Asfotase alfa (2) – Strensiq®

• Clinical trials
  • The ENB-002-08 study is a single-arm, multicentre, international, open-label Phase II study investigating the safety, tolerability and pharmacology of asfotase alfa, with a treatment duration of 24 weeks.
  • The ENB-010-10 study is a single-arm, multicentre, international, open-label Phase II study investigating the safety, efficacy and pharmacokinetics of asfotase alfa in infants and children with HPP aged five years or younger.
  • The ENB-011-10 study is a global retrospective epidemiological study based on data from medical records.
  • Study ENB-009-10 is a randomised, controlled, open-label study that enrolled 19 patients with hypophosphatasia aged between 13 and 65 years, in whom the disease manifested in infancy, childhood or adulthood.
  • The ENB-006-09 and ENB-008-10 studies are an open-label, randomised dose-finding study over 24 weeks and its extension study over at least 72 months.

a) Infants (≤ 5 years) with perinatal or infantile hypophosphatasia (onset of the disease by the 6th month of life)

• For young children with perinatal or infantile hypophosphatasia, asfotase alfa offers a non-quantifiable additional benefit compared with best supportive care.
• Overall, for patient population a), there is a hint of a non-quantifiable additional benefit of asfotase alfa compared with best supportive care.
• Overall, therefore, the certainty of the evidence is classified as a hint.
• mortality
  • The pooled analysis of ENB-002-08/003-08 and ENB-010-10, compared with the historical control group receiving supportive care, shows a statistically significant, marked survival benefit for infants treated with asfotase (mortality of 11.5%) compared with the historical control (mortality of 72.9%).
  • Overall, despite the methodological shortcomings described above, the extent of the effect suggests an advantage in overall survival and thus an additional benefit.
  • However, due to the high potential for bias, the extent of the additional benefit cannot be estimated.
• Morbidity – respiratory function
  • Due to the methodological limitations mentioned above, the analyses of respiratory function are not usable and cannot be taken into account for the assessment of additional benefit.
• Health-related quality of life
  • Health-related quality of life was not investigated in the studies presented.
• Side effects
  • No side effects were recorded in the historical control group (ENB-011-10). Consequently, no comparative analyses are available for this endpoint category for the purpose of benefit assessment.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of asfotase alfa compared with the appropriate comparator therapy, best supportive care, for the treatment of young children with perinatal or infantile hypophosphatasia, data are available for the endpoint of overall survival from two pooled single-arm studies (ENB-002-08/003-08 and ENB-010-10) and a historical control (ENB-011-10).
  • Given the severity and rarity of the condition, as well as the paediatric study population, the data were used for the benefit assessment despite the high potential for bias inherent in a historical control and shortcomings arising from differences in data collection methods.
  • With regard to morbidity, the pharmaceutical manufacturer submitted analyses of respiratory function; however, due to differences in data collection and operationalisation between the historical control and the asfotase studies, these cannot be used for the benefit assessment.
  • No comparative data are available on health-related quality of life or side effects.
  • For overall survival, a clear advantage of asfotase alfa over best standard care (BSC) was observed. However, when evaluating these results, the high potential for bias arising from the historical control and differences in data collection must be taken into account.
  • The observed difference for this endpoint is so large that it cannot be explained solely by the influence of confounders. There is additional benefit; however, the magnitude of the difference between the treatment groups cannot be determined on the basis of the data provided.
  • The additional benefit of asfotase alfa compared with BSC is therefore classified as non-quantifiable, as the scientific evidence does not permit this.

b) Young children (≤ 5 years) with juvenile hypophosphatasia (onset of the disease from 6 months of age)

• For young children with juvenile hypophosphatasia, the additional benefit of asfotase alfa compared with the appropriate comparator therapy is not proven.
• The pharmaceutical manufacturer has not submitted any studies for this patient group.
• Overall, therefore, an additional benefit is not proven for patient population b).

c) Children (> 5 years), adolescents and adults with perinatal, infantile or juvenile hypophosphatasia (onset of the condition up to 18 years of age)

• For children, adolescents and adults with perinatal, infantile or juvenile hypophosphatasia, the additional benefit of asfotase alfa compared with the appropriate comparator therapy is not proven.
• No data suitable for benefit assessment were submitted for children over 5 years of age, adolescents and adults with perinatal, infantile or juvenile hypophosphatasia.
• Overall, therefore, an additional benefit is not proven for patient population c).
• Overall assessment / Conclusion
  • The pharmaceutical manufacturer presents data for children over 5 years of age, adolescents and adults with perinatal, infantile or juvenile hypophosphatasia from a randomised, controlled trial (ENB-009-10), an observational longitudinal study (EmPATHY) and a patient registry (ALX-HPP-501).
  • Furthermore, data from a randomised dose-finding study (ENB-006-09) and its extension study (ENB-008-10) were compared with a historical control based on medical records (ALX-HPP-502s).
  • The studies presented could not be used for the benefit assessment, as either the dosing did not comply with the authorised protocol (ENB-009-10) or no comparison with the appropriate comparator therapy, best supportive care (BSC), was possible (EmPATHY).
  • For the historical control presented, only radiological endpoints were available, and no patient-relevant endpoints.
  • The analyses of patient-relevant endpoints from the ENB-006-09/ENB-008-10 study (BOT-2, 6-minute walk test and anthropometric parameters) in relation to reference values from the healthy population were not suitable for the present benefit assessment due to the high uncertainty in the results of before-and-after comparisons.
  • Nor are the registry data suitable for assessing the additional benefit. In addition to shortcomings in data collection and analysis, the differences in symptom burden between patients treated with asfotase alfa and those treated purely symptomatically, as well as the incomplete data collection, are regarded as particularly critical.
  • Taken together, there are no suitable data available to assess the additional benefit compared with the appropriate comparator therapy. The additional benefit is therefore not proven.

Courtesy translation only, please refer to the German original.