Luspatercept (4) – Reblozyl®

• Clinical trials
  • A total of 336 adults were randomised in a 2:1 ratio to receive treatment with luspatercept plus best supportive care (BSC) (N = 224 patients) or to the control arm receiving placebo plus BSC (N = 112 patients).

Adults with transfusion-dependent anaemia associated with β-thalassaemia

• An additional benefit is not proven.
• Taking these uncertainties into account, it is concluded overall that an additional benefit is not proven for luspatercept compared with on-demand transfusion therapy with red blood cell concentrates in combination with chelation therapy in accordance with the marketing authorisation, preferably as monotherapy.
• mortality
  • Deaths were recorded as safety events in the BELIEVE study. At the time of the relevant data cut-off, one death occurred in each of the two treatment arms. There is therefore no statistically significant difference in overall survival for the purposes of the benefit assessment.
• Morbidity – Transfusion avoidance (transfusion-free period)
  • A transfusion-free period of ≥ 24 weeks was observed in five patients in the intervention arm and in no patients in the control arm by the time the study was unblinded. There was no statistically significant difference between the treatment arms.
  • The endpoint of transfusion avoidance (transfusion-free period), as presented by the pharmaceutical manufacturer, operationalised as the proportion of patients who did not require a red blood cell concentrate transfusion for ≥ 24 weeks up to the unblinding of the study, is assessed as clinically relevant and is used for the present benefit assessment.
• Morbidity – transfusion burden
  • The reduction in transfusion frequency alone is not considered patient-relevant per se, as it does not provide any indication of long-term avoidance of transfusions in the sense of transfusion independence.
  • The endpoint ‘transfusion burden’ is assessed neither as a directly patient-relevant endpoint nor as a validated surrogate endpoint and is therefore presented only as supplementary information in this assessment.
• Morbidity – Total hospitalisations
  • In the BELIEVE study, the endpoint ‘total hospitalisation’ was defined as the number of adults hospitalised for any cause. A statistically significant difference was observed to the detriment of luspatercept.
• Quality of life – TranQoL (Transfusion-dependent quality of life questionnaire)
  • Overall, based on the responder analyses, there were no statistically significant differences between the treatment arms.
• Quality of life – SF-36v2 (Short Form-36 Health Survey version 2)
  • No statistically significant differences were observed between the treatment groups in terms of improvement in the PCS or the MCS.
• Conclusion on health-related quality of life
  • Overall, there were no statistically significant differences between the treatment arms in terms of health-related quality of life, as measured by TranQoL and SF-36v2.
• Side effects – serious AEs (SAEs) and severe AEs (CTCAE grade ≥ 3)
  • With regard to SAE and severe AEs (CTCAE grade ≥ 3), there is a statistically significant difference to the detriment of luspatercept compared with placebo in each case.
• Side effects – Therapy discontinuation due to AEs
  • With regard to therapy discontinuations due to AEs, there was no statistically significant difference between the study arms.
• Side effects – Specific AEs – Bone pain
  • For the endpoint of bone pain (Preferred Term), there was a statistically significant difference to the detriment of luspatercept.
• Conclusion on side effects
  • An overall review of the results on side effects reveals statistically significant differences to the detriment of luspatercept in the endpoints of serious and severe adverse events (CTCAE grade ≥ 3), as well as, in detail, for the specific AE of bone pain.
• Overall assessment
  • There is no statistically significant difference in overall survival.
  • For the morbidity endpoint category, results are available on transfusion avoidance and total hospitalisation. For the present assessment, a period of ≥ 24 weeks without transfusion is considered the relevant timeframe for assuming long-term avoidance of transfusions (transfusion-free status). Based on the results for transfusion avoidance of ≥ 24 weeks, no statistically significant difference can be identified between the treatment groups. For the endpoint of total hospitalisation, there is a statistically significant disadvantage associated with luspatercept.
  • With regard to health-related quality of life, as measured by the TranQoL and the SF-36v2, no statistically significant differences were observed between the study arms.
  • With regard to the endpoint category of side effects, there is a statistically significant disadvantage of luspatercept in terms of serious and severe AEs (CTCAE grade ≥ 3) and, more specifically, bone pain. There are no statistically significant differences for the endpoint of therapy discontinuations due to AEs.
  • The interpretation of the study results is subject to uncertainty due to ambiguities regarding the use of luspatercept in accordance with the prescribing information in the BELIEVE study. In particular, with regard to the luspatercept arm, it cannot be ruled out that some of the adverse events occurring during treatment might have been avoidable had treatment been discontinued earlier in accordance with the prescribing information.
  • Taking these uncertainties into account, the disadvantages observed in the endpoints of total hospitalisation, serious AEs and severe AEs are not considered sufficient to conclude, in the overall assessment, that luspatercept offers less benefit compared with on-demand transfusion therapy with red blood cell concentrates in combination with chelation therapy as per the marketing authorisation, preferably as monotherapy. It is therefore concluded that an additional benefit is not proven for Luspatercept compared with on-demand transfusion therapy with red blood cell concentrates in combination with chelation therapy under marketing authorisation, preferably as monotherapy.

Courtesy translation only, please refer to the German original.