Elosulfase alfa (2) – Vimizim®

• Clinical trials
  • In the randomised, placebo-controlled, double-blind MOR-004 trial, patients with mucopolysaccharidosis type IVA aged five years and older, with a baseline walking distance of between 30 and 325 metres, were studied over a treatment period of 24 weeks.
  • In the uncontrolled extension study MOR-005, patients who had successfully completed the MOR-004 study were followed up for up to a maximum of 240 weeks.
  • The MOR-001 study is a longitudinal study designed to investigate the natural course of MPS IVA.

a) Patients of all age groups with mucopolysaccharidosis type IVA (Morquio A syndrome, MPS IVA)

• There is a minor additional benefit for patients of all age groups with mucopolysaccharidosis type IVA (Morquio A syndrome, MPS IVA).
• The minor extent of improvement in physical exercise capacity was attributed to the unclear clinical relevance of the results, the wide variation in baseline values and the short study duration in relation to the long-term course and progression of the disease.
• Based on these considerations, the information in the dossier, the results of the benefit assessment and the expert opinions, the G-BA has concluded that the extent of the additional benefit of elosulfase alfa should be classified as minor.
• mortality
  • No data on mortality are available; therefore, no conclusion can be drawn regarding the extent of the additional benefit in terms of mortality.
• Morbidity – Change in walking distance in the six-minute walk test (6MWT)
  • The primary endpoint of the MOR-004 study was the change in walking distance from baseline to week 24, as determined by the six-minute walk test.
  • The adjusted treatment difference between the elosulfase alfa and placebo arms was approximately 22.5 m and was statistically significant in favour of elosulfase alfa (p = 0.0174).
  • Even after 72 and 120 weeks, respectively, treatment with elosulfase alfa showed a mean improvement in walking distance of 32.3 and 32.7 m, respectively, compared with baseline, whereas the subpopulation of the historical, natural control cohort (MOR-001) showed a deterioration in walking distance of –8.9 m and –16.2 m, respectively, after one and two years of follow-up. The difference is statistically significant in favour of elosulfase alfa (p = 0.0049 and p = 0.0029).
  • However, the interpretability of the results is significantly limited due to the aforementioned uncertainties in the historical control.
• Morbidity – Change in the three-minute step climbing test (3MSCT)
  • There was no statistically significant improvement in the 3MSCT with elosulfase alfa compared with placebo.
  • As the evidence base, operationalisation and conduct of this test have not changed in the updated benefit assessment, the endpoint is not classified as relevant for assessment.
  • With regard to the change in the 3MSCT, no conclusion can be drawn from the available results as to the extent of the additional benefit.
• Morbidity – MPS Health Assessment Questionnaire (MPS HAQ)
  • No statistical significance was observed in the differences in the three overall scores: self-care, mobility and assistance from carers.
  • It therefore remains unclear to what extent the MPS HAQ is a suitable and valid tool for assessing morbidity in MPS IVA.
  • With regard to the MPS HAQ, no conclusions can be drawn from the available results regarding the extent of the additional benefit.
• Morbidity – wheelchair use and use of walking aids
  • Overall, compared with baseline values, there was a numerical advantage in terms of an improvement (no/minor reduction in wheelchair use) with elosulfase alfa treatment compared with the natural control group (18.5% vs. 5.7%).
  • However, the difference was not statistically significant.
  • With regard to the use of walking aids, a significant difference in favour of treatment with elosulfase alfa was demonstrated after 2 years (p=0.037).
  • The interpretability of the result is therefore severely limited.
  • With regard to wheelchair use and the use of walking aids, no conclusion can be drawn from the available results regarding the extent of the additional benefit due to the uncertainties mentioned above.
• Morbidity – Respiratory function
  • Overall, at both time points in the comparison between the group treated with elosulfase alfa and the subpopulation of the historical control cohort (MOR-001), no statistically significant differences were observed in the change in FEV1 values from baseline.
  • With regard to respiratory function, no conclusions can be drawn from the available results regarding the extent of the additional benefit.
• quality of life
  • No data on quality of life are available; therefore, no conclusion can be drawn regarding the extent of the additional benefit in terms of quality of life.
• Side effects
  • Serious AEs occurred in 9 patients (15.5 %) in the elosulfase alfa arm compared with 2 patients (3.4 %) in the placebo arm. This difference is statistically significant (RR: 4.58; 95% CI: [1.03; 20.29]; p = 0.0452).
  • Adverse events (AEs) that led to the interruption or discontinuation of the infusion and required medical intervention occurred in 13 patients (22.4%) in the elosulfase alfa arm, compared with no patients in the placebo arm. This difference is statistically significant (RR: 26.45; 95% CI: [1.61; 435.50]; p = 0.0219).
  • The comparative results regarding the side effects of treatment with elosulfase alfa versus placebo treatment are of limited interpretative value due to the short duration of the study; however, they indicate that treatment with elosulfase alfa is harmful.
  • No comparative data are available in the ‘side effects’ category for the benefit assessment.
• Overall assessment
  • With regard to the endpoints in the morbidity category, treatment with elosulfase alfa compared with placebo showed an improvement in physical capacity in the 6-minute walk test after 24 weeks and an indication that, even after 120weeks’ treatment with elosulfase alfa, an improvement in walking distance is achieved compared with the natural course of the disease.
  • However, the results of the historical control are subject to the uncertainties mentioned, which are due, amongst other things, to selective patient selection from the MOR-001 population used for the historical control and a lack of information on operationalisation.
  • Furthermore, no clear advantages of treatment with elosulfase alfa could be demonstrated with regard to other endpoints.
  • The extent of improvement in physical capacity achieved at the endpoint ‘change in walking distance in the 6MWT’ is assessed as low due to the still unclear clinical relevance and limited interpretability of the results, the minor uncertainty in the data from the historical control studies and the wide variation in baseline values.

Courtesy translation only, please refer to the German original.