Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial

Abstract

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41.

Choroideremia: The Endpoint Endgame

“…In contrast, the number of patients gaining two lines of vision was statistically significant compared to the control group. Unfortunately, this did not reach the primary endpoint, and hence, there was no regulatory approval [ 91 ].…”

Gene therapy for choroideremia using an adeno-associated viral vector encoding Rab escort protein 1: the REGENERATE open-label trial

“…The results of the STAR Phase III clinical trial have recently been reported. 42 In the primary end-point analysis, 3 of 65 participants (5%) in the high-dose group, 1 of 34 (3%) participants in the low-dose group and 0 of 62 (0%) participants in the control group had ≥ 15-letter ETDRS improvement from baseline BCVA at 12 months (high dose, p = 0.245 vs. control; low dose, p = 0.354 vs. control). As the primary end point was not met, key secondary end points were not tested for significance.…”

Retinal Imaging Findings in Inherited Retinal Diseases

“…AO-guided microperimetry studies have shown that retinal sensitivity is preserved within areas with contiguous cone mosaics, while dense scotomas are evident in atrophic areas [84]. Fundus-guided microperimetry has been performed in clinical trials evaluating treatments for CHM; however, given the advanced stage of the disease in these participants, the microperimetry data were generally found to be inconsistent [85][86][87]. Thus, to summarize, the main outcome measures to assess retinal structure adopted in clinical trials testing gene therapy in choroideremia are EZ preservation area and RPE preservation area evaluated by OCT and FAF, respectively [86][87][88][89].…”