Asfotase alfa (1) – Strensiq®

• Clinical trials
  • With the exception of one RCT (study ENB-009-10), the studies on which the benefit assessment is based are uncontrolled intervention studies, the results of which were in some cases compared with data from two historical control groups.
  • Study ENB-002-08 was an open-label, non-randomised and uncontrolled Phase II study investigating the safety, tolerability and pharmacokinetics of asfotase alfa.
  • The ENB-010-10 study is an 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-006-09 study was an open-label, dose-randomised study (6 mg/kg/week vs. 9 mg/kg/week) which enrolled 13 patients.
  • The open-label, single-arm ENB-008-10 study is the follow-up to ENB-006-09 and included 12 patients who had completed the ENB-006-09 study.
  • ENB-009-10 was a randomised, controlled, open-label study for the first 24 weeks, followed by a single-arm study design.

a) Patients aged ≤ 5 years

• For patients in whom hypophosphatasia developed during childhood, there is a non-quantifiable additional benefit.
• Due to the methodological limitations of the study and the historical control, as well as the overall limited evidence base, the G-BA classifies the extent of the additional benefit of asfotase alfa, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition is non-quantifiable.
• mortality
  • For patients treated with asfotase alfa, overall survival was significantly improved compared with the historical control group. Whilst 4 out of 37 (10.8%) patients in the asfotase group died, the figure in the historical control group was 35 out of 48 patients (72.9%) (p<0.0001).
  • Despite the uncertainties associated with a historical control, it is assumed that the natural course of hypophosphatasia is associated with a high mortality rate due to the lack of adequate treatment options to date.
  • When taking into account age at diagnosis and at study entry, as well as the year of diagnosis, the difference in survival between the historical control group and the asfotase alfa group was no longer statistically significant (HR 2.49 [95% CI 0.48; 12.83]; p=0.2765).
  • Due to the differing mortality rates in the ENB-002-08/ENB-003-08 and ENB-010-10 and the historical control (10.8% vs. 72.9%), an overall additional benefit of asfotase alfa can be inferred.
  • In view of the uncertainties already discussed regarding the availability of a historical control, the results do not permit a quantitative assessment of the positive effects in terms of the extent of the additional benefit.
• Morbidity – Survival without invasive ventilation (IVFS) and ventilator-free survival
  • Whilst 4 out of 25 patients (16.0%) in the treated patient group experienced an event, this figure was 36 out of 48 patients (75.0%) in the historical control group (p<0.0001).
  • The difference in the proportion of patients experiencing events between the treatment groups (16% vs. 75%) suggests an additional benefit of asfotase alfa.
  • As the IVFS endpoint is a composite endpoint (mortality and morbidity), the limitations arising from the historical control with regard to overall survival must also be taken into account here.
• Morbidity – Mechanical function, gait, mobility
  • Improvements in motor function are considered to be of relevance to patients; however, this is an open-label, uncontrolled study design with a before-and-after comparison.
  • Although all the data presented show improvements on the scales assessed, no valid conclusions can be drawn from the results regarding the extent of the additional benefit.
  • For all the instruments used, the relevance of any change is unclear, as no information is available on clinically relevant differences in HPP patients.
• Morbidity – Anthropometric parameters
  • In both the ENB-010-10 study and the ENB-002-08/ENB-003-08 study, an upward trend in the mean height and weight Z-scores was observed over the course of the study.
  • Due to the limitations regarding the reliability of before-and-after comparisons, particularly in conjunction with an open-label, uncontrolled study design, the extent of the additional benefit for this endpoint is non-quantifiable.
• Morbidity – Bone mineralisation
  • The evidence submitted by the pharmaceutical manufacturer is not sufficient to demonstrate an adequate correlation or validation of the surrogate endpoints (bone mineralisation) with patient-relevant endpoints (such as pain, respiratory function, mobility, walking ability and mortality).
  • Against this background, the RGI-C and RSS, as purely radiological endpoints, are classified as not patient-relevant.
• Side effects – Adverse events / serious adverse events / therapy discontinuation due to adverse events / adverse events of particular interest
  • All patients in the studies experienced at least one adverse event during treatment with asfotase alfa. Approximately 63% of patients experienced a serious adverse event.
  • The most common events included injection site reactions (58.6%).
  • The interpretability of the available results regarding side effects is limited due to a lack of control data and the minor patient population.
  • However, no valid conclusions can be drawn regarding the extent of the additional benefit in relation to the AEs of particular interest discussed, based on the available data and, in particular, given the limited safety data and the described limitations of the study.
• Overall assessment
  • In the present case scenario and indication, the results on overall mortality and survival without invasive ventilation / ventilator-free survival—which demonstrate an additional benefit for asfotase alfa—are particularly relevant to decision-making.
  • Assuming that the natural course of hypophosphatasia is associated with a high mortality rate and serious symptoms – partly due to the lack of adequate treatment options to date – it is considered appropriate, despite the uncertainties associated with a historical control and single-arm studies, to use the study results on overall mortality and survival without invasive ventilation / ventilator-free survival to determine the additional benefit.

