Eladocagene exuparvovec (1) – Upstaza®

• Clinical trials
  • Study AADC-010: Study AADC-010 is an open-label, single-arm, single-centre, prospective Phase I/IIstudy investigating the safety and efficacy of eladocagene exuparvovec in children aged over 2 years with a confirmed diagnosis of AADC deficiency.
  • Study AADC-011: This is an open-label, single-arm, single-centre, prospective Phase IIb study to assess the safety and efficacy of eladocagene exuparvovec in children aged between 2 and 6 years with a confirmed diagnosis of AADC deficiency.
  • Study AADC-CU/1601: The AADC-CU study is a prospective, single-arm, single-centre study investigating the administration of eladocagene exuparvovec as part of a compassionate use programme.
  • Study AADC-1602: Patients from the AADC-010, AADC-011 and AADC-CU/1601 studies were enrolled in the long-term follow-up study AADC-1602, subject to their informed consent, and were monitored thereafter.

Patients aged 18 months and over with a clinically, molecularly and genetically confirmed diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency with a severe phenotype

• Hint for a non-quantifiable additional benefit, as the scientific evidence does not permit quantification.
• Overall, a hint of a non-quantifiable additional benefit is derived for eladocagene exuparvovec, as the scientific evidence does not permit quantification.
• The strength of the evidence is therefore classified as ‘hint’.
• mortality
  • There were 6 deaths in the long-term follow-up study AADC-1602 as at the data cut-off date of 15 July 2022.
• Morbidity – Peabody Developmental Motor Scales – Second Edition (PDMS-2)
  • The Peabody Developmental Motor Scales – Second Edition (PDMS-2) was used to assess motor skills.
  • The change in the PDMS-2 total score between baseline and month 60 was 115 points for the AADC-1602 long-term follow-up study. These changes suggest that the children demonstrated improved function compared with baseline.
  • The results of the time-to-event analyses for the milestones ‘full head control’ and ‘sitting without support’ show very large effects in favour of eladocagene exuparvovec, which fall within the range of ‘dramatic effects’.
  • No analysis was presented for the next defined milestone (‘standing with support’). The between-group difference in the subsequent milestone ‘walking with support’ did not reach statistical significance.
• Morbidity – Bayley Scales of Infant Development – Third Edition (BSID-III), Language Scale and Cognitive Scale
  • Compared with baseline, a change of 22 points was achieved on the cognitive scale at month 60 for the pooled AADC population.
  • For the expressive communication scale, a change of 6 points was observed between baseline and month 60, and for the receptive communication scale, a change of 8 points was observed at month 60.
  • As information on the possible maximum scores for the scales is lacking, no further conclusions can be drawn regarding an improvement in function beyond the positive direction of the changes.
• Morbidity – Alberta Infant Motor Scale (AIMS)
  • The change in the total AIMS score for the AADC-1602 study was 25 points between baseline and month 36.
  • Given a maximum total score of 58 points and the very low baseline scores in the AADC studies, it can therefore be assumed that the study participants’ motor function had improved by this point compared with baseline.
• Health-related quality of life
  • Health-related quality of life was not assessed.
• Side effects
  • Adverse events were recorded in patients from the AADC-010, AADC-011 and AADC-CU/1601 studies as part of the long-term follow-up study AADC-1602.
  • Adverse events occurred in all patients up to the data cut-off date. Serious adverse events were observed in almost all study participants.
• Overall assessment
  • For eladocagene exuparvovec for the treatment of patients aged 18 months and over with a clinically, molecularly and genetically confirmed diagnosis of aromatic L-amino acid decarboxylase(AADC) deficiency with a severe phenotype, results are available from the single-arm long-term follow-up study AADC-1602 regarding the endpoints of mortality, morbidity and side effects.
  • The indirect comparison presented cannot be taken into account due to the limitations described.
  • Even though the indirect comparison cannot be used for the benefit assessment, the NHDB documents a deterministic natural course of the disease in children with AADC deficiency, in which the vast majority of patients fail to reach motor milestones. Consequently, the dramatic effects demonstrated in the AADC-1602 long-term follow-up study can be taken into account in the milestone analyses for the benefit assessment, and advantages of eladocagene exuparvovec for the endpoints ‘achievement of full head control’ and ‘sitting without support’ compared with the natural course of the disease.
  • As no robust data are available for a comparative assessment, it is not possible to quantify the extent of the additional benefit on the basis of the data presented.
  • Furthermore, due to a lack of data on quality of life and a lack of comparative data on mortality and the safety profile of eladocagene exuparvovec, there are relevant uncertainties that do not allow for an assessment of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.