Erenumab (1) – Aimovig®

• Clinical trials
  • The LIBERTY trial is a randomised, double-blind, parallel-group RCT comparing erenumab + best standard care (BSC) with placebo + BSC over a 12-week period in adult patients with a documented history of episodic migraine for at least 12 months.

a) Untreated adult patients and patients who have had an inadequate response to, are unable to tolerate, or are unsuitable for at least one prophylactic medication

• For migraine prophylaxis in untreated adult patients and patients who have responded inadequately to, are intolerant of, or are unsuitable for at least one prophylactic medication, the additional benefit of erenumab compared with the appropriate comparator therapy is not proven.
• For this patient population, the pharmaceutical manufacturer did not submit any study that would have been suitable for assessing the additional benefit of erenumab compared with the appropriate comparator therapy.

b) Adult patients who do not respond to, are unsuitable for, or cannot tolerate the drug therapies/classes of active substances metoprolol, propranolol, flunarizine, topiramate and amitriptyline

• For the prophylaxis of migraine in adult patients who do not respond to, are unsuitable for, or cannot tolerate the drug therapies/classes of active substances metoprolol, propranolol, flunarizine, topiramate or amitriptyline, are unsuitable for these, or cannot tolerate them, the additional benefit of erenumab compared with the appropriate comparator therapy is not proven.
• For this patient population, the pharmaceutical manufacturer did not submit any study that would have been suitable for assessing the additional benefit of erenumab compared with the appropriate comparator therapy.

c) Adult patients who do not respond to any of the aforementioned drug therapies/classes of active substances (metoprolol, propranolol, flunarizine, topiramate, amitriptyline, valproic acid, Clostridium botulinum toxin type A), are unsuitable for these, or cannot tolerate them

• For the prophylaxis of migraine in adult patients who do not respond to any of the aforementioned drug therapies/classes of active substances (metoprolol, propranolol, flunarizine, topiramate, amitriptyline, valproic acid, Clostridium botulinum toxin type A), are unsuitable for these, or cannot tolerate them, there is a hint of a considerable additional benefit of erenumab compared with the appropriate comparator therapy, Best Supportive Care (BSC).
• mortality
  • Overall mortality
  • In the LIBERTY study, no deaths occurred in either treatment arm. No statistically significant difference was observed between the treatment groups for the endpoint of overall mortality.
• Morbidity – Symptoms (migraine days per month; migraine attacks per month)
  • In the LIBERTY study, a migraine day was defined as a calendar day on which a patient documented a migraine headache. A migraine headache, in turn, was defined as a migraine with or without aura lasting at least 30 minutes, which also met the criteria of the ICHD-3 classification with regard to pain intensity and/or the use of acute medication. Pain is considered to be patient-relevant.
  • For the endpoint ‘migraine days per month’, the responder analyses for a reduction of ≥ 50% are used. A statistically significant advantage in favour of erenumab + BSC compared with placebo + BSC can be inferred: whilst in the LIBERTY study, 30% of patients (26 out of 86) on erenumab + BSC achieved a reduction in migraine days per month of ≥ 50%, this was the case for 14% of patients (14 out of 104) in the placebo + BSC group (RR: 2.25 [95% CI: 1.25; 4.03]; p = 0.005). This advantage is considered considerable.
  • In addition, the pre-specified responder analyses for the endpoint ‘migraine attacks per month’ are also presented. In the LIBERTY study, a migraine attack was defined as an episode of a qualified migraine headache or the use of migraine-specific acute medication in the context of an aura. The statistically significant advantage in favour of erenumab + BSC is also evident in the endpoint ‘migraine attacks per month’ shown here; in the LIBERTY study, 23% of patients (20 out of 86) on erenumab + BSC achieved a reduction of ≥ 50% in migraine attacks per month, whereas 12% of patients (12 out of 104) achieved this outcome (RR: 2.02 [95% CI: 1.05; 3.88]; p = 0.033).
• Health-related quality of life – General impairment due to headache (HIT-6) – Improvement of ≥ 5 points
  • Health-related quality of life was assessed in the LIBERTY study using the Headache Impact Test-6 (HIT-6). This is a tool for measuring the impact of headaches on a patient’s quality of life over the past month.
  • A statistically significant advantage was observed for erenumab + BSC compared with placebo + BSC; a statistically significantly higher proportion of patients achieved an improvement of ≥ 5 points on the HIT-6 with erenumab + BSC (51%) compared with treatment with placebo + BSC (27%) (RR: 1.90 [95% CI: 1.30; 2.77]; p < 0.001). This advantage is considered considerable.
• Side effects – SUEs and discontinuation due to AEs
  • For the endpoints of SUEs and discontinuation due to AEs, there was no statistically significant difference between the erenumab + BSC and placebo + BSC treatment groups at week 12.
• Overall assessment
  • In summary, statistically significant, considerable advantages were observed for erenumab + BSC compared with placebo + BSC in the endpoint categories of morbidity (for the endpoint ‘migraine days per month’) and health-related quality of life at week 12. For the endpoint ‘activity impairment’ (WPAI), there is a non-quantifiable, statistically significant, clinically relevant advantage for erenumab + BSC compared with placebo + BSC.
  • In the category of side effects, no advantages or disadvantages for erenumab compared with the appropriate comparator therapy (BSC) can be identified at week 12.
  • Overall, in the endpoint categories of morbidity and health-related quality of life, erenumab showed exclusively positive effects compared with the appropriate comparator therapy within the study at week 12, with no negative results from other categories to offset these.
  • Based on these considerations, on the basis of the information in the dossier and the results of the benefit assessment, the G-BA considers that erenumab offers additional benefit compared with the appropriate comparator therapy, Best Supportive Care, for migraine prophylaxis in adult patients who do not respond to any of the aforementioned drug therapies or classes of active substances (metoprolol, propranolol, flunarizine, topiramate, amitriptyline, valproic acid, Clostridium botulinum toxin type A), do not respond to any of the aforementioned drug therapies or classes of active substances, are unsuitable for them, or cannot tolerate them, to be a significant improvement in treatment-related benefit not previously achieved, and classifies the extent of the additional benefit as considerable.
  • The assessment of the additional benefit is based on the randomised, double-blind Phase III LIBERTY trial. The subset of patients included in this trial that met the characteristics of patient population c on the basis of their prior treatments was relevant for the benefit assessment.
  • The risk of bias for the submitted LIBERTY study is classified as low at the study level. Whilst the risk of bias at the endpoint level is classified as low for the endpoints of all-cause mortality, general impairment due to headache (HIT-6), health status (EQ-5D VAS), as well as serious adverse events (SUEs) and discontinuation due to adverse events, is classified as low, it is considered high for the endpoints of symptomatic burden (migraine days per month), physical functioning (MPFID) and impairment of work productivity and activity (WPAI-Headache) is considered high. For the endpoints with a high potential for bias, it is unclear whether a significant number of days or significant periods during the observation phase were not taken into account.
  • Overall, with regard to the certainty of the evidence, there is a hint of additional benefit.

Courtesy translation only, please refer to the German original.