Discussion
Visual acuity reduction, vision, ocular TEAEs, gain, visual acuity gain, TEAEs, mean gain, decline in visual acuity, retinal detachment, ocular inflammation, choroideremia
REFLUXED, DETACHMENT, DEGENERATE, INFLAMMATION, DISEASE, RETINA, SURGICAL COMPLICATIONS, RETINAL DETACHMENT, EVENTS, CHOROIDEREMIA, TOTAL BLINDNESS
The primary endpoint of a three-line gain was not met in this phase 3 trial. Although a spontaneous gain of three lines of vision was not observed in any of the control group participants, there were not enough participants gaining three lines of vision in the treatment groups to meet statistical significance. However, there were notable observations related to BCVA changes in participants undergoing retinal gene therapy for choroideremia in all visual acuity endpoints tested, including the proportion of participants reporting a two-line gain and mean gain in vision and preservation of at least one line of vision.A ≥10-letter ETDRS improvement from baseline in BCVA has been considered clinically relevant from the patient’s perspective according to scientific advice given at a workshop by the European Medicines Agency (EMA)The proportion of individuals gaining three lines of vision in a meta-analysis of the phase 1/2 choroideremia trials was more than twice the rate observed in this pivotal STAR studyAlthough it was not considered for significance per the hierarchical procedure, it is interesting that there was a greater numerical difference in BCVA score from the high-dose group versus control than the low-dose group versus control (Table Although no efficacy claims can be made on the basis of this study, it is interesting to note that the treated eyes underwent iatrogenic retinal detachment in thin and degenerate tissues, which would ordinarily be associated with reduced visual acuity. Instead, there was a trend for improvements in visual acuity to occur more frequently in the high-dose group compared to the control group, albeit not enough to meet statistical significance in this cohort. Because of the low percentage of participants who achieved three lines of visual acuity gain across the study, including none in the control group, a larger study size would be needed to confirm the differences between the treatment groups and control group. Alternatively, the results from this cohort suggest that another trial with a two-line gain as the primary endpoint (if acceptable to the regulators) could be more appropriate for smaller enrollment populations, based on the power calculation derived from the current STAR study data.The safety profile of timrepigene emparvovec was determined to be acceptable. Most TEAEs in the timrepigene emparvovec treatment groups were related to study procedure rather than to study drug. Most ocular inflammation–related TEAEs occurred within 30 d of study drug administration or surgery and were likely related to the surgical procedure. The occurrence of ocular inflammation–related and visual acuity reduced–related events was not dose dependent. Visual acuity reduction events were the most reported serious ocular TEAEs.Natural history studies have reported a transition age from slow to rapid BCVA decline of ~39 yearsThe efficacy of AAV2-based gene therapy in younger patients is unknown. For instance, although improvement in BCVA was not demonstrated, it is possible that preservation of vision with timrepigene emparvovec is more likely to be seen in younger patients who are able to tolerate the risks associated with subretinal gene therapy administration.To get a large gain in vision, three factors need to be aligned. First, the retina needs to be healthy enough to be able to improve visual acuity by two or more lines; second, the surgery needs to be completed without damaging the retinal architecture; and third, the vector needs to be sequestered at a high enough dose subretinally, without being refluxed back into the vitreous. With the high dose, this is more likely to be achieved, because the third factor is countered by having a log unit higher dose of vector particles. Nevertheless, the other factors remain because there will be some retinas that are simply too advanced to be able to achieve large gains in vision. Similarly, in others, there will be surgical complications that might offset the potential gains. It should be expected, though, that large gains in vision might be seen in some low-dose patients when all three factors go well.For examining the dose effect more accurately, however, it is more logical to look at the effects on BCVA across the whole cohort because then data from every participant can be included, rather than from only the few who have large BCVA gains. If there were no beneficial effect at all from the vector, then one would predict that the mean BCVA loss from the retinal detachment would be similarly worse in both the high-dose and low-dose groups compared to the control group, because of the negative effects of iatrogenic retinal detachment. The observations of the mean BCVA change from this study, however, are the reverse. Although these values were not formally tested for significance per the hierarchical procedure, the direction and pattern of BCVA changes across the entire participant group with these subanalyses is consistent with a treatment effect that is better with the high dose, especially given that these participants underwent an invasive surgery.To summarize some previous points in this discussion, this study had several limitations that would be important to address in future trials of gene therapy in choroideremia. COVID-19 resulted in some major protocol deviations in this trial as noted previously, including some out-of-window visits and performance of BCVA measurements by unmasked assessors. However, on the basis of consistent results of analyses of the per-protocol and intent-to-treat populations for the primary endpoint, the protocol deviations did not appear to have a substantial effect on the study outcomes. Additionally, the primary endpoint requiring a three-line gain in BCVA may not have been realistic in this cohort, and a two-line gain should be considered, especially in cohorts with more advanced disease. Participants in the treatment arm also underwent vitrectomy and pre-injection subretinal formation before subretinal injections, inducing a transient and localized detachment of the central retina. Variable success with the surgery could, therefore, potentially be an additional confounder for the treatment effect in participants with advanced choroideremia, as there may have been only a small preserved retinal area for vector delivery, which might not have been accurately targeted in every caseAlthough the primary endpoint was not met in this pivotal trial, gene therapy for choroideremia remains a promising therapeutic approach. Furthermore, visual acuity gains lower than the prespecified threshold for primary endpoint can still be clinically meaningful. However, for advanced disease with a rapid decline in visual acuity, perhaps a more realistic expectation may be to slow down progression and prevent total blindness rather than to improve vision. Potential opportunities to enhance future gene therapy studies for choroideremia include selection of participants with a more preserved retinal area and optimization of surgical techniques and clinical endpoints.