Elosulfase alfa (1) – Vimizim®

• Clinical trials
  • The assessment of the extent of the additional benefit of elosulfase alfa is based on the MOR-004 trial. The randomised, placebo-controlled, double-blind MOR-004 trial investigated patients with mucopolysaccharidosis type IVA aged five years and older, with a baseline walking distance of between 30 and 325 metres, over a treatment period of 24 weeks.

Treatment of a rare disease (Morquio A disease, MPS IVA) in accordance with Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan drugs

• There is a minor additional benefit for patients of all age groups with mucopolysaccharidosis type IVA (Morquio A syndrome, MPS IVA).
• The G-BA classifies the extent of the additional benefit of elosulfase alfa as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in treating it. In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a reduction in non-serious symptoms of the disease (morbidity endpoint) is achieved.
• 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).
  • The extent of improvement in physical capacity achieved for the ‘change in walking distance in the 6MWT’ endpoint is considered to be low due to the unclear clinical relevance of the results for this endpoint, The wide variation in baseline values and the short study duration in relation to the long-term course and progression of the disease are considered minor.
  • With regard to the endpoints in the morbidity category, there is overall a minor additional benefit in terms of the change in walking distance in the 6MWT.
• Morbidity – Change in the 3-minute step climbing test (3MSCT)
  • In addition to the 6MWT, endurance was assessed in the MOR-004 study using the 3-minute step climbing test (3MSCT).
  • There was no statistically significant improvement in the 3MSCT with elosulfase alfa compared with placebo.
  • 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 – Change in the MPS Health Assessment Questionnaire (MPS HAQ)
  • The MPS HAQ is not considered a suitable tool for assessing quality of life in MPS patients. Furthermore, no validation studies of the tool are available.
  • No statistical significance was observed in the differences in the three total scores: self-care, mobility and assistance from carers.
  • With regard to the MPS HAQ, no conclusions regarding the extent of the additional benefit can be drawn on the basis of the available results.
• Morbidity – Respiratory function
  • Respiratory function was measured using various parameters. In particular, the forced expiratory volume in 1 second (FEV1) and maximum voluntary ventilation (MVV) were addressed in the dossier. No statistically significant changes were observed in MVV and FEV1 up to week 24.
  • With regard to respiratory function, no conclusions can be drawn from the available results as to the extent of the additional benefit.
• Morbidity – Anthropometry
  • In the MOR-004 study, various anthropometric parameters were measured: growth rate, standing height, sitting height and weight.
  • The differences between the elosulfase alfa arm and the placebo arm were not statistically significant up to week 24, neither for the change in normalised z-scores for standing height nor for the change in normalised z-scores for growth rate.
  • With regard to anthropometry, 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
  • In the MOR-004 study, adverse events (AEs) were recorded up to the last visit and up to 30 days after the last visit if they were serious.
  • 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).
  • Infusion-related adverse reactions (IARs) 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 interpretability of the available results regarding side effects is limited due to the short duration of the study; however, they provide an indication that treatment with elosulfase alfa is harmful.
• Overall assessment
  • In the overall assessment, the findings on morbidity, when taken together with the findings on side effects, are evaluated as a moderate—and not merely minor—improvement in treatment-related benefit that has not been achieved previously. Based on these considerations, the information in the dossier, the results of the benefit assessment and the statements received, the G-BA has concluded that the extent of the additional benefit of elosulfase alfa should be classified as minor.

Courtesy translation only, please refer to the German original.