Real-word data from voretigene neparvovec treatment of RPE65-LCA2 reports retinal atrophy in Germany and US studies.

At least two independent reports on the treatment of VN (voretigene neparvovec) for RPE65-LCA2 has identified retinal atrophic changes on fundus autofluorescence images, following sub-retinal injection among an estimated 18 patients in real-world studies (ref.: Reichel FF, et al. Br J Ophthalmol 2022;0:1–5, and; Gange WS, et al. Ophthalmol Retina. 2022 Jan;6(1):58-64).  The two reports, one in Tübingen, in the Centre for Ophthalmology, Universitätsklinikum Tübingen, was led by Dr. M. Dominik Fischer; and the further study was in Los Angeles, in the Vision Centre, Department of Surgery, Children’s Hospital Los Angeles, led by Dr. Aaron Nagiel.  VN is a gene therapy treatment that was approved on December 18th, 2017 in FDA and subsequently on November 22nd, 2018 in the EMA.  The primary end-point for the phase III, at 1 year, showed a mean bilateral MLMT (multi-luminance mobility testing) change score of 1.8 (SD 1.1) light levels in the intervention group versus 0.2 (1.0) in the control group – a difference of 1.6, (95% CI 0.72–2.41, p=0.0013), with a n=29.


In the recent Tübingen report, 8 patients were assessed over a 6-24 month period following a retinotomy with a sub-retinal injection of 300µl of VN.  Areas of atrophy were observed in all eyes in the cohort, showing the atrophy beyond the retinotomy site.  In addition, the areas of atrophy appeared to increase with time and progression continued over 12 months.  The patients included had a mean age of 23.9 years (range, 17–35 years), with a 50:50 proportion of female and male cohort. In the Los Angeles report, 10 patients were assessed at each of 4 participating sites using the same retinotomy and sub-retinal injection procedure with VN.  Eight of ten of the patients developed bilateral atrophy following surgery.  Atrophy was observed at an average of 4.7 months after the procedure and the atrophy appeared to progressively increase, in all cases up to a mean follow-up period of 11.3 months (range, 4–18 months). The mean age in this cohort was 11.6 years (range, 5–20 years), and 6 patients (60%) were male. Similar to the Tübingen study, the atrophy developed within and outside the area of the subretinal bleb.


Commenting in the report in Tübingen, Dr Fischer stated that: “[t]aken together, our results suggest that the retinal degeneration in patients treated with VN exceeds the rate of the natural disease progression at the location of the retinotomy site, the area of transient retinal detachment, and also beyond”.  It is still unclear how these atrophic changes may have arisen from the surgical procedure, the vector, the gene therapy itself, or perhaps some subclinical immune response. In the same Tübingen report, Dr. Fischer commented that: “[i]t remains to some extent unclear why these atrophic changes have not been observed in the phase III study or in other cohorts. One possible reason is that it was simply overlooked”.  Regardless, one of the limitations on these real-world studies was that only a combined 18 patients was available and this population is small, and the period of postoperative observation time is limited.  Combining the Tübingen and Los Angeles study cohort, 16 of the 18 RPE65-LCA2 patients have reported retinal atrophic changes following VN, a proportion of 89%; comparing the phase III study (n=29, FDA) reporting no retinal atrophic changes in the original paper (Russell, 2017, Lancet 390: 849–60). Consequently, more data from real-world outcomes are clearly required.