Safety Profile of the Surgical Procedure for the Administration of Ocular Gene Therapies

Abstract

Purpose : To characterize the safety profile of the surgical procedure including vitrectomy followed by a subretinal injection used to administer lentiviral gene therapies to patients with Stargardt Macular Degeneration (SMD) and retinitis pigmentosa (RP) associated with Usher Syndrome, Type 1B (USH1B).

Methods :
All reported adverse events (AEs) including descriptions of event severity, relatedness to surgery or the investigational medicinal product (IMP), and preferred term per the MedDRA dictionary were collected from two ongoing 48-week dose-escalation Phase I/II clinical trials investigating the safety and tolerability of SAR422459 (an ABCA4 gene replacement therapy for SMD; NCT01367444) and SAR421869 (a MYO7A gene replacement therapy for USH1B; NCT01505062) administered to the subretinal space by subretinal injection.

Results : As of 9 November 2016, 20/23 patients with end-stage SMD and 8/9 patients with advanced RP have received SAR422459 and SAR421869, respectively via subretinal injection in the worse eye, and experienced at least 1 AE. Of the total 190 reported AEs, including 4 serious AEs, from the two studies 106: (56%) were related to the surgery only, 6 (3%) to the IMP only and 21 (11%) to both the surgery and IMP. The vast majority, 115 (91%) of the surgery related AEs were mild in severity and 119 (94%) were reported within 4 weeks of the procedure. The most frequent surgery related AEs were conjunctival hemorrhage (12%), increased intraocular pressure (IOP) (11%), eye pain (7%), eye pruritus, subretinal fluid, and retinal hemorrhage (6%) and decreased IOP (5%). Of the 4 reported SAEs in 4 patients, 2 (uveitis, reduced visual acuity) were related to the surgery and the IMP, 1 (uveitis) to the IMP only and 1 (elevated IOP) to the surgery only.

Conclusions : The 1-year surgery related AEs from these two studies demonstrates that the safety profile for events related only to the surgical procedure is acceptable and raises no particular safety concerns beyond those associated with other vitreoretinal surgeries. The occurrence of uveitis in 2 patients has helped to refine the postoperative management of inflammation in the trials. Our experience indicates that the establishment of surgical standards for the perioperative care of patients receiving gene therapies administered by subretinal injection will be particularly important to insure the safe delivery of such treatments.

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