Luspatercept (3) – Reblozyl®

• Clinical trials
  • The benefit assessment is based on the results of the completed, randomised, double-blind Phase III BEYOND trial comparing luspatercept plus best supportive care (BSC) with placebo + BSC in adult patients with non-transfusion-dependent β-thalassaemia.

Adults with non-transfusion-dependent anaemia due to β-thalassaemia

• Overall, based on the advantages of luspatercept in the morbidity endpoint category and in the patient-reported symptom endpoints, a moderate—and not merely minor—improvement in treatment-related benefit, which has not been achieved previously, has been observed.
• The G-BA therefore concludes that, for the treatment of adults with anaemia due to non-transfusion-dependent β-thalassaemia.
• Overall, the certainty of evidence for the established additional benefit is classified as‘indication’.
• mortality
  • Deaths were recorded in the BEYOND study as part of the adverse event monitoring. Over the entire observation period up to the data cut-off date of 14 September 2020, no deaths occurred in either study arm.
  • There is therefore no relevant difference in terms of overall survival for the benefit assessment.
• Morbidity – Total hospitalisations
  • In the BEYOND study, all documented inpatient hospital stays during the study were counted as hospitalisations, regardless of their cause.
  • There was no statistically significant difference between the study arms with regard to total hospitalisations.
• Morbidity – Symptoms (NTDT-PRO)
  • The NTDT-PRO is a validated questionnaire developed for patients with non-transfusion-dependent β-thalassaemia, which is used to assess the anaemia-related symptoms of fatigue/weakness and shortness of breath.
  • For the NTDT-PRO, a statistically significant advantage in favour of luspatercept was observed in both domains: fatigue/weakness and shortness of breath.
• Morbidity – Symptoms (PGIS)
  • The PGIS consists of a single question in which the patient rates the severity of β-thalassaemia-related symptoms on a 10-point scale.
  • For the PGIS, a statistically significant difference in favour of luspatercept was observed between the treatment arms.
• Morbidity – Symptoms (PGIC)
  • The PGIC consists of a single question in which the patient assesses the overall change in their β-thalassaemia-related symptoms since the start of the study.
  • For the PGIC, a statistically significant difference in favour of luspatercept was observed between the treatment arms.
• Morbidity – Conclusion on morbidity
  • For the morbidity endpoint category, there are overall statistically significant differences in patient-reported symptoms (NTDT-PRO, PGIS, PGIC) in favour of luspatercept.
• Health-related quality of life – FACIT-F
  • The FACIT-F consists of 13 items that assess the intensity of fatigue, as well as weakness and difficulties in performing everyday activities due to fatigue over the past 7 days.
  • For the FACIT-F, there were no statistically significant differences between the study arms, either in the total score or in the individual subscales.
• Side effects – Serious adverse events (SAE)
  • For the endpoint of serious AEs (SAEs), there was a statistically significant difference in favour of luspatercept between the study arms.
  • There is an effect modification by the characteristic ‘previous splenectomy’. In patients with a history of splenectomy, a statistically significant difference in favour of luspatercept was observed (HR = 0.08 [0.02; 0.37]; < 0.001). For patients without a history of splenectomy, there is no statistically significant difference between the treatment arms (HR = 1.18 [0.25; 5.62]; 0.832).
  • Overall, the statistical power of the subgroup analysis is considered insufficient to allow separate conclusions to be drawn regarding the additional benefit of Luspatercept in the overall assessment.
• Overall assessment
  • For the assessment of the additional benefit of luspatercept in the treatment of adults with anaemia associated with non-transfusion-dependent β-thalassaemia, results are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects from the completed, double-blind Phase III BEYOND trial.
  • No advantage or disadvantage to Luspatercept can be identified with regard to overall survival.
  • For the endpoint category of morbidity, results are available for the endpoints of total hospitalisation and patient-reported symptoms, as assessed using the NTDT-PRO, PGI-S and PGI-C questionnaires.
  • For the endpoint of total hospitalisation, there were no statistically significant differences between the treatment arms. For patient-reported symptoms, a statistically significant advantage for luspatercept was observed across all questionnaires used in the study.
  • With regard to health-related quality of life, as measured using the FACIT-F and SF-36v2 questionnaires, neither an advantage nor a disadvantage can be identified for treatment with luspatercept.
  • With regard to the endpoint category of side effects, there were no statistically significant differences in the endpoints of severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs. For the endpoint ‘serious AEs’, an advantage of luspatercept was observed, driven by the patient population that had previously undergone splenectomy. More specifically, a disadvantage of luspatercept was observed for the specific AE ‘bone pain’.
  • Overall, based on the advantages of luspatercept in the ‘morbidity’ endpoint category, a moderate—and not merely minor—improvement in treatment-related benefit, which has not been achieved previously, is observed in the endpoints relating to patient-reported symptoms. The G-BA therefore concludes that, for the treatment of adults with anaemia due to non--transfusion-dependent β-thalassaemia.

Courtesy translation only, please refer to the German original.