Burosumab (1) – Crysvita®

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

• For children aged 1 year and over and adolescents in the skeletal growth phase with X-linked hypophosphataemia (XLH) and radiographic evidence of bone disease, Burosumab offers a non-quantifiable additional benefit.
• Consequently, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, the G-BA has determined that there is a non-quantifiable additional benefit for Burosumab in the treatment of children aged 1 year and over and adolescents in the skeletal growth phase with X-linked hypophosphataemia (XLH) and radiological evidence of bone disease.
• mortality
  • No deaths occurred in the UX023-CL201, UX023-CL205 and UX023-CL301 studies.
• Morbidity – symptoms of rickets as measured by the Rickets Severity Scale (RSS)
  • For the radiological endpoint RSS, a statistically significant difference was observed at week 64 compared with baseline (LS Mean (SE) [95% CI]: -1.0 (0.11) [-1.22; -0.79]; p<0.0001).
  • This statistically significant difference was also confirmed in study UX023-CL205 for the RSS compared with baseline.
  • In study UX023-CL301, a statistically significant change in the RSS was observed for burosumab compared with the control at week 40 (LS mean [95% CI]: -1.34 [-1.74; -0.94]; p<0.0001).
  • 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, mortality).
• Morbidity – symptoms of rickets as assessed by the Radiographic Global Impression of Change (RGI-C)
  • For the radiological endpoint RGI-C, a statistically significant change was observed for buurosumab compared with the control group at week 40 (LS mean difference [95% CI]: 1.1 [0.8; 1.2]; p<0.001).
  • No data are available to provide proof of the validity of the RGI-C as a surrogate for morbidity in this therapeutic indication.
• Morbidity – Serum phosphate
  • For serum phosphate levels, a statistically significant difference was observed at week 40 compared with baseline (LS mean (SE) [95% CI]: 0.96 (0.12) [0.73; 1.20]; p<0.0001).
  • This statistically significant increase in serum phosphate levels compared with baseline was confirmed in study UX023-CL201 at week 64.
  • Furthermore, a difference in serum phosphate levels compared with baseline was also observed at week 40 in study UX023-CL301 (LS mean (SE): 0.92 (0.08)).
  • In addition, study UX023-CL301 showed a statistically significant change in serum phosphate levels for buurosumab compared with conventional therapy at week 40 (LS mean difference [95% CI]: 0.71 [0.52; 0.91]; p<0.0001).
  • The results regarding serum phosphate levels suggest that, under treatment with Burosumab, serum phosphate levels reach the normal range and that the pathologically altered serum phosphate levels caused by the genetic defect are stabilised.
• Overall assessment
  • Overall, a non-quantifiable additional benefit remains.
  • The studies UX023-CL201, UX023-CL205 and UX023-CL301 provide data on mortality, morbidity and side effects.
  • No deaths occurred in any of the studies. Endpoints in the morbidity category included symptoms of rickets as measured by the RGI-C and RSS scales, serum phosphate levels, height: standing height or lying length, physical endurance as measured by the 6MWT, motor function as measured by the BOT-2, function and pain as measured by the POSNA-PODCI, pain, physical functioning and fatigue as measured by PROMIS, and pain intensity as measured by the FPS-R.
  • Statistically significant increases in serum phosphate levels were observed in all three studies. The results suggest that serum phosphate levels return to the normal range during treatment with burosumab.
  • In both single-arm studies, statistically significant improvements in the RSS were observed compared with baseline. Furthermore, in the UX023-CL301 study, statistically significant changes in the RSS were observed in favour of burosumab compared with the control group. Statistically significant changes in favour of burosumab compared with the control were also observed for the RGI-C endpoint assessed in the UX023-CL301 study. However, surrogate validation for the two radiological endpoints, RSS and RGI-C, was not sufficiently proven for patient-relevant endpoints.
  • The endpoint of improvement in the 6MWT, assessed in the single-arm study UX023-CL201, shows a statistically significant difference compared with baseline; however, it cannot be conclusively assessed to what extent the increased walking distance is attributable to the patients’ advancing age and development. In contrast, the controlled study UX023-CL301 showed no statistically significant difference.
  • The endpoint of motor function as measured by the BOT-2 in the ‘Strength and Dexterity’ scale (single-arm study UX023-CL201) showed an improvement compared with baseline, although the clinical relevance of this change remains unclear.
  • Furthermore, in the endpoint ‘pain interference’, assessed using PROMIS, an advantage in favour of buurosumab was observed in the ‘Paediatric Pain Interference Score’ domain (comparative RCT UX023-CL301), an advantage in favour of burosumab was observed; however, its significance is unclear and its extent is non-quantifiable.
  • No usable data on quality of life are available (studies UX023-CL201, UX023-CL301) or no assessment was carried out (study UX023-CL205).
  • In study UX023-CL301, there was an increased incidence of side effects during treatment with buurosumab.

Courtesy translation only, please refer to the German original.