Phase I/IIa Visual Acuity Outcomes 1.5-Years Post-Treatment with rAAV2/2-ND4, an Investigational Gene Therapy for ND4 LHON

Abstract

Purpose : rAAV2/2-ND4 is an experimental gene therapy enabling allotopic transgene expression. We report visual acuity (VA) outcomes 1.5-years post-treatment in a Phase I/IIa (NCT02064569) open-label, dose-escalation safety study.

Methods : LHON patients with G11778A-ND4 mutation with stable vision loss received a single intravitreal injection of rAAV2/2-ND4 in their worst-seeing eye. Three patients were included in each dose-escalation cohort (9x10⁹, 3x10¹⁰, 9x10¹⁰, 1.8x10¹¹ vg/eye) and the extension cohort (9x10¹⁰ vg/eye) for a total of 15 patients. Post-hoc analysis of patient groups with ≤2-years vs. >2-years of vision loss at treatment and excluding the worst baseline VA (LogMAR>2.79) was performed.

Results : At baseline (N=15) mean/median (range) LogMAR in treated-worst and untreated-best eyes was 2.29/2.79 (1.10-3.01) and 2.03/2.01 (1.00-3.18) respectively; the difference between means is 0.265 (p=0.0342). Mean (range) vision loss duration was 72.3 months (8-271; median 22). All patients completed 48-week follow-up; one patient withdrew consent and 14 patients have completed 1.5-year follow-up. Mean LogMAR changes from baseline to 1.5-years post-treatment are as follows: For all patients (N=14): treated-worst eyes -0.612 vs. untreated-best eyes -0.308; mean difference -0.304. Excluding patients with baseline LogMAR>2.79: group with ≤2-years vision loss (N=5) treated-worst eyes -0.632 vs. untreated-best eyes -0.234; mean difference -0.398. In comparison, for this group, mean differences at weeks 24, 36 and 48 were: +0.136, -0.218, -0.338. In the >2-year vision loss group (N=6) treated-worst eyes -0.451 vs. untreated-best eyes +0.071; mean difference -0.523 with VA change of 3/6 patients driving results.

Conclusions : Mean LogMAR change at 1.5-years improved in treated-worst and untreated-best eyes; there is a sustainable, clinically relevant, greater improvement of ≥0.3LogMAR in treated-worst versus untreated-best eyes. For patients with ≤2-years vision loss, mean differences favoring treated-worst eyes are noted at 36-weeks and increase in magnitude at subsequent follow-up. Those affected >2-years show a clinically relevant (≥0.3LogMAR) mean difference for the first time at 1.5-years post-treatment.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.