One Year Results of a Phase I/IIa Study of SAR422459 in Patients with Stargardt Macular Degeneration (SMD)

Abstract

Purpose : SAR422459 is a lentiviral vector which encodes the ABCA4 gene. We present the one year safety, visual acuity and visual field results of a gene therapy trial investigating SAR422459 in adult SMD patients with biallelic pathogenic mutations in ABCA4.

Methods : The objectives of this ongoing 48-week phase I/IIa dose-escalation trial are to assess safety and tolerability of SAR422459 and to evaluate for biological activity. Twenty-two patients were enrolled at two clinical sites in 5 cohorts by groups based on disease severity and treated with ascending doses of SAR422459 administered by subretinal injection to the worse eye (Table 1). Group A was composed of patients with visual acuity (VA) ≤ 20/200 and no detectable or severely abnormal full field ERG (ffERG) for both rod and cone responses. Group B had VA ≤ 20/200 and abnormal ffERG responses. Group C had VA ≤ 20/100 and abnormal ffERG.

Results : At 48 weeks mean change (range) from baseline in ETDRS letters for Cohorts 1, 2, 3, 4,and 5 was +7 (2 to 12), -1 (-4 to 2), +3 (-1 to 8), +7 (4 to 16), and +2 (-2 to 10) respectively, in the study eyes and +5 (-4 to 14), -2 (-10 to 3), +3 (-4 to 7), +3 (0 to 9), +2 (-1 to 6), respectively, for the untreated eyes. Mean change (range) in Hill of Vision (HOV) total volume (V_TOT) for Cohorts 1, 2, 3, 4,and 5 was 5.9 (-3.8 to +17.6), 2.4 (-0.8 to 5.3), 5.0 (-10.1 to 36.2), -8.3 (-10.7 to -4.0), and -0.9 (-137 to 9.1), respectively, for the study eyes and +9.7 ( +0.5 to 25.5), +3.4 (+0.1 to 6.9), +4.5 (-6.9 to 15.9), -3.6 (-8.4 to 1.0), +5.2 (-4.4 to 22.8) for the untreated eyes. 22 patients experienced 125 treatment emergent adverse events (AEs) and 2 serious AEs (intraocular inflammation and elevated intraocular pressure).

Conclusions : Based on test-retest variability analysis of the baseline data in this group of 22 patients with advanced stages of SMD, the difference required to achieve a significant statistical difference for ETDRS letter score and V_TOT is 8 letters and 14.62 dB-sr (Parker et. al. Transl Vis Sci Technol 5:10, 2016). At 48 weeks few patients had changes in VA greater than 8 letters and no patient experienced decreases greater than 14.62 in their HOV (V_TOT) in study or untreated eyes. These outcomes confirm a favorable safety profile of SAR422459 that warrant further evaluation in patients with less advanced disease.

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

 

Table 1