Six-year results of a Phase I/IIa gene therapy trial in patients with Usher Syndrome Type-1B (USH1B)

Abstract

Purpose : To present results of a Phase I/IIa clinical trial for MYO7A gene replacement with a lentiviral vector in patients with retinitis pigmentosa (RP) secondary to USH1B.

Methods : Nine participants aged 22-56 years diagnosed with advanced forms of MY07A-associated RP were enrolled in the SAR421869 (NCT01505062) gene therapy clinical trial. Participants were tested in triplicate at baseline, and test-retest variability was calculated to establish repeatability coefficients (RC) or threshold values for statistically significant change from the corresponding baseline average. Participants received EIAVMYO7A in the worse-seeing eye at three dose levels (n=3 per cohort) via subretinal injection nasal or temporal to the optic nerve and were followed for six years after treatment. Visual function endpoints included: best corrected visual acuity (BCVA) ETDRS letter score, kinetic perimetry (KP) isopter area (I4e, III4e, V4e, and VI4e); and static perimetry (SP) using a 185-loci grid (size V) and a 111-loci grid (size VI) with volumetric endpoints from hill of vision modeling (VFMA).

Results : Subretinal administration was well tolerated in cohorts 1-2, however two subjects from cohort 3 had significant adverse events related to study product or study procedure. One participant developed severe panuveitis in the study eye, resulting in a significant decline in visual function. Another participant had a break in the Bruch’s membrane during the surgery at the site of injection with subsequent RPE atrophy that was associated with a decline in BCVA but not central sensitivity as measured by static perimetry. Other participants experienced a temporary post-operative decline in BCVA and visual fields, which recovered by week 12. On average, the RC threshold values were high for each efficacy endpoint (Table 1), likely due to advanced vision loss in our cohort. Thus, none of the subjects had any significant improvements from baseline up to year 4. Some subjects had a slow significant decline after year 4, likely due to natural history of disease progression.

Conclusions : Lower doses of EIAVMYO7A appear to be well-tolerated, but there were 2 SAEs in the highest dose cohort. Larger studies would be required to fully assess the potential of lentivirus-based retinal gene therapy, however SAR421869 was discontinued early due to the risk/benefit profile.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.