Voretigen Neparvovec (2) – Luxturna®

• Clinical trials
  • The benefit assessment is based on the randomised, controlled, multicentre, open-label Phase III registration trial 301, which investigated Voretigen Neparvovec compared with a ‘watch-and-wait’ approach.

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

• mortality
  • In studies 301 and LTFU, mortality was recorded as a safety endpoint as part of the adverse event monitoring. No deaths were reported during either 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. Among patients receiving early treatment with neparvovec, none performed worse on the test at Year 1 than at baseline.
  • For the MLMT, this result lies entirely outside the irrelevance range of -0.2 to 0.2, meaning that a statistically significant, clinically relevant advantage of early treatment with Neparvovec over a ‘watch-and-wait’ approach is inferred.
  • In the LTFU study, 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 are of a similar magnitude up to year 5.
• quality of life
  • In studies 301 and LTFU, health-related quality of life was assessed using the Visual Function Questionnaire.
  • Due 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 analyses cannot be taken into account in the context of the benefit assessment.
• Side effects
  • SAE and severe AEs occurred in Study 301 only in the intervention group. In Study 301, 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 between treatment with Voretigen Neparvovec and a ‘watch-and-wait’ approach.
  • In detail, a statistically significant difference to the detriment of the intervention was observed for the AE SOC ‘Blood and lymphatic system disorders’ and the PT ‘Leucocytosis’.
  • Based on the available data and given the high potential for bias, new AEs occurred in only a few individuals in the LTFU study after year 1.
• Overall assessment / Conclusion
  • In the mortality category, no deaths occurred during studies 301 and the LTFU.
  • In the morbidity category, within Study 301, there were statistically significant, clinically relevant benefits in favour of Voretigen Neparvovec for the patient-relevant endpoints MLMT (functional vision/orientation), FST (light sensitivity) and perimetry (visual field), there were statistically significant, clinically relevant advantages in favour of Voretigen Neparvovec; no statistically significant change in visual acuity could be demonstrated for Voretigen Neparvovec compared with a ‘watch-and-wait’ approach.
  • In the LTFU extension study, the descriptive, non-comparative analyses up to year 5 showed an improvement in the values for the endpoints MLMT, FST, visual acuity and perimetry in both original treatment groups compared with baseline.
  • No suitable data are available for the benefit assessment with regard to quality of life.
  • In the endpoint category of side effects, Study 301 revealed no differences between the treatment groups that were relevant for the benefit assessment. In the LTFU study, only isolated new side effects occurred after year 1.
  • The analyses of the LTFU study (as at 30 June 2020) suggest that the positive effects achieved with Voretigen Neparvovec in Study 301 are maintained at a similar magnitude up to 5 years after administration.
  • Overall, the long-term data presented confirm with a reasonable degree of certainty the long-term efficacy and safety of Voretigen Neparvovec for at least 5 years following a single administration of the gene therapy.
  • In summary, the statistically significant and clinically relevant advantages of Voretigen Neparvovec demonstrated in Study 301 compared with a watch-and-wait approach, with regard to the endpoints MLMT, FST and perimetry are confirmed in their extent by the LTFU study and, taken as a whole, are classified as considerable.
• Overall assessment / Conclusion
  • In the mortality category, no deaths occurred in either Study 301 or the LTFU study.
  • In the morbidity category, Study 301 demonstrated statistically significant, clinically relevant benefits in favour of Voretigen Neparvovec for the patient-relevant endpoints MLMT (functional vision/orientation), FST (light sensitivity) and perimetry (visual field), there were statistically significant, clinically relevant advantages in favour of Voretigen Neparvovec; no statistically significant change in visual acuity could be demonstrated for Voretigen Neparvovec compared with a ‘wait-and-see’ approach.
  • In the LTFU extension study, the descriptive, non-comparative analyses up to year 5 showed an improvement in the values for the endpoints MLMT, FST, visual acuity and perimetry in both original treatment groups compared with baseline.
  • No suitable data are available for the benefit assessment with regard to quality of life.
  • In the endpoint category of side effects, Study 301 revealed no differences between the treatment groups that were relevant for the benefit assessment. In the LTFU study, only isolated new side effects occurred after year 1.
  • The analyses of the LTFU study (as at 30 June 2020) suggest that the positive effects achieved with Voretigen Neparvovec in Study 301 are maintained on the same scale up to 5 years after administration.
  • Overall, the long-term data presented confirm with a reasonable degree of certainty the long-term efficacy and safety of Voretigen Neparvovec for at least 5 years following a single administration of the gene therapy.
  • In summary, the statistically significant and clinically relevant advantages of Voretigen Neparvovec demonstrated in Study 301 compared with a ‘watch-and-wait’ approach, with regard to the endpoints MLMT, FST and perimetry are confirmed in their extent by the LTFU study and, taken as a whole, are classified as considerable.

Courtesy translation only, please refer to the German original.