Vosoritid (2) – Voxzogo®

• Clinical trials
  • Study 206 is a double-blind, randomised Phase II study comparing vosoritid with placebo in children aged 0 to < 5 years with genetically confirmed achondroplasia over 52 weeks.
  • Study 301 is a double-blind, randomised Phase III study lasting 52 weeks comparing vosoritide with placebo in children and adolescents aged 5 to < 18 years with genetically confirmed achondroplasia.

Patients with achondroplasia aged 2 years and over whose epiphyses have not yet closed

• For patients with achondroplasia aged 2 years and over whose epiphyses have not yet closed, there is an indication of a non-quantifiable additional benefit for vosoritide.
• Overall, the certainty of the evidence is classified as ‘indication’.
• mortality
  • Overall mortality was recorded as part of the adverse event data. No deaths occurred in studies 206 and 301.
• Morbidity – Height (z-score)
  • Height (z-score) is classified as patient-relevant in the present therapeutic indication for achondroplasia.
  • The meta-analysis of studies 206 and 301 for the endpoint of height as a z-score relative to the US reference population shows a significant improvement in height with vosoritide compared with placebo.
  • Children aged ≥ 2 to < 5 years (Study 206) grew an average of 0.96 cm more over the 52-week study duration whilst on vosoritide treatment than in the placebo arm. For participants aged ≥ 5 years in Study 301, the difference was 1.57 cm.
  • Supporting analysis of the long-term data from studies 901/301/302 (2-year comparison with placebo), 206/208 (up to 2.5 years, comparison with baseline), 301/302 (up to 3.5 years, comparison with baseline) and 202/205 (up to 7 years, comparison with baseline) shows that the effect on the endpoint of height (z-score) is sustained and does not call into question the results of the meta-analysis of studies 206 and 301 regarding the benefit of vosoritide.
  • Furthermore, it is assumed that the results of the meta-analysis are transferable to the German healthcare context, as in study 301 the respective group difference does not differ significantly when using the German or the American reference population.
• Morbidity – Annual growth velocity
  • The growth rate endpoint describes the annual increase in standing height [cm/year] and is presented solely for supplementary purposes, as it does not provide any information on growth beyond standing height that is relevant to the benefit assessment.
  • The meta-analytic summary of studies 206 and 301 showed a statistically significant increase in growth rate over a 1-year period in favour of vosoritide compared with the control group.
• Morbidity – ratio of upper to lower body segments and body proportion ratio
  • Achondroplasia is characterised by disproportionate short stature. The endpoints ‘ratio of upper to lower body segments’ and ‘body proportion ratios’ are therefore considered to be patient-relevant in the present therapeutic indication.
  • However, the operationalisation of the endpoints ‘ratio of upper to lower body segments’ and ‘body proportion ratios’ presented in the dossier does not allow for an assessment of a patient-relevant change in disproportion, as only the change compared with baseline was analysed. No comparison of body proportions against a suitable healthy reference population was provided.
  • After 52 weeks of treatment, the meta-analysis of studies 206 and 301 shows no statistically significant differences between the treatment groups.
• Morbidity – Functional Independence (WeeFIM)
  • The WeeFIM is a tool for assessing the functional independence of children aged between 6 months and 7 years with developmental disorders or special care needs, as perceived by parents or carers.
  • In Study 206, no difference was observed between the treatment groups for the endpoint of functional independence.
  • For study 301, only an analysis of the entire study population is available, which also included children and adolescents over the age of 7. As the validity of the instrument has only been proven for children up to the age of 7, the results are not taken into account for the present benefit assessment.
• quality of life
  • Health-related quality of life was assessed in Study 301 using a generic instrument – the Paediatric Quality of Life Inventory (PedsQL) – and a disease-specific instrument – the Quality of Life in Short Stature Youth (QoLISSY). In Study 206, the Infant and Toddler Quality of Life Questionnaire (ITQoL) was used.
  • For health-related quality of life, as assessed using the disease-specific QoLISSY questionnaire and the generic PedsQL instrument in Study 301, no statistically significant differences were observed between the vosoritide + BSC and BSC groups.
  • For the endpoint of health-related quality of life, assessed using the ITQoL in study 206, there were no significant differences overall between the treatment groups.
  • However, for the ‘getting along with others’ subscale, no suitable data are available due to excessive differences in the number of participants analysed between the treatment arms, and regarding ‘change in health’, there are uncertainties as to whether the results for this ITQoL subscale were appropriately transformed.
• Side effects
  • In Study 206, no events occurred for the endpoints ‘severe adverse events’ and ‘discontinuation due to adverse events’. For ‘severe adverse events’ and ‘discontinuation due to adverse events’, Study 301 shows no significant differences between the treatment groups.
  • For the endpoint ‘serious AEs’ (SUEs) and the specific AE ‘injection site reactions’, the meta-analysis of studies 206 and 301 showed no significant difference between the treatment groups.
• Overall review
  • In the overall review, an additional benefit of vosoritide is identified for patients with achondroplasia whose epiphyses have not yet closed, based on the advantage observed for the endpoint ‘body height (z-score)’. However, the extent of the additional benefit cannot be quantified, as it cannot be conclusively assessed how the improvement in height affects the complications associated with achondroplasia and the functional impairment experienced by patients. Furthermore, there is a lack of long-term follow-up data extending to the closure of the epiphyseal plates to assess the final height achieved with vosoritide treatment.
  • Furthermore, there are uncertainties as to how, or indeed whether, vosoritide treatment affects the disproportionate body proportions resulting from achondroplasia, as no suitable data are available for comparison with a healthy reference population.

Courtesy translation only, please refer to the German original.