Evolocumab (3) – Repatha®

• Clinical trials
  • The randomised, controlled, double-blind HAUSER-RCT trial investigated the administration of evolocumab versus placebo, in each case in combination with a low-fat diet and stable lipid-lowering therapy, in children and adolescents aged 10 to 17 years with a diagnosis of heterozygous familial hypercholesterolaemia (HeHF).

a1) Children and adolescents with heterozygous familial hypercholesterolaemia aged between 10 and 17 years, in whom dietary and pharmacological options for lipid-lowering therapy have not been fully utilised

• The additional benefit is not proven.
• To assess the additional benefit of evolocumab for the treatment of children and adolescents aged 10 to 17 years with heterozygous familial hypercholesterolaemia in whom dietary and pharmacological options for lipid-lowering therapy have not been exhausted, the pharmaceutical manufacturer submits the HAUSER-RCT study.
• Prior treatment with the maximum tolerated statin dose not confirmed
• According to the marketing authorisation, the prerequisite for the use of evolocumab in this indication for patients for whom statin therapy is an option is the failure to achieve LDL-C target levels with a maximum tolerated statin dose.
• The HAUSER-RCT study included children and adolescents who were already being treated with atorvastatin, rosuvastatin, pravastatin or simvastatin at the start of the study. In most cases, the dosage of these statins did not correspond to the maximum permitted dose for children and adolescents with HeFH.
• Implementation of the appropriate comparator therapy
• As an appropriate comparator therapy for children and adolescents with HeFH aged between 10 and 17 years, in whom dietary and pharmacological options for lipid-lowering had not been fully utilised, a maximum tolerated drug therapy as prescribed by a doctor, taking into account statins, cholesterol absorption inhibitors and anion exchangers.
• Throughout the entire course of the study, no adjustments or optimisations to lipid-lowering therapy were planned in either the intervention or control arms. Rather, the therapy in place at the start of the study was to be continued unchanged.
• The continuation of inadequate therapy (including dosage) during the course of the study, provided that the individually maximally tolerated drug therapy has not yet been exhausted, does not constitute the implementation of the appropriate comparator therapy as defined by the G-BA.
• Conclusion
• Since, on the one hand, in the HAUSER-RCT study it cannot be guaranteed for the majority of the children and adolescents included that they were treated with a maximally tolerated dose of statins, nor that treatment with evolocumab was even indicated in accordance with the terms of the marketing authorisation; and, on the other hand, the appropriate comparator therapy defined by the G-BA, namely a maximum tolerated drug therapy as prescribed by a doctor, was not implemented, the study cannot be used to derive the additional benefit. Furthermore, the duration of the study is not suitable for assessing the long-term effects of evolocumab in this indication.
• Overall assessment
  • However, the study is not suitable for a benefit assessment, as, on the one hand, it cannot be guaranteed that the majority of the children and adolescents included were treated with a maximally tolerated dose of statins, and therefore treatment with evolocumab was not even indicated in accordance with the terms of the marketing authorisation. Furthermore, despite elevated LDL-C levels that were above the target range, the children and adolescents did not receive any adjustment to their lipid-lowering therapy as the study progressed, meaning that the appropriate comparator therapy was not implemented. Furthermore, the duration of the study is not sufficient to assess the long-term effects of evolocumab in this indication.

a2) Children and adolescents with heterozygous familial hypercholesterolaemia aged between 10 and 17 years, in whom dietary and pharmacological options for lipid-lowering have been exhausted

• An additional benefit is not proven.

b1) Children and adolescents with homozygous familial hypercholesterolaemia aged between 10 and 11 years, in whom dietary and pharmacological options for lowering lipid levels have not been exhausted

• An additional benefit is not proven.
• For the assessment of the additional benefit of evolocumab in the treatment of children and adolescents with homozygous familial hypercholesterolaemia (HoHF) aged 10 to 11 years, in whom dietary and pharmacological options for lowering lipids have not been exhausted, the pharmaceutical manufacturer additionally submits the single-arm HAUSER-OLE study.
• In line with the pharmaceutical manufacturer’s assessment, however, the single-arm HAUSER-OLE study is not suitable for drawing conclusions regarding the additional benefit of evolocumab compared with the appropriate comparator therapy, due to the lack of a control group.

b2) Children and adolescents with homozygous familial hypercholesterolaemia aged between 10 and 11 years, in whom dietary and pharmacological options for lowering lipid levels have been exhausted

• An additional benefit is not proven.
• No data were submitted for the assessment of the additional benefit of evolocumab for the treatment of children and adolescents aged 10 to 11 years with homozygous familial hypercholesterolaemia in whom dietary and pharmacological options for lipid-lowering therapy have been exhausted.

Courtesy translation only, please refer to the German original.