Sam Minaker MD, MSc
Illinois Retina Associates/Rush University Medical Center
During the Age-Related Macular Degeneration II Session, moderated by Dr. Jennifer Lim and Dr. Charles Wykoff, Dr. David Eichenbaum presented preliminary results from a First-in-Human Phase I/II Gene Therapy Trial (FOCUS) of GT005, an investigational AAV2 Vector, delivered using the Orbit Subretinal System in Patients with Geographic Atrophy Secondary to Age-Related Macular degeneration. The FOCUS study is a phase I/II study assessing the delivery of the GT005 Vector via two approaches, first the familiar pars plana vitrectomy approach with transvitreal injection of the drug into the subretinal space through a retinotomy and a second is a suprachoroidal delivery to subretinal space using the proprietary Orbit Subretinal system that obviates the need for vitrectomy and retinotomy. The Orbit Subretinal system has received CE marking approval.
GT005 is an adenoviral therapy which induces expression of compliment factor I which is a downregulator of the complement system though binding of free compliment C3b. Since compliment dysregulation is “always on”, one-time gene therapy providing constant protein production may be superior to pulsatile dosing of intravitreal injections to turn compliment dysregulation “always off” or reduce its activity in addition to the benefit of reduced treatment burden.
Subretinal delivery via vitrectomy carries the standard risks of vitrectomy including retinal detachment and cataract progression, with the additional risk of efflux of drug through the injection retinotomy. The Orbit Subretinal System utilizes a suprachoroidal flexible canula which a dual bore 38G subretinal needle which places the infusate subretinally without the need for vitrectomy or retinotomy. The device offers control through an advancement knob that is magnetically attached to a flexible pad placed on the patient’s forehead which allows for ergonomic positioning during the procedure.
Dr. Eichenbaum then presented safety data on 3 cohorts of patients, 25 in total, who were dosed with GT005 via the Orbit Subretinal System and followed up between 2 and 81 weeks. Overall there were no serious ocular adverse events, there were some RPE changes in the area of the bleb which were consistