Migalastat (1) – Galafold®

• Clinical trials
  • Study 011 is a double-blind, randomised Phase III trial evaluating the efficacy, safety and pharmacodynamics of migalastat compared with placebo.
  • Study AT1001-012 (012) compares migalastat with a treatment regimen appropriate to the German healthcare context.
  • In the multicentre, open-label, randomised non-inferiority trial 012, migalastat was investigated in terms of efficacy and safety compared with enzyme replacement therapy (ERT).

Adults and adolescents aged 16 years and over with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency) who have a mutation responsive to treatment

• Based on the data from Study 012, in which no advantage of migalastat over ERT could be demonstrated, the G-BA classifies the extent of the additional benefit of migalastat as non-quantifiable, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease, the written submissions and the oral hearing.
• An additional benefit exists in accordance with the statutory requirements, but it is non-quantifiable.
• mortality
  • No deaths occurred in Study 012. Consequently, no conclusion can be drawn regarding the extent of the additional benefit in terms of mortality.
• Morbidity – measured and estimated glomerular filtration rate (GFR)
  • The primary endpoint was the annual change in glomerular filtration rate (mGFR-iohexol; measured as plasma clearance of iohexol) between baseline and 18 months. During the course of the study, the annual change in estimated GFR (calculated using the CKD-EPI formula, corresponding to eGFR-CKD-EPI) from baseline to 18 months was added as a co-primary endpoint.
  • According to the information provided by the pharmaceutical manufacturer in the dossier, it is not clear that the GFR endpoint constitutes a validated surrogate for the preservation of renal function. Furthermore, the pharmaceutical manufacturer has not submitted any studies to establish a clinically meaningful difference (MID) for the patient population in question. The validity of the endpoint therefore remains unclear.
  • There are differing views within the G-BA as to whether renal function, as measured by GFR, constitutes a patient-relevant endpoint that should be included in the benefit assessment of migalastat. As a consequence for the resolution on the benefit assessment, the primary endpoints of the annual change in measured and estimated GFR are presented; however, it is noted that these endpoints do not constitute factors relevant to the resolution regarding the assessment outcome. Given the comparable effects of migalastat and ERT on GFR, the overall conclusion regarding the extent of the additional benefit would remain unchanged even if this endpoint were included.
• Morbidity – change in the left ventricular mass index (LVMi), the globotriaosylsphingosine (plasma Lyso-Gb-3) level and α-galactosidase A activity
  • The above-mentioned endpoints are surrogate parameters. On the basis of the data submitted by the pharmaceutical manufacturer, it is not possible to establish their validity in terms of patient relevance. Furthermore, the Plasma-Lyso-Gb-3 endpoint was only added retrospectively as an exploratory endpoint. The linear correlation presented between plasma Lyso-Gb-3 and the MSSI (Mainz Severity Score Index) score – a tool for quantifying the Fabry phenotype – is insufficient to assess the validity of the surrogate endpoint.
• Morbidity – pain, cardiac and cerebrovascular events
  • To assess the extent of the additional benefit, the measurement of pain experience, as well as the combined cardiac and cerebrovascular endpoint, were taken into account as morbidity endpoints. Both pain experience and the individual components of the composite endpoints, such as heart failure and stroke, are considered to be of direct relevance to patients. As none of the endpoints showed a significant difference between the migalastat and ERT groups, no conclusions can be drawn regarding the extent of the additional benefit.
• health-related quality of life
  • The generic SF-36v2 questionnaire was used to assess quality of life. No significant change was observed between the treatment groups from baseline to month 18.
• Side effects
  • The results presented relate to the safety population (migalastat = 36 patients, ERT = 21 patients), which comprised all patients who had received at least one dose of study medication. The incidence of adverse events (AEs) was comparable between the treatment groups (Migalastat: 94%; ERT: 95%). The percentage of patients with moderate AEs (Migalastat: 20 (56%) vs. ERT: 11 (52%)) and severe AEs (Migalastat: 3 (8%) vs. ERT: 2 (10 %)) was similar between the two treatment groups. Overall, serious AEs occurred in 7 patients in the migalastat group (19 %) and in 7 patients in the ERT group (33 %) during the study.
• Overall assessment
  • In summary, the data on mortality, morbidity, quality of life and adverse events do not allow the additional benefit of migalastat to be quantified. The results for the patient-relevant endpoints in Study 012 show no statistically significant advantages of migalastat over enzyme replacement therapy, which is used in everyday healthcare situations in Germany. A possible advantage arising from the oral formulation of migalastat was not reflected in any endpoint within Study 012, not even in the results for quality of life, and therefore remains unclear.

Courtesy translation only, please refer to the German original.