Early findings in a Phase I/IIa clinical program for Usher syndrome 1B (USH1B; MIM #276900)

Abstract

Purpose: To present the early findings of a Phase I/IIa clinical program for Usher syndrome 1B (USH1B; MIM #276900) designed to evaluate the safety of MYO7A gene replacement with a lentiviral based vector (UshStat®) administered by subretinal injection.

Methods: UshStat® is a treatment for Usher syndrome 1B via ocular gene replacement therapy of MYO7A using lentiviral based vector (recombinant Equine Infectious Anaemia Virus [EIAV]). UshStat® is currently under clinical evaluation in a Phase I/IIa program. The clinical program is a 48-week open-label study (NCT01505062) designed as a 3-cohort dose escalation phase followed by two additional cohorts testing further the highest safe and tolerated dose and a long‑term follow-up study (NCT02065011). To date, four patients with advanced‑stage retinitis pigmentosa have been enrolled and evaluated using best-corrected visual acuity, dilated slit-lamp examination, indirect ophthalmoscopy, VFQ-25, full-field semi-automated kinetic perimetry, full-field GATE static perimetry, microperimetry, electroretinography, fundus photography, autofluorescence, optical coherence tomography and adaptive optics imaging.

Results: The dose-escalation phase of the trial has enrolled four patients and the expanded cohort is in progress for the patients already treated. The fovea of one patient was detached at the time of surgery but had reattached and the visual acuity returned to baseline by Week 4. Following surgery, patients experienced a temporary decline in visual function measures, but function clinically recovered in all patients. There have been no drug related complications or sustained surgical sequelae. Subretinal administration of UshStat® has been well tolerated, causing no significant ocular inflammation in any patients to date.

Conclusions: UshStat® has been safe and well tolerated. From the data analysis of the first 4 patients, neither clinically significant harmful effects nor biological activity was observed in the treated population thus far. Completion of patient enrollment is important to further assess the safety and efficacy profiles of UshStat®.