Vestronidase alfa (1) – Mepsevii®

• Clinical trials
  • The UX003-CL301 trial is a randomised, placebo-controlled, blind-start, crossover, parallel-group trial with a 1:1:1:1 allocation ratio across four treatment groups and a study duration of 48 weeks, designed to assess the efficacy and safety of 4.0 mg/kg vestronidase alfa.
  • The UX003-CL203 study is an open-label, single-arm, Phase II study to evaluate the efficacy, safety and tolerability of 4.0 mg/kg vestronidase alfa, administered every two weeks.
  • The UX003-CL201 study is an open-label, single-arm Phase I/II dose-finding study in which vestronidase alfa was administered every two weeks at doses of 1.0 mg/kg, 2.0 mg/kg and 4.0 mg/kg every two weeks to a total of 3 patients with MPS VII.
  • Study UX003-CL202 is an open-label, single-arm extension study of study UX003-CL301 involving MPS VII patients who were either treatment-naïve at the start of the study or had previously been treated with vestronidase alfa.

Patients with mucopolysaccharidosis VII (MPS VII; Sly syndrome) for the treatment of non-neurological symptoms

• Consequently, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, the G-BA has determined that vestronidase alfa offers a non-quantifiable additional benefit for the treatment of non-neurological manifestations of the disease in patients with mucopolysaccharidosis VII (MPS VII; Sly syndrome).
• mortality
  • No deaths occurred.
• Morbidity – concentration of the glycosaminoglycan dermatan sulphate in urine (uGAG-DS)
  • With regard to the concentration of uGAG-DS, a statistically significant difference in uGAG-DS concentration was observed at week 24 in favour of vestronidase alfa compared with the control group (difference in the least squares (LS) mean change [95% CI]: –60.1 [–73.9; –46.3], p < 0.0001).
  • A significant difference was also observed in the percentage change in the intra-individual comparison of the uGAG-DS concentration relative to baseline in the UX003-CL301 studies (LS mean percentage change [95% CI]: -64.8 [-69.7, -60.0] p < 0.0001) and UX003-CL203 (LS mean percentage change [95% CI]: -60.9 [-71.2; -50.6] p < 0.0001).
  • Systemic accumulation of glycosaminoglycans in the lysosomes of cells is responsible for the clinical presentation of mucopolysaccharidosis VII. The urinary concentration of glycosaminoglycans is typically elevated in patients with MPS VII and is used as a clinical laboratory parameter as part of the diagnostic process and for monitoring disease progression. Beyond this, the significance of changes in urinary glycosaminoglycan concentration remains unclear.
• Morbidity – Clinical Global Impression (CGI), Patient Clinical Global Impression (P-CGI)
  • The Clinical Global Impression (CGI) questionnaire is used in clinical trials to obtain a brief, independent assessment of a patient’s overall functional status from the perspective of the treating doctor.
  • In the UX003-CL301 study, general functional ability was also assessed by the patient or their parents, carers or guardians (P-CGI). However, as the CGI was developed for the assessment of functional status by the clinician, it remains unclear to what extent the results are transferable when the questionnaire is completed by the patient or by their parents, carers or guardians.
  • In light of the uncertainties mentioned, these endpoints are presented only as supplementary information.
• Morbidity – Bruininks-Oseretsky Test of Motor Proficiency (BOT-2)
  • The BOT-2 is a measure of gross and fine motor skills in children and adolescents aged 4 to 21 years.
  • In the UX003-CL301 study, four subtests of the BOT-2 were assessed: ‘Fine Motor Accuracy’, ‘Manual Dexterity’, ‘Balance’ and ‘Speed and Dexterity’. There was a statistically significant difference to the detriment of vestronidase alfa compared with placebo for the ‘Fine Motor Accuracy’ subtest, and no significant difference for the ‘Manual Dexterity’ subtest (LS mean difference -0.9 [-1.5; -0.3], p=0.004).
  • For all four subtests, no statistically significant difference was observed following 24 weeks’ treatment with vestronidase alfa compared with baseline.
• Morbidity – Total score on the PedsQL-Fatigue
  • The PedsQL Fatigue is a component of the PedsQL and was used only in study UX003-CL301.
  • No statistically significant difference was observed between the treatment groups.
• quality of life
  • No data were collected for the quality of life endpoint category.
• Side effects
  • In the single-arm study UX003-CL203, AEs were observed in 7 out of 8 patients, whilst 2 patients (25.0 %) each experienced a SAE or an AE of CTCAE grade ≥ 3.
  • Three patients (37.5%) experienced infusion-related reactions (IARs), but these were not classified as SAE or as CTCAE Grade ≥ 3 adverse events.
  • In the controlled study UX003-CL301, numerically more events occurred under vestronidase alfa therapy compared with the control group with regard to the occurrence of CTCAE Grade ≥ 3 AEs or SAE.
  • There were more IARs during treatment with vestronidase alfa than during placebo treatment (vestronidase alfa vs. placebo: 66.7% vs. 22.2%).
  • In neither study were there any AEs that led to death or therapy discontinuation.
  • Antibodies against human β-glucuronidase occurred in the majority of patients receiving vestronidase alfa. The significance of these antibodies remains unclear at this stage.
  • Due to the minor number of patients and the limited duration of follow-up, a definitive assessment of safety is not possible.
• Overall assessment
  • To assess the extent of the additional benefit of vestronidase alfa, data from the uncontrolled clinical studies UX003-CL201, UX003-CL202 and UX003-CL203 were also submitted.
  • The studies provide results on mortality, morbidity and side effects. No data on quality of life are available.
  • For the endpoint category of mortality, no conclusion regarding additional benefit can be drawn from the data presented, as no deaths occurred.
  • For the morbidity endpoint – the concentration of the glycosaminoglycan dermatan sulphate in urine (uGAG-DS) – a statistically significant improvement was observed following treatment with vestronidase alfa compared with the control group and compared with the baseline value after 24 weeks. This laboratory parameter is clinically relevant for the diagnosis and monitoring of the disease; however, the significance of a change in the concentration of glycosaminoglycan in urine beyond this is unclear. For the endpoint category of morbidity, no conclusions regarding the quantification of the additional benefit can be drawn on the basis of the data presented.
  • Given the small number of patients and the short duration of observation, it is not possible to assess the safety profile; consequently, no conclusions regarding the quantification of the additional benefit can be drawn.
  • Consequently, on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, the G-BA determines that there is a non-quantifiable added benefit for vestronidase alfa in the treatment of non-neurological clinical manifestations in patients with mucopolysaccharidosis VII (MPS VII; Sly syndrome), the G-BA concludes that the non-quantifiable additional benefit of vestronidase alfa is not present.

Courtesy translation only, please refer to the German original.