Emicizumab (1) – Hemlibra®

• Clinical trials
  • The benefit assessment is based, amongst other things, on the direct comparative registration trial HAVEN 1. This was an open-label, actively controlled, multicentre Phase III trial, the randomised part of which compared emicizumab as routine prophylaxis with on-demand treatment with bypassingpreparations in adults and adolescents (aged 12 years and over) with haemophilia A and factor VIII inhibitors over a period of 6 months.

a) Patients with haemophilia A and factor VIII inhibitors for whom on-demand treatment with bypassing agents alone constitutes a patient-specific therapy

• For patients with haemophilia A and factor VIII inhibitors, for whom on-demand treatment with bypassing agents alone constitutes a patient-specific therapy, there is a hint of a non-quantifiable additional benefit for emicizumab as routine prophylaxis compared with the appropriate comparator therapy of on-demand treatment with bypassing agents alone.
• Consequently, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, the G-BA assesses, for patients for whom on-demand treatment with bypassing agents alone constitutes a patient-specific therapy, the extent of the additional benefit of emicizumab for routine prophylaxis of bleeding in haemophilia A and factor VIII inhibitors, compared with on-demand treatment with bypassing agents, is non-quantifiable.
• mortality
  • In the mortality category, no events occurred in the HAVEN 1 study at week 25.
• morbidity
  • In this assessment, morbidity is characterised using annualised bleeding rates and health status (EQ-5D-VAS).
  • Annualised bleeding rates
  • For all bleeding rates recorded, a statistically significant ABR ratio was observed in favour of prophylaxis with emicizumab. Under emicizumab prophylaxis, annualised bleeding rates are statistically significantly reduced compared with on-demand treatment with bypassing agents, both for treated bleeds and for joint bleeds [ABR ratio (treated bleeds) 0.13 [95% CI 0.06; 0.28]; p-value < 0.001; ABR ratio (joint haemorrhages) 0.11 [0.03; 0.52]; p = 0.005].
  • Compared with on-demand treatment with bypassing agents alone, there is a positive effect in favour of emicizumab maintenance prophylaxis.
  • Health status as measured by the EQ-5D VAS
  • There is a statistically significant advantage in favour of emicizumab prophylaxis compared with on-demand treatment with bypassing agents (MD 9.72 [1.82; 17.62]; p-value = 0.017). The effect cannot be classified as clinically relevant, as the 95% confidence interval of the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2 (Hedges’ g: 0.74 [95% CI 0.11; 1.37]).
• Health-related quality of life
  • Haem-A-QoL, Haemo-QoL SF
  • For the Haem-A-QoL total score, a statistically significant effect in favour of emicizumab prophylaxis compared with on-demand treatment with bypassing agents can be inferred (MD -14.01 [-22.45; –5.56]; p-value = 0.002). Furthermore, for the five Haem-A-QoL domains‘physical health’, ‘emotions’, ‘self-perception’, ‘treatment’ and ‘thoughts about the future’ each showed a statistically significant advantage in favour of emicizumab prophylaxis compared with on-demand treatment with bypassing agents.
  • These effects can be classified as clinically relevant, as the 95% confidence interval for the standardised mean differences for both the Haem-A-QoL total score(Hedges’ g: -1.06 [95% CI -1.76; -0.36]), and for four of the five statistically significant domains of the Haem-A-QoL mentioned above (with the exception of the ‘Thoughts about the future’ domain), lies entirely outside the irrelevance range of -0.2 to 0.2.
  • However, based solely on this analysis (Hedges’ g), the extent of the clinically relevant advantage cannot be quantified with sufficient certainty.
  • The age-specific Haemo-QoL SF questionnaire, used to assess quality of life in patients under 18 years of age, did not provide any usable data, as the proportion of patients in this age group within the study arms relevant to the benefit assessment was too small (4 patients in the intervention arm, 2 patients in the comparator arm).
  • Overall, there is a statistically significant, clinically relevant effect in favour of emicizumab with regard to health-related quality of life; however, the extent of this effect cannot be quantified .
• Side effects
  • SAE, discontinuation due to AEs
  • For the patient-relevant endpoints SAE and discontinuation due to AEs, there were no statistically significant differences between emicizumab prophylaxis and the comparator treatment with bypassing agents on an as-needed regimen.
  • Thromboembolic events, thrombotic microangiopathy, injection site reaction
  • For the patient-relevant endpoints ‘thromboembolic events’ and ‘ ’ thrombotic ‘microangiopathy’ , there were also no statistically significant advantages or disadvantages of prophylaxis with emicizumab compared with bypassing agents administered on an as-needed basis.
  • Under weekly subcutaneous treatment with emicizumab, events classified under the Preferred Term (PT) ‘injection site reactions’ occurred at a statistically significantly higher rate than under treatment with bypassing agents, which were administered intravenously on an as-needed basis, varying according to individual patient requirements. ‘Injection site reactions’ are not classified as serious adverse events.
• Overall view
  • Overall, in the population presented here—comprising patients for whom on-demand treatment with bypassingpreparations constitutes the patient-specific therapy, the endpoint categories of morbidity and quality of life for emicizumab, compared with the appropriate comparator therapy within the study, show exclusively positive effects—non-quantifiable in their extent—that are not called into question by the results in the side effects category.

b) Patients with haemophilia A and factor VIII inhibitors, for whom a therapy other than on-demand treatment with bypassing agents alone constitutes their individualised treatment

• For patients with haemophilia A and factor VIII inhibitors, for whom a treatment other than on-demand therapy with bypassing agents alone constitutes the patient-specific treatment, the additional benefit of emicizumab as routine prophylaxis compared with the appropriate comparator therapy is not proven.
• Due to the methodological limitations described, neither the intra-individual comparisons nor the adjusted, indirect comparison can be taken into account for the purpose of benefit assessment.

Courtesy translation only, please refer to the German original.