermore, no conclusions regarding the additional benefit of evolocumab versus ezetimibe can be drawn from the study for patients for whom ezetimibe represents the individually optimised treatment, as the 12-week study duration is considered too short to demonstrate any additional benefit.

a2) Hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia – patients for whom statin therapy is not an option due to statin intolerance or contraindications

• The additional benefit is not proven.
• Conclusions regarding the additional benefit of evolocumab compared with the appropriate comparator therapy cannot be drawn from the GAUSS-2 study, as the study duration of 12 weeks is considered too short to demonstrate any additional benefit.
• It is unclear to what extent combination therapy with ezetimibe and other lipid-lowering agents in this patient population corresponds to the appropriate comparator therapy ‘other (non-statin) lipid-lowering agents (fibrates, anion exchange resins, cholesterol absorption inhibitors) as monotherapy and dietary therapy for lipid-lowering’ in this patient population.

a3) Hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia – patients in whom pharmacological and dietary options for lipid-lowering have been exhausted

• The additional benefit is not proven.
• As no direct comparative study of evolocumab against the appropriate comparator therapy “LDL apheresis (as a ‘last resort’ in treatment-refractory cases), possibly with concomitant lipid-lowering drug therapy”, the pharmaceutical manufacturer has conducted a search for suitable studies for the purpose of an indirect comparison. No studies suitable for an indirect comparison could be identified.

b1) Homozygous familial hypercholesterolaemia – patients in whom pharmacological and dietary options for lipid-lowering have not been exhausted

• The additional benefit is not proven.
• It is unclear whether these are patients whose drug therapy has already been optimised to the maximum extent possible or not. However, the present question concerns patients for whom pharmacological and dietary options for lowering lipids have not been exhausted; consequently, for the appropriate implementation of the appropriate comparator therapy in the study, a dose adjustment of the baseline lipid-lowering therapy should have been provided for.
• Furthermore, due to its short study duration of 12 weeks, the TESLA study is not suitable for assessing the additional benefit of evolocumab, as a 12-week study duration is considered too short to demonstrate any additional benefit.

b2) Homozygous familial hypercholesterolaemia – patients in whom pharmacological and dietary options for lipid-lowering have been exhausted and who are not receiving LDL apheresis treatment

• An additional benefit is not proven.
• As there is no directly comparative study of evolocumab against the appropriate comparator therapy ‘LDL apheresis (as a “last resort” in treatment-refractory cases), where appropriate with concomitant lipid-lowering drug therapy’ the pharmaceutical manufacturer has conducted a search for suitable studies for the purpose of an indirect comparison. No studies suitable for an indirect comparison with LDL apheresis could be identified.

b3) Homozygous familial hypercholesterolaemia – patients who are also receiving LDL apheresis treatment

• An additional benefit is not proven.
• As no directly comparative study exists for evolocumab against the appropriate comparator therapy “LDL apheresis (as a ‘last resort’ in treatment-refractory cases), where appropriate in combination with concomitant lipid-lowering drug therapy.” the pharmaceutical manufacturer has conducted a search for suitable studies for the purpose of an indirect comparison. No studies could be identified that are suitable for an indirect comparison with LDL apheresis.

Courtesy translation only, please refer to the German original.