Fosdenopterin (1) – Nulibry®

• Clinical trials
  • The MCD-501 study is a retrospective data collection from patient records designed to investigate the safety and efficacy of rcPMP in patients with MoCD who were treated with rcPMP as part of a ‘Named-Patient Treatment Plan’.
  • The MCD-201 study is a prospective, single-arm Phase II study investigating the safety and efficacy of fosdenopterin in paediatric patients with MoCD type A who had previously been treated with rcPMP.
  • The MCD-202 study is a prospective, single-arm Phase II/III study investigating the efficacy and safety of fosdenopterin in paediatric patients up to the age of 5 years with MoCD type A.

Patients with molybdenum cofactor deficiency (MoCD) type A

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification.
• Overall, there is a hint of a non-quantifiable additional benefit of fosdenopterin for the treatment of patients with molybdenum cofactor deficiency (MoCD) type A, as the scientific evidence does not permit quantification.
• mortality
  • In the three studies, deaths were recorded as part of the safety monitoring.
  • In the MCD-501 study (patient population relevant to the assessment: N = 4), the median treatment duration for rcPMP was 17.5 days (min; max: 6; 451). There were 2 deaths. The other 2 patients were withdrawn from the study prematurely due to a poor prognosis. It is unclear whether these individuals are still alive.
  • In the MCD-201 study (N = 8), the median duration of treatment with fosdenopterin as of the current data cut-off date of 16 September 2022 was 86.0 months (min; max: 29.3; 94.7). No deaths were recorded.
  • In the MCD-202 study (N = 3), the median duration of treatment with fosdenopterin as of the current data cut-off date of 16 September 2022 was 17.1 months (min; max: 0.3; 72.2). No deaths had been recorded up to that point. One patient was withdrawn from the study 9 days after enrolment at the clinician’s discretion due to a poor neurological prognosis. It is not possible to determine from the data whether this person is still alive, as the follow-up period was too short.
  • On the basis of the single-arm data on mortality, no conclusion can be drawn regarding the extent of the additional benefit of fosdenopterin.
• Morbidity – Food intake
  • In the dossier, the endpoint was presented as a dichotomous variable with the categories ‘oral’ and ‘non-oral’.
  • No corresponding results are available for the MCD-501 study. In the MCD-201 study, 5 patients were able to take their food orally at baseline, whilst 3 patients required non-oral feeding. At month 12, 5 patients were still able to take food orally and 3 required non-oral feeding. At month 48, 4 patients were taking food orally, 3 non-orally, and no data were available for one patient.
  • In the MCD-202 study, at baseline, 2 patients were able to eat orally and one patient required non-oral feeding. At month 12, 2 patients were still able to eat orally, and no results were available for one patient.
• Morbidity – Motor function assessed using the Gross Motor Function Classification System – Expanded and Revised version (GMFCS-E&R)
  • The GMFCS-E&R is a tool for assessing the gross motor functions of children with cerebral palsy based on their self-initiated movement.
  • No results are available for the GMFCS-E&R for the MCD-501 study. The response rate for the MCD-501 study was < 70% at baseline and at subsequent assessment time points.
  • In the MCD-201 study, at baseline, 3 patients were at Level I (no limitations) on the GMFCS-E&R and 3 patients were at Level V (severe limitations); data were missing for 2 patients. At month 48, 3 patients were at Level I and 4 patients were at Level V; no data were available for one patient.
• Morbidity – Height and weight
  • Anthropometric parameters are considered to be patient-relevant morbidity parameters, particularly in children with characteristic, disease-related growth disorders.
  • For the MCD-501 and MCD-202 studies, there are no (MCD-501) or no suitable (MCD-202) analyses available for the growth parameters. In the MCD-201 study, the average z-score for height was -0.51 at baseline and -0.73 at month 48. The average z-score for body weight was 0.06 at baseline and -0.24 at month 48.
• quality of life
  • No results on quality of life are available.
• Side effects
  • No analyses are available for the evaluation-relevant patient population of the MCD-501 study (N = 4).
  • In the MCD-201 study, all adverse events (AEs) that occurred from the first dose of fosdenopterin up to 7 days after discontinuation of the study were recorded; whilst in the MCD-202 study, all AEs that occurred from the first dose of fosdenopterin up to 28 days after the last administration of the study medication were recorded.
  • The median duration of treatment in the MCD-201 study was 86 months (min; max: 29.3; 94.7). By the data cut-off date of 16 September 2022, AEs had occurred in all 8 patients. Of these, 5 experienced a severe AE and 7 experienced a serious adverse event (SAE). There were no therapy discontinuations due to adverse events.
  • The median duration of treatment in the MCD-202 study was 17.1 months (min; max: 0.3; 72.2). By the current data cut-off date of 16 September 2022, all 3 patients had experienced severe AEs and SAEs. There were no therapy discontinuations due to AEs.
  • Based on the single-arm safety data, no conclusion can be drawn regarding the extent of the additional benefit of fosdenopterin.
• Overall assessment
  • The benefit assessment of fosdenopterin for the treatment of patients with type A molybdenum cofactor deficiency (MoCD) is based on analyses of the single-arm studies MCD-501, -201 and 202. Results are available on mortality, morbidity and side effects. Due to the single-arm study design, no comparative conclusions can be drawn.
  • In summary, it is not possible to quantify the extent of the additional benefit of fosdenopterin on the basis of the data provided. In its overall assessment of the available results, the G-BA classifies the extent of the additional benefit of fosdenopterin for the treatment of patients with molybdenum cofactor deficiency (MoCD) type A as non-quantifiable, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.