Burosumab (4) – Crysvita®

• Clinical trials
  • To assess the additional benefit of Burosumab for the treatment of X-linked hypophosphataemia (XLH) in children and adolescents aged 1 to 17 years with radiographically confirmed bone disease, the pharmaceutical manufacturer has submitted the pivotal, multicentre, randomised, open-label Phase IIIUX023-CL301, which formed the basis for marketing authorisation, with a data cut-off at week 64.
  • In the UX023-CL301 study, burosumab was compared with conventional therapy (consisting of oral phosphate and active vitamin D).

Children and adolescents aged 1 year and over up to ≤ 17 years with X-linked hypophosphataemia (XLH) with radiographic evidence of bone disease

• Overall, for children and adolescents aged 1 year and over up to ≤ 17 years with XLH and radiographic evidence of bone disease, there is a hint of a non-quantifiable additional benefit compared with phosphate replacement and active vitamin D in combination.
• mortality
  • No deaths occurred in the UX023-CL301 study.
• morbidity
  • Symptoms of rickets assessed using the Radiographic Global Impression of Change (RGI-C) and the Rickets Severity Scale (RSS)
  • No data are available to provide proof of the validity of the RGI-C and the RSS as surrogates for morbidity in this therapeutic indication. Consequently, no patient-relevant conclusions can be drawn.
  • Serum phosphate
  • For the endpoint of serum phosphate levels, study UX023-CL301 demonstrated a statistically significant advantage of burosumab compared with phosphate replacement and active vitamin D.
  • The results for 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.
  • Motor function: 6-minute walk test (6MWT)
  • In the UX023-CL301 study, a statistically significant advantage of buurosumab compared with phosphate replacement therapy and active vitamin D was observed in the change in 6MWT distance (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, there was no statistically significant difference between the treatment groups at week 64.
  • Anthropometric parameters: height
  • 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 compared with phosphate replacement and active vitamin D; however, the clinical significance of this is unclear given the magnitude of the difference observed.
  • Pain, physical functioning and fatigue as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS)
  • For the endpoint of pain, physical functioning and fatigue assessed using PROMIS, no statistically significant difference was observed between the treatment groups in the UX023-CL301 study for the domains of pain impairment, physical functioning and fatigue.
  • Pain intensity using the Faces Pain Scale-Revised (FPS-R)
  • For the endpoint of pain intensity, no statistically significant difference was observed between the treatment arms.
  • Dental events
  • No statistically significant difference was found between the treatment arms for the endpoint ‘dental events’.
• quality of life
  • Quality of life among paediatric patients was assessed in the UX023-CL301 study using the Short Form Health Survey-10 for Children (SF-10).
  • Due to a lack of information on various test quality criteria, this questionnaire cannot be taken into account for the present benefit assessment with regard to its validity.
  • No usable data on quality of life were presented in the UX023-CL301 study.
• Side effects
  • Serious adverse events (SAEs), severe adverse events
  • In the UX023-CL301 study, no statistically significant difference was observed between the buurosumab and control arms for the endpoints of SUEs and severe adverse events (CTCAE Grade 3 and 4).
  • Discontinuation due to AEs
  • No statistically significant difference was observed between the treatment groups for the endpoint ‘discontinuation due to AEs’.
  • Specific adverse events
  • For the endpoints ‘General disorders and administration site conditions’, ‘Injury, poisoning and procedural complications’, and ‘Respiratory, thoracic and mediastinal disorders’ (SOC, AEs in each case) and constipation (PT, AEs), a statistically significant disadvantage was observed in each instance compared with phosphate replacement and active vitamin D.
  • No data were submitted by the pharmaceutical manufacturer for adolescents aged 13–17 years.
  • In the category of side effects, the overall assessment reveals no relevant advantages or disadvantages for Burosumab.
• Overall assessment
  • For the benefit assessment of Burosumab for the treatment of X-linked hypophosphataemia (XLH) in children and adolescents aged 1 to 17 years with radiographically confirmed bone disease, the pivotal, multicentre, randomised, open-label Phase IIIUX023-CL301 trial, which formed the basis for marketing authorisation, with a data cut-off at week 64, was used.
  • 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 phosphate substitution and active vitamin D was observed, although the extent of this advantage cannot be conclusively assessed. For the endpoint of height (z-score), a statistically significant advantage of buurosumab compared with phosphate replacement and active vitamin D was observed; however, the clinical significance of this is unclear given the magnitude of the difference shown.
  • For the endpoints of percentage of expected 6MWT distance, pain, physical functioning and fatigue, as assessed using PROMIS, and pain intensity, as assessed using the 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, there are no relevant advantages or disadvantages for buurosumab when viewed as a whole.
  • No data were provided by the pharmaceutical manufacturer for adolescents aged 13–17 years.
  • Given that the underlying genetic cause of the condition is identical and that adolescents aged 13–17 with open growth plates have a pathophysiology comparable to that of children aged 1 to 12 years, the additional benefit is extrapolated to the overall population. The extent of the demonstrated advantage in the 6MWT endpoint cannot be quantified. Overall, a non-quantifiable additional benefit is inferred for children and adolescents aged 1 year to ≤ 17 years with XLH and radiographic evidence of bone disease.

Courtesy translation only, please refer to the German original.