Crizanlizumab (1) – Adakveo®

• Clinical trials
  • The pharmaceutical manufacturer submitted data from the pivotal, randomised, double-blind, placebo-controlled Phase II SUSTAIN trial for the benefit assessment.
  • In this three-arm trial, treatment with crizanlizumab at two different doses (2.5 mg/kg and 5.0 mg/kg) was compared with treatment with placebo.

Patients aged 16 years and over with sickle cell disease; prevention of recurrent vaso-occlusive crises (VOCs)

• Overall, based on the positive effect of reducing or delaying the onset of VOCs, the G-BA assesses the extent of the additional benefit of crizanlizumab (+ HU where applicable) compared with placebo (+ HU where applicable) for the prevention of recurrent vaso-occlusive crises (VOCs) in patients aged 16 years and over with sickle cell disease as minor.
• Particularly due to the high number of patients who withdrew from the study prematurely, uncertainties regarding the statistical analysis of the results on VOCs, and the transferability of the operationalisation of VOCs to the German healthcare context, there is a hint of additional benefit with regard to the validity of the evidence.
• mortality
  • Overall survival was not assessed as an independent endpoint in the SUSTAIN study.
  • Deaths were recorded as part of the adverse event monitoring, and two deaths were reported descriptively in each of the two study arms.
  • The available data show no significant difference between the treatment arms.
• Morbidity – vaso-occlusive crises (VOC)
  • Vasocclusive pain crises associated with sickle cell disease and other vasocclusive complications perceptible to patients are considered patient-relevant events.
  • In the SUSTAIN study, a vaso-occlusive pain crisis was defined as: an acute episode of pain with no cause other than a vaso-occlusive event, c) which required presentation at a healthcare facility and d) oral or parenteral treatment with opioids or parenteral treatment with non-steroidal anti-inflammatory drugs (NSAIDs).
  • The following events associated with vaso-occlusive crises were also classified as vaso-occlusive pain crises in the SUSTAIN study: acute thoracic syndrome (ATS), liver sequestration, spleen sequestration and priapism.
  • Endpoints relating to VOC – annual VOC rate
  • The annual VOC rate was the primary endpoint of the SUSTAIN study.
  • The primary analysis of this endpoint included 109 versus 166 events (intervention versus control arm), comprising mainly pain crises in the strict sense (‘uncomplicated VOC’) and 12 events of ATS in each group.
  • Consequently, the pre-specified sensitivity analysis PS-1 (according to the CRC), in which no imputation of missing values was performed, shows a statistically significant advantage of crizanlizumab (+ HU where applicable) compared with placebo (+ HU where applicable), whilst the two post hoc sensitivity analyses with imputation, PhS-M6a (as per the CRC) and PhS-M6b (as per the investigator), no longer showed any statistically significant differences.
  • Endpoints relating to VOC – time to first VOC
  • The endpoint ‘time to first VOC’ was defined as the number of months from randomisation to the date of the first VOC.
  • For this endpoint (as defined by the CRC), there was a statistically significant advantage of crizanlizumab (+ HU where applicable) compared with placebo (+ HU where applicable). In the intervention arm, the median time to first VOC was prolonged by approximately 2.7 months.
  • Conclusion on VOCs
  • Overall, the available data on VOCs are subject to uncertainties.
  • However, when considering the results for both VOC endpoints as a whole, it is assumed – despite remaining uncertainties – that there is an effect towards a reduction or a delay in the occurrence of VOCs.
  • Consequently, an advantage of crizanlimizumab (+ HU where applicable) over placebo (+ HU where applicable) is identified in this regard.
• Morbidity – Pain (BPI-LF)
  • In the SUSTAIN study, pain as perceived by patients was assessed using the Brief Pain Inventory – Long Form (BPI-LF).
  • However, the response rates for the BPI-LF were below 70% in the intervention arm both at the first measurement point and throughout the remainder of the study; consequently, the validity of the results cannot be regarded as reliable.
  • The BPI-LF results are therefore not used to assess the extent of the additional benefit.
• Quality of life – Short Form Health Survey (SF-36)
  • Data on health-related quality of life were collected in the SUSTAIN study using the SF-36, with the mental health sub-score (MCS) and the physical health sub-score (PCS) considered separately.
  • The results show no statistically significant difference between the treatment groups in either score at week 26.
• Side effects – Total adverse events (AEs)
  • AEs occurred in approximately 90% of patients in both the intervention and control arms.
• Side effects – severe AEs
  • The available data on the endpoint ‘severe AEs’ are therefore considered unevaluable.
• Side effects – serious AEs (SAEs) and therapy discontinuations due to AEs
  • There were no statistically significant differences between the treatment arms for the endpoints of SAEs and therapy discontinuations due to AEs.
• Overall assessment
  • The results of the SUSTAIN study are available for the benefit assessment of crizanlizumab as monotherapy or as an add-on to hydroxyurea (HU) for the prevention of recurrent vaso-occlusive crises (VOCs) in patients aged 16 years and over with sickle cell disease.
  • With regard to overall survival, two deaths in each study arm were reported descriptively; these were documented as part of the AE data collection.
  • For the morbidity endpoint category, results on the occurrence of VOCs are available from the endpoints ‘annual VOC rate’ and ‘time to first VOC’.
  • Taking both endpoints into account, and despite remaining uncertainties, it is assumed that there is an effect of crizanlimab (+ HU where applicable) compared with placebo (+ HU where applicable) in the direction of a reduction or a delay in the occurrence of VOCs.
  • Based on the available data, the extent of the effect is assessed as a relevant improvement, but no more than a minor one.
  • With regard to patient-reported quality of life, the SF-36 results show no statistically significant difference between the treatment groups.
  • As regards side effects, overall, neither advantages nor disadvantages of crizanlizumab (where applicable, in combination with HU) compared with placebo (where applicable, in combination with HU) can be inferred.
  • In its overall assessment, the G-BA, based on the positive effect of reducing or delaying the onset of VOCs, the extent of the additional benefit of crizanlizumab (+ HU where applicable) compared with placebo (+ HU where applicable) for the prevention of recurrent vaso-occlusive crises (VOCs) in patients aged 16 years and over with sickle cell disease is minor.

Courtesy translation only, please refer to the German original.