Baseline Structural and Psychophysical Profiles of Subjects Enrolled in Phase 3 Trials with rAAV2/2-ND4, an Investigational Gene Therapy for ND4 LHON

Abstract

Purpose : Patients with LHON currently have no compelling treatment to improve visual function. Recent advances in molecular biology allow for transduction of affected retinal ganglion cells (RGC) and the co-translocation of ND4 wild type protein into the RGC’s mitochondrial matrix. rAAV2/2-ND4 is an intravitreally-injected gene therapy formulated as treatment of ND4 LHON.
Two phase three trials RESCUE LHON (NCT02652767) and REVERSE (NCT02652780)) are testing this treatment for vision loss for ≤6-months (RESCUE) and vision loss between 6 months and 1 year (REVERSE). This abstract explores the baseline structure-function relationships between pre-treatment visual acuity, vision loss duration, and retinal structures.

Methods : 76 patients with G11778A-ND4 mutation LHON aged 15 or older were enrolled with vision of CF or better. We analyzed baseline demographic, visual acuity, SD-OCT measurements of the macula, GCL, RNFL, temporal quadrant , and PMB from all cohorts. We looked for a relationship between visual acuity, duration of vision loss and retinal structures using GEE.

Results : Mean duration of vision loss for RESCUE was 112 days (range: 24-179), and 271 for REVERSE (range of 181-364 days). Visual acuity differed at baseline (Table 1). Visual acuity levels were significantly associated with vision loss duration in both the best ( √R²=0.254; p=0.033) and worst ( √R²=0.266; p=0.020) eyes, driven by the RESCUE trial.

Total macular volume was smaller in REVERSE (mean (sd): 8.4(0.5) ml³ vs. 7.8 (0.4); p< 0.0001), and this difference was reflected in the GCL, RNFL, and temporal quadrant thickness. In both studies, a statistically significant relationship existed between thinner retinal structures and time since vision loss, as well as visual acuity at baseline (Figure 1).

Conclusions : Our analysis found significant differences for pre-treatment visual acuity between the two trials which were balanced by age and gender, and similarly found a positive correlation between vision loss duration and LogMAR in all participants. REVERSE participants (and those with longer vision loss duration and worse visual acuity) present with thinner retinal structures.
Our findings extend the characterization of LHON subjects in our trials and afford additional supporting evidence to the import of imaging in such gene therapy interventions

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.