Vosoritid (1) – Voxzogo®

• Clinical trials
  • The double-blind, controlled, multicentre Phase 3 trial 301 investigated the administration of either vosoritid or placebo in children and adolescents aged between 5 and 17 years who, following genetic testing, were found to have achondroplasia (ACH).
  • The uncontrolled Phase II dose-escalation study BMN 111-202 and its extension study -205 investigated the administration of vosoritide in children and adolescents aged 5 to < 15 years.

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

• Hint of a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Against this background, the G-BA concludes that there is a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• mortality
  • No deaths occurred during Study 301.
• Morbidity – Height (z-score)
  • Height (z-score) is classified as clinically relevant in this therapeutic indication.
  • After 52 weeks of treatment, the standing height (z-score) of children and adolescents in the vosoritide arm increased; in the control arm, a decrease in the z-score was observed.
  • The difference in results between the groups when using the German or American reference populations is comparable: in each case, the differences are statistically significant in favour of vosoritid.
  • However, analyses of clinical relevance are only available for the American reference population. These show that the observed difference is also clinically relevant.
  • In the morbidity endpoint category, Study 301 shows a statistically significant advantage for the endpoint ‘height (z-score)’ in favour of Vosoritid.
• Morbidity – Growth velocity
  • The primary endpoint ‘growth velocity’ describes the annual increase in standing height [cm/year] and is presented here solely for supplementary purposes, as it does not provide any information on growth beyond standing height that is relevant to the benefit assessment.
  • A statistically significant increase in growth velocity over a 1-year period was observed in favour of vosoritid compared with the control group.
• Morbidity – Ratio of upper to lower body segments and body proportions
  • The endpoints ‘ratio of upper to lower body segments’ and ‘body proportion ratio’ are not considered, in themselves, to be patient-relevant.
  • After 52 weeks of treatment, no statistically significant differences were observed between the treatment groups.
• Morbidity – Child Behaviour Checklist (CBCL)
  • In Study 301, only a few baseline values for the CBCL are available. The results cannot therefore be taken into account.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The results of the self-reported version of the PedsQL (children aged 8 years and over) in Study 301 show no statistically significant differences between the treatment groups up to week 52.
  • The pharmaceutical manufacturer has not provided separate analyses for the parent-reported version for children aged 5 to 7 years.
• Quality of life – Quality of Life in Short Stature Youth Questionnaire (QoLISSY)
  • In Study 301, the results of the self-reported QoLISSY quality of life questionnaire (for children aged 8 years and over) up to week 52 show no statistically significant differences between the treatment groups.
  • The pharmaceutical manufacturer has not provided separate analyses for the parent-reported version for children aged 5 to 7 years.
• Quality of Life – Functional Independence Measure for Children (WeeFIM)
  • As the dossier does not contain a separate analysis for the 5 to 7-year-old age group and the validity for older children and adolescents is not proven, the WeeFIM is not taken into account for the benefit assessment.
• Side effects
  • In Study 301, there were only a few serious or severe adverse events (AEs) or therapy discontinuations due to AEs. The results of Study 301 do not show any statistically significant differences between the treatment groups.
  • With regard to side effects, Study 301 does show a disadvantage in detail for the AE ‘hypersensitivity’; however, overall there are no relevant differences between the treatment groups.
• Side effects – AEs of particular interest
  • With regard to the endpoint ‘hypersensitivity’, there were statistically significantly more events in the vosoritide arm. For all other AEs of particular interest, the results did not differ statistically significantly between the treatment groups; either no events occurred or no data were available.
• Overall assessment
  • The benefit assessment is based on the results of the double-blind, controlled, multicentre Study 301, which investigated the administration of vosoritid versus placebo in children and adolescents with achondroplasia aged between 5 and 17 years over 52 weeks.
  • In Study 301, a statistically significant advantage was observed exclusively for the endpoint ‘height (z-score)’ in favour of vosoritid. However, there was no improvement with regard to the additional endpoints relating to the disproportion of body proportions.
  • No other patient-relevant endpoints in the morbidity category (e.g. functional limitations and mobility) were assessed in Study 301. Overall, this makes it difficult to interpret the positive result regarding increased height (z-score).
  • All things considered, it is not possible to assess the extent of the additional benefit of vosoritide solely on the basis of the positive effects on height. Furthermore, it is uncertain whether the extent of the positive effects demonstrated by vosoritid in terms of growth will be maintained over a longer period.

Courtesy translation only, please refer to the German original.