Burosumab (2) – Crysvita®

• Clinical trials
  • To assess the additional benefit of buurosumab for children aged 1 year and over and adolescents in the skeletal growth phase with X-linked hypophosphataemia and radiographic evidence of bone disease, the pharmaceutical manufacturer submitted the pivotal, multicentre, randomised, open-label Phase III trial UX023-CL301, with data cut-off at week 64.
  • The UX023-CL301 study investigated burosumab compared with conventional therapy (consisting of oral phosphate and active vitamin D) in children aged 1 to 12 years with XLH.

Children aged 1 year and over and adolescents in the skeletal growth phase with X-linked hypophosphataemia and radiographic evidence of bone disease

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Overall, a non-quantifiable additional benefit remains, as the scientific evidence does not permit quantification.
• The authorised population of 13–17-year-olds is not covered by the submitted study UX023-CL301.
• mortality
  • No deaths occurred in the UX023-CL301 study.
• Morbidity – symptoms of rickets assessed using the Radiographic Global Impression of Change (RGI-C)
  • In the UX023-CL301 study, the RGI-C score was used as the primary endpoint for measuring bone mineralisation.
  • For the radiological endpoint RGI-C, a statistically significant change was observed at week 64 in favour of burosumab compared with conventional therapy.
  • No data are available to provide proof of the validity of the RGI-C as a surrogate for morbidity in this therapeutic indication.
• Morbidity – rickets symptoms assessed using the Rickets Severity Scale (RSS)
  • In the UX023-CL301 study, rickets symptoms were assessed using the Rickets Severity Scale (RSS) as an endpoint, in order to evaluate the severity of rickets on an absolute scale of 0–10 based on X-rays of the wrists and knees.
  • In the UX023-CL301 study, a statistically significant change in the RSS was demonstrated at week 64 in favour of burosumab compared with conventional therapy.
  • The evidence submitted by the pharmaceutical manufacturer is not sufficient to demonstrate an adequate correlation or validation of the surrogate endpoint (symptoms of rickets as measured by the RSS) with patient-relevant endpoints (such as pain, mobility, ability to walk, and mortality).
• Morbidity – Serum phosphate
  • The increase in the pathologically low serum phosphate level until the normal range is reached is the clinically significant parameter serving as the treatment target.
  • For the serum phosphate level endpoint, Study UX023-CL301 demonstrated a statistically significant change at week 64 in favour of burosumab compared with conventional therapy.
  • The results regarding serum phosphate levels suggest that, under treatment with burosumab, serum phosphate levels reach the normal range and the pathologically altered serum phosphate levels caused by the genetic defect are stabilised.
• Morbidity – Anthropometric parameters: height
  • The anthropometric parameter of height is considered a patient-relevant morbidity parameter, particularly in children with characteristic, disease-related growth disorders.
  • For the endpoint ‘absolute change in the z-score for standing height/lying length’, the UX023-CL301 study demonstrated a statistically significant advantage of buurosumab over conventional therapy; however, the clinical significance of this advantage is unclear due to the magnitude of the difference observed.
• Morbidity – Motor function: 6-minute walk test (6MWT)
  • The 6MWT is a standardised and established tool for assessing physical capacity (the distance patients can walk within 6 minutes).
  • In the UX023-CL301 study, a statistically significant advantage of buurosumab over conventional therapy was observed in the change in 6MWT distance at week 64 (an improvement in walking distance of 43.2 metres), the extent of which cannot be conclusively assessed.
  • In terms of the percentage of the expected 6MWT distance, no statistically significant difference was observed between the treatment groups at week 64.
• quality of life
  • No usable data on quality of life were presented in the UX023-CL301 study.
• Side effects
  • In the ‘Side effects’ category, there are no overall advantages or disadvantages for buurosumab.
  • Due to differences in the methods used to record adverse events (via home visits and telephone interviews) between the study arms, the results in the ‘Side effects’ category may be biased.
• Overall assessment
  • For the benefit assessment of buurosumab in children aged 1 year and over and adolescents in the skeletal growth phase with X-linked hypophosphataemia and radiographic evidence of bone disease, the pivotal, multicentre, randomised, open-label Phase IIIUX023-CL301, which formed the basis for marketing authorisation, with a data cut-off at week 64.
  • No deaths occurred in the UX023-CL301 study.
  • For the morbidity endpoint of motor function, as assessed by the 6MWT, a statistically significant advantage of burosumab over conventional therapy (consisting of oral phosphate and active vitamin D) was observed; however, the extent of this advantage cannot be conclusively assessed.
  • For the endpoint ‘standing height/lying length’ (z-score), a statistically significant advantage of burosumab over conventional therapy was observed; however, the clinical significance of this is unclear due to the magnitude of the difference shown.
  • For the clinically significant endpoint of serum phosphate, a statistically significant difference was observed in favour of Burosumab compared with conventional therapy.
  • For the endpoint of rickets symptoms assessed using the RGI-C and RSS, a statistically significant difference in favour of Burosumab compared with conventional therapy was observed in each case. However, surrogate validation for the two radiological endpoints, RSS and RGI-C, was not sufficiently proven for patient-relevant endpoints.
  • For the endpoints of percentage of expected 6MWT distance, pain, physical functioning and fatigue assessed using PROMIS, and pain intensity assessed using FPS-R, no statistically significant differences were observed between the treatment groups.
  • No usable data on quality of life were presented in the UX023-CL301 study.
  • In the category of side effects, the overall review reveals no advantages or disadvantages for buurosumab.
  • Overall, a non-quantifiable additional benefit remains, as the scientific evidence does not allow for quantification.

Courtesy translation only, please refer to the German original.