Burosumab (3) – Crysvita®

• Clinical trials
  • To assess the additional benefit of buurosumab for adults with X-linked hypophosphataemia, the pharmaceutical manufacturer submitted the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase III-trial UX023-CL303, which formed the basis for marketing authorisation, with data cut-off at week 24.

Adult patients with X-linked hypophosphataemia (XLH)

• mortality
  • No deaths occurred in the UX023-CL303 study.
• 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 goal.
  • For the endpoint ‘proportion of subjects with a mean serum phosphate level ≥ 2.5 mg/dL at the midpoint of the dosing cycle’, the UX023-CL303 study demonstrated a statistically significant advantage of burosumab compared with placebo.
  • At the end of the dosing cycle, 46 patients in the burosumab arm (67.6%) and 4 patients in the placebo arm (6.1%) achieved a mean serum phosphate level of ≥ 2.5 mg/dL.
  • The results regarding serum phosphate levels show that, in the majority of patients, serum phosphate levels return to the normal range during treatment with burosumab and that the pathologically altered serum phosphate levels caused by the genetic defect are stabilised.
• quality of life
  • Quality of life was not assessed in the UX023-CL303 study.
• Side effects
  • In the UX023-CL303 study, serious adverse events (SAEs) were observed in 2 patients in the burosumab arm (2.9%) and in 2 patients in the control arm (3.0%).
  • Severe adverse events (AEs, CTCAE Grade 3 or 4) were observed in 8 patients in the burosumab arm (11.8%) and 9 patients in the control arm (13.6%).
  • Consequently, no overall difference between the treatment groups can be inferred for the endpoints of SUEs and CTCAE Grade 3 or 4 AEs.
  • In the UX023-CL303 study, no patient discontinued treatment with buurosumab or placebo due to an AE.
  • Consequently, there is no difference between the treatment groups.
  • At the SOC (system organ class) and PT (preferred term) levels, it cannot be ruled out that symptoms of XLH are also included.
  • A statistically significant difference in favour of burosumab was observed for the endpoints arthralgia (PT) and oropharyngeal pain (PT).
  • In the category of side effects, there are no overall advantages or disadvantages for Burosumab.
• Overall assessment / Conclusion
  • For the benefit assessment of Burosumab in adults with X-linked hypophosphataemia, the pharmaceutical manufacturer presented the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase IIIUX023-CL303, which formed the basis for marketing authorisation, with data cut-off at week 24.
  • The UX023-CL303 study provides data on mortality, morbidity and side effects.
  • No deaths occurred in the UX023-CL303 study.
  • For the morbidity endpoint of walking ability, assessed using the 6MWT, a statistically significant advantage of burosumab over placebo was observed, although the extent of this advantage cannot be conclusively assessed.
  • For the clinically relevant endpoint of serum phosphate levels, study UX023-CL303 showed a statistically significant advantage of burosumab over placebo in the proportion of participants with a mean serum phosphate level of ≥ 2.5 mg/dL at the midpoint of the dosing cycle.
  • At the end of the dosing cycle, 46 patients in the buurosumab arm (67.6%) and 4 subjects in the placebo arm (6.1%) achieved a mean serum phosphate level of ≥ 2.5 mg/dL.
  • The results show that, in the majority of patients, serum phosphate levels reached the normal range during treatment with buurosumab.
  • For the endpoints of pain assessed using WOMAC, fatigue assessed using BFI and general health status assessed using PGI-I, no statistically significant differences were observed between the treatment groups.
  • For the ‘stiffness’ subscale, the responder analysis (reduction of ≥ 15 nu) demonstrated a statistically significant advantage of burosumab over placebo.
  • For the ‘Physical Function’ subscale, no statistically significant difference between the treatment groups was observed in the responder analysis.
  • No responder analyses were submitted for the ‘Pain’ subscale.
  • For the ‘Pain Intensity’ and ‘Pain Impairment’ domains of the BPI-SF, no statistically significant difference was observed between the treatment groups in the mean change from baseline to week 24 for either domain.
  • For the ‘Worst Pain’ endpoint, no statistically significant difference between the treatment groups was observed in the responder analysis of the BPI-SF (Item 3) for a reduction of > 15%.
  • Quality of life was not assessed in the UX023-CL303 study.
  • In the ‘Side effects’ category, the overall review reveals no advantages or disadvantages for burosumab.
  • Overall, the G-BA concludes that there is a minor additional benefit of Burosumab for the treatment of adult patients with XLH.
• Overall assessment / Conclusion
  • For the benefit assessment of buurosumab in adults with X-linked hypophosphataemia, the pharmaceutical manufacturer submitted the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase IIIUX023-CL303, which formed the basis for marketing authorisation, with data cut-off at week 24.
  • The UX023-CL303 study provides results on mortality, morbidity and side effects.
  • No deaths occurred in the UX023-CL303 study.
  • For the morbidity endpoint of walking ability, assessed using the 6MWT, a statistically significant advantage of burosumab over placebo was observed, although the extent of this advantage cannot be conclusively assessed.
  • For the clinically relevant endpoint of serum phosphate levels, study UX023-CL303 showed a statistically significant advantage of burosumab over placebo in terms of the proportion of participants with a mean serum phosphate level of ≥ 2.5 mg/dL at the midpoint of the dosing cycle.
  • At the end of the dosing cycle, 46 patients in the buurosumab arm (67.6%) and 4 subjects in the placebo arm (6.1%) achieved a mean serum phosphate level of ≥ 2.5 mg/dL.
  • The results show that, in the majority of patients, serum phosphate levels reached the normal range during treatment with buurosumab.
  • For the endpoints of pain assessed using WOMAC, fatigue assessed using BFI and general health status assessed using PGI-I, no statistically significant differences were observed between the treatment groups.
  • For the ‘stiffness’ subscale, the responder analysis (reduction of ≥ 15 nu) demonstrated a statistically significant advantage of burosumab over placebo.
  • For the ‘Physical Function’ subscale, no statistically significant difference between the treatment groups was observed in the responder analysis.

Courtesy translation only, please refer to the German original.