b) Patients aged > 5 years

• For patients in whom hypophosphatasia developed during childhood or adolescence, there is a non-quantifiable additional benefit.
• Due to the methodological limitations of the studies and the overall limited evidence base, the G-BA classifies the extent of the additional benefit of asfotase alfa, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition, as non-quantifiable, because the scientific evidence does not permit this.
• mortality
  • The endpoint of mortality was not explicitly assessed in the ENB-006-09/ENB-008-10 study; therefore, no conclusion can be drawn regarding the extent of the additional benefit in terms of mortality.
  • The endpoint of mortality was not explicitly assessed in the ENB-009-10 study.
• Morbidity – bone mineralisation
  • With regard to the relevance of this endpoint, reference is made to the comments on the age group < 5 years.
  • A link between RGI-C and patient-relevant endpoints has not been sufficiently demonstrated (e.g. no validation with external study data, no correlation at the effect level).
  • The validity of the RGI-C as a surrogate for morbidity is therefore not proven.
• Morbidity – Motor function (6-minute walk tests)
  • In the combined AA group (N=13), there was a significant median improvement in walking distance compared with baseline of 124.00 metres (p<0.0001) at week 24 and of 221.00 metres (p<0.0001) by week 240.
  • No information is available regarding the validity and the minimum clinically relevant difference in the HPP population (taking into account the different age groups).
  • After 24 weeks of treatment with asfotase alfa, 12 out of 13 enrolled patients showed a mean improvement of 8.8 percentage points in the proportion of the predicted 6-minute walking distance achieved, whilst in the untreated control group, 3 out of 6 patients were unable to walk for 6 minutes due to physical limitations.
  • The comparison between the AA group and the untreated control group at week 24 showed no statistically significant difference.
• Morbidity – Motor function (BOT-2)
  • At the start of the ENB-006 study, the standardised score for the median walking speed and agility was 3.00 points (N=13) and improved significantly by 8.00 points from baseline by week 240 (p<0.0001).
  • At the start of the study, the total score for the median running speed and agility score for the combined AA group (N=13) was 6.0 points and improved by 4.0 points compared with baseline by week 240 (p<0.0001) and by 3.5 points by week 192.
• Morbidity – Pain/Disability (POSNA PODCI)
  • The PODCI was used throughout the study to assess the patients’ functional status. At the start of the study, the median standardised score for the asfotase alfa group (N=13) was 27.0 and improved by a major 22.5-point increase compared with baseline by week 240.
  • Particularly due to the minor number of cases, the absence of a control group and the lack of data to assess clinical relevance, no conclusions can be drawn regarding the extent of the additional benefit for this endpoint.
• Morbidity – Anthropometric parameters
  • At the start of the study, the median Z-score for height in the combined asfotase alfa group was –1.26 and the Z-score for weight was –1.21. With regard to height, a significant improvement in the median Z-score of 0.65 (p=0.0017) was observed at week 240 compared with baseline.
  • The results compared with baseline may be considered invalid. In patients who survive the first few years of the disease, a spontaneous improvement in symptoms and disease progression often occurs upon entering adolescence.
  • The data, when compared with the historical control group, show no statistically significant differences.
• Health-related quality of life
  • No data on health-related quality of life are available for the ENB-006-09/ENB-008-10 study; therefore, no conclusions can be drawn regarding the extent of the additional benefit in terms of health-related quality of life.
  • No data on health-related quality of life are available for the ENB-009-10 study; therefore, no conclusion can be drawn regarding the extent of the additional benefit in terms of health-related quality of life.
• Side effects – Adverse events/serious adverse events/therapy discontinuation due to adverse events/adverse events of particular interest
  • The positive effects of asfotase alfa are counterbalanced in the EPAR by adverse events (AEs) discussed as being of particular interest (injection site reactions, lipohypertrophy, craniosynostosis, ectopic calcification).
  • Among the 13 study participants, injection-site reactions occurred in 12 (92.3%), lipohypertrophy in 8 (61.5%), craniosynostosis in 7 (53.8%) and ectopic calcification in 6 (46.2%).
  • Of the 19 study participants, 18 (94.7%) experienced reactions at the injection site, 4 (21.1%) developed lipohypertrophy and 9 (47.4%) developed ectopic calcification.
  • The interpretability of the present findings regarding side effects is limited due to a lack of control data and the minor patient population.
  • However, no valid conclusions can be drawn regarding the extent of the additional benefit with respect to the AEs of particular interest under discussion, based on the available data and, in particular, given the limited safety data and the described limitations of the study.
• Overall view
  • In the age group > 5 years, the results of the studies for patients aged 12–66 years (study ENB-009-10) and for patients in the 5–12-year-old age group (ENB-006-09/ENB-008-10).
  • In the age group of patients aged 13 to 66 years, no statistically significant difference compared with an untreated control group was demonstrated for any patient-relevant endpoint (motor function, pain and disability) following 24 weeks of treatment with asfotase alfa.
  • A (controlled) observation period of 24 weeks is considered too short to demonstrate the effects of AA, such as functional improvement mediated by improved bone structure.

Courtesy translation only, please refer to the German original.