Voxelotor (1) – Oxbryta®

• Clinical trials
  • The pharmaceutical manufacturer submitted data from the pivotal, randomised, double-blind, placebo-controlled Phase III HOPE trial for the benefit assessment.
  • In this three-arm trial, treatment with voxelotor at two different doses (900 mg/day and 1500 mg/day) was compared with treatment with placebo.

Patients aged 12 years and over with haemolytic anaemia resulting from sickle cell disease

• Overall, the G-BA classifies the extent of the additional benefit of voxelotor (+ hydroxycarbamide where applicable) for the treatment of patients aged 12 and over with haemolytic anaemia resulting from sickle cell disease as non-quantifiable, because the scientific evidence does not permit quantification.
• The strength of the evidence is classified as ‘hint’.
• mortality
  • Overall survival was not assessed as an independent endpoint in the HOPE study.
  • Deaths were recorded as part of the adverse event monitoring, with two deaths reported descriptively in each of the two study arms.
  • The available data show no relevant difference between the treatment arms.
• Morbidity – vaso-occlusive crises (VOC)
  • Vasocclusive pain crises associated with sickle cell disease and other vasocclusive complications experienced by patients are considered patient-relevant events.
  • Neither the analysis of the ‘annual event rate’ nor the supplementary analysis of the ‘time to first VOC’ reveals a statistically significant difference between the treatment arms.
  • In line with the comments made by clinical experts during the commenting procedure, great importance is attached to the long-term end-organ damage resulting from VOCs.
  • However, no conclusions regarding long-term end-organ damage can be drawn from the available data from the HOPE study.
• Morbidity – Acute Thoracic Syndrome (ATS) or Pneumonia
  • The endpoint ‘ATS or pneumonia’ was defined in the HOPE study as a newly occurring pulmonary infiltrate, diagnosed by the investigator via chest X-ray, accompanied by fever and/or respiratory symptoms.
  • No statistically significant difference between the treatment arms was observed either in the analysis of the ‘annual event rate’ or in the supplementary analysis of the ‘time to first ATS or pneumonia’.
• Morbidity – freedom from red blood cell transfusions
  • The endpoint ‘absence of red blood cell transfusions’ is therefore not included in this assessment.
• health status
  • However, the response rates do not exceed 70% at any measurement point in time, meaning that the validity of the results cannot be regarded as reliable.
  • The results on health status are therefore not used to assess the extent of the additional benefit.
• quality of life
  • No data on health-related quality of life were collected in the HOPE study.
• Side effects – total adverse events (AEs)
  • AEs occurred in approximately 90% of patients in the intervention arm and in approximately 90% of patients in the control arm.
  • The results are presented here for supplementary information only.
• Side effects – serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs
  • No statistically significant differences were observed between the treatment arms for the endpoints SAEs, severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs.
• Side effects – Other relevant safety events
  • In detail, regarding the results for SAE and severe AEs (CTCAE grade ≥ 3) that occurred with an incidence > 5% in one study arm, a statistically significant difference in favour of Voxelotor (+ hydroxycarbamide, where applicable) compared with placebo (+ hydroxycarbamide, where applicable) was observed solely for severe AEs (CTCAE grade ≥ 3) within the system organ class ‘General disorders and administration site conditions’ showed a statistically significant difference in favour of voxelotor (+ hydroxycarbamide where applicable) compared with placebo (+ hydroxycarbamide where applicable).
• In the overall analysis of the side effect endpoint category
  • In the overall analysis of the ‘Side Effects’ endpoint category, there are therefore no differences between voxelotor (+ hydroxycarbamide where applicable) and placebo (+ hydroxycarbamide where applicable) that are relevant to the assessment.
• In the overall assessment of the results on morbidity
  • In the overall assessment of the results on morbidity, neither an advantage nor a disadvantage can be identified for Voxelotor (plus hydroxycarbamide where applicable) compared with placebo (plus hydroxycarbamide where applicable).
• Overall assessment
  • The results of the HOPE study are available for the benefit assessment of voxelotor as monotherapy in combination with hydroxycarbamide for the treatment of haemolytic anaemia resulting from sickle cell disease in patients aged 12 years and over.
  • With regard to overall survival, two deaths in each study arm were reported descriptively; these were documented as part of the adverse event (AE) monitoring.
  • No effect estimates are available, so the available data do not allow any conclusions to be drawn regarding the extent of the additional benefit.
  • For the morbidity endpoint category, results are available on the incidence of vaso-occlusive crises (VOC) and acute chest syndromes (ACS) or pneumonia.
  • However, no statistically significant difference was observed between the treatment arms for either VOCs, ATS or pneumonia.
  • No data on health-related quality of life were collected in the HOPE study.
  • Nor are there, overall, any differences relevant to the assessment between voxelotor (+ hydroxycarbamide where applicable) and placebo (+ hydroxycarbamide where applicable) with regard to side effects.
  • Overall, the G-BA classifies the extent of the additional benefit of Voxelotor (+ hydroxycarbamide where applicable) for the treatment of patients aged 12 years and over with haemolytic anaemia resulting from sickle cell disease as non-quantifiable, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.