Voretigen Neparvovec (1) – Luxturna®

• Clinical trials
  • The benefit assessment is based on the randomised, controlled, multicentre, open-label Phase III registration trial 301, which investigated voretigene neparvovec in comparison with a ‘wait-and-see’ approach.
  • Following Study 301, patients could be followed up for up to 15 years in the single-arm extension study 302.

Adults and paediatric patients with vision loss due to an inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations, who have sufficient viable retinal cells

• For adult and paediatric patients with vision loss due to an inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations, and who have a sufficient number of viable retinal cells, there is a hint of a considerable additional benefit.
• Overall, for the treatment of adult and paediatric patients with vision loss due to an inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations, and who have a sufficient number of viable retinal cells, there is a hint of considerable additional benefit from Voretigen Neparvovec compared with a watch-and-wait approach; the resolution is limited until 31 December 2021 pending the results of ongoing studies.
• mortality
  • In Study 301, mortality was recorded as a safety endpoint as part of the adverse event monitoring.
  • No deaths were reported during the study.
• Morbidity – Functional vision assessed using the Multi-Luminance Mobility Test (MLMT)
  • The Multi-Luminance Mobility Test (MLMT) is used to measure changes in functional vision, in particular the ability to orientate oneself and move independently through an obstacle course under varying light conditions.
  • In the MLMT, a statistically significant advantage in favour of early treatment with Neparvovec compared with a ‘watch-and-wait’ approach was observed at Year 1 (difference in observed mean changes: 1.6 [95% CI 0.7; 2.4]; p < 0.001).
  • Among patients receiving Voretigen Neparvovec, no patient performed worse on the test at year 1 than at baseline.
  • Notwithstanding the methodological limitations mentioned, there is a statistically significant, clinically relevant advantage for Voretigen Neparvovec compared with a watch-and-wait approach for the MLMT endpoint.
  • In Study 302, changes from baseline were reported for the MLMT endpoint.
  • The purely descriptive, non-comparative data on change from baseline for the original intervention and control groups up to Visit 3 and Visit Year 2, respectively, are of a similar magnitude to those in Study 301.
• Morbidity – light sensitivity assessed using the full-field light sensitivity threshold test (FST)
  • To measure full-field sensitivity, the full-field light sensitivity threshold test (FST) was used as part of Study 301.
  • Light sensitivity is considered to be clinically relevant.
  • For the FST, statistically significant effects in favour of Voretigen Neparvovec compared with a ‘wait-and-see’ approach were observed for white, blue and red light.
  • Furthermore, the post-hoc SMD calculated according to Hedges’ g, measured exclusively for the test using white light, lies entirely outside the irrelevance range of -0.2 to 0.2.
  • The potential for bias is considered high due to the open-label study design and the lack of blinding in the evaluation of the FST.
• Morbidity – Visual acuity using the ETDRS/HOTV eye chart
  • Visual acuity was assessed during the study using either the ETDRS eye chart or the HOTV eye chart, depending on the child’s cognitive abilities.
  • Visual acuity is a patient-relevant endpoint.
  • The results of the a priori defined analyses, in which both visual acuity charts (ETDRS and HOTV charts) were evaluated together, were not statistically significant between the treatment groups at Year 1 and remained consistent throughout the entire study period up to Year 1 after baseline.
  • Overall, an improvement of ≥10 letters when using the ETDRS chart was observed in 6 participants in the intervention group (n=18 in whom the ETDRS chart was used), whilst this was not the case for any participant in the control group; there is no statistically significant difference between the treatment groups.
• quality of life
  • In Study 301, health-related quality of life was assessed using the Visual Function Questionnaire.
  • Owing to the major differences, it does not appear possible to transfer either the psychometric properties or the MID from the NEI VFQ-25 to the Visual Function Questionnaire newly developed here.
  • The results cannot be taken into account in the context of the benefit assessment.
  • No suitable data on quality of life are available for the benefit assessment.
• Side effects
  • SAE and severe AEs occurred in Study 301 only in the intervention group, and the proportion of participants with AEs ≥ Grade 3 was higher in the intervention group than in the control group.
  • Neither the number of patients with AEs nor the number of patients with severe AEs, SAEs or therapy discontinuations due to AEs differed statistically significantly in Study 301 between treatment with Voretigen Neparvovec and a ‘watch-and-wait’ approach.
  • In the endpoint category of side effects, there are currently no statistically significant differences between the comparison arms.
  • Due to the minor number of cases, the reliability of the results is limited.
  • Furthermore, due to the open-label study design, the potential for bias regarding the safety endpoints is considered high.
• Overall assessment
  • In the morbidity category, statistically significant, clinically relevant advantages in favour of Voretigen Neparvovec were observed for the patient-relevant endpoints MLMT (functional vision/orientation), FST (light sensitivity) and perimetry (visual field); no statistically significant change in visual acuity could be demonstrated for Voretigen Neparvovec compared with a ‘wait-and-see’ approach.
  • In summary, the existing statistically significant and clinically relevant advantages of Voretigen Neparvovec compared with a ‘watch-and-wait’ approach, in relation to the endpoints MLMT, FST and perimetry, are, on balance, classified as considerable in extent.
  • The analyses of the extension study 302 (as at 5 May 2017) suggest that the positive effects on MLMT achieved with Voretigen Neparvovec in Study 301 are maintained at a similar magnitude even 2 to 3 years after administration.
  • Nor is it possible at this stage to make statements with sufficient certainty regarding the sustainability of the changes achieved with Voretigen Neparvovec.

Courtesy translation only, please refer to the German original.