Fremanezumab (1) – Ajovy®

• Clinical trials
  • The FOCUS trial was a randomised, multicentre, double-blind RCT with a parallel-group design, comparing fremanezumab with placebo over a double-blind period of 12 weeks in adult patients with documented chronic or episodic migraine for at least 12 months.
  • The two studies submitted by the pharmaceutical manufacturer for the benefit assessment, HALO CM and HALO EM, are—regardless of the analyses presented—unsuitable for the patient population a in answering the question of the benefit assessment regarding the additional benefit of fremanezumab compared with the appropriate comparator therapy.

a) Untreated adult patients and patients who have responded inadequately to, are intolerant of, 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 fremanezumab 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 fremanezumab compared with the appropriate comparator therapy.
• The continuation of an existing, inadequate treatment in the comparator arm in both studies, or the administration of placebo alone, does not constitute the implementation of the appropriate comparator therapy.

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

• For migraine prophylaxis 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 fremanezumab 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 fremanezumab 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 migraine prophylaxis 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 them or cannot tolerate them, there is a hint of considerable additional benefit from fremanezumab compared with the appropriate comparator therapy, Best Supportive Care (BSC).
• Based on these considerations, and on the basis of the information in the dossier and the results of the benefit assessment, the G-BA considers that fremanezumab offers additional benefit compared with the appropriate comparator therapy, Best Supportive Care, for the prophylaxis of migraine 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, are not suitable for, or cannot tolerate these, 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 FOCUS trial.
• mortality
  • In the FOCUS 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)
  • For the reduction in migraine days per month by ≥ 50% compared with the baseline phase, averaged over the treatment period, there was a statistically significant advantage in favour of fremanezumab + BSC compared with placebo + BSC.
  • For the reduction in migraine days per month by ≥ 75% compared with the baseline phase, averaged over the treatment period, there was also a statistically significant difference in favour of fremanezumab + BSC compared with placebo + BSC.
  • No statistically significant difference in the reduction in migraine days per month by 100 per cent compared with the baseline phase, averaged over the treatment period, could be demonstrated between fremanezumab + BSC and placebo + BSC.
• Morbidity – headache days per month
  • For the endpoint ‘mean change in headache days per month’, a statistically significant advantage in favour of fremanezumab + BSC compared with placebo + BSC was observed relative to the baseline phase, averaged over the 12-week treatment period.
• Morbidity – Health status (EQ-5D VAS)
  • For the mean change in VAS at week 12 compared with baseline, the FOCUS study shows a statistically significant difference in favour of fremanezumab + BSC compared with placebo + BSC.
  • To assess the clinical relevance of the result, the SMD is examined in terms of Hedges’ g. In this case, the 95% CI of the SMD does not lie entirely outside the irrelevance range of −0.2 to 0.2. Consequently, it cannot be concluded with sufficient certainty that the effects are clinically relevant in each case.
• Health-related quality of life – General impairment due to headache (HIT-6)
  • For the endpoint ‘general impairment due to headache’ (HIT-6), the mean differences are used. At week 12, compared with baseline, there is a statistically significant advantage in favour of fremanezumab + BSC versus placebo + BSC.
  • To assess the clinical relevance of the results, the standardised mean difference (SMD) in the form of Hedges’ g is used in each case. In this case, the 95% confidence interval for the SMD lies entirely outside the irrelevance range of −0.2 to 0.2. This is interpreted as a clinically relevant effect.
• Health-related quality of life – Migraine-Specific Quality of Life Questionnaire (MSQoL)
  • For all three domains of the MSQoL (role functioning, role prevention and emotional state), a statistically significant advantage in favour of fremanezumab + BSC compared with placebo + BSC was observed at week 12 relative to baseline.
  • Furthermore, the 95% CI of the SMD for the two domains ‘Role Functioning’ and ‘Emotional State’ lies entirely outside the non-significant range of −0.2 to 0.2.
  • For the domain ‘Role Functioning’, the 95% CI of the SMD does not lie entirely outside the irrelevance range of −0.2 to 0.2. Consequently, for the MSQoL domain ‘Role Functioning’, it cannot be concluded with sufficient certainty that the effects at week 12 are clinically relevant, whereas for the other two MSQoL domains, ‘Role Functioning’ and ‘Emotional State’, there is a statistically significant, clinically relevant effect at week 12 in each case.
• Side effects – SUEs and discontinuation due to AEs
  • For the endpoints SUEs and discontinuation due to AEs, there was no statistically significant difference between the fremanezumab + BSC and placebo + BSC treatment groups at week 12.
• Overall assessment
  • In summary, within the morbidity endpoint category, for the endpoints ‘reduction in migraine days per month by ≥ 50% and ≥ 75%’ there were statistically significant and, in terms of extent, considerable advantages in favour of treatment with fremanezumab + BSC compared with placebo + BSC. This advantage is also reflected in the additional endpoint ‘mean change in headache days per month’.
  • With regard to health-related quality of life, statistically significant and clinically relevant advantages were observed for fremanezumab + BSC compared with placebo + BSC at week 12 for two of the three domains of the MSQoL. Furthermore, a statistically significant, clinically relevant advantage for fremanezumab + BSC compared with placebo + BSC can be inferred for the endpoint ‘overall impairment due to headache’ at week 12.
  • In the category of side effects, no advantages or disadvantages could be identified for fremanezumab compared with the appropriate comparator therapy (BSC) at week 12.
  • Overall, in the endpoint categories of morbidity and health-related quality of life, fremanezumab 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.

Courtesy translation only, please refer to the German original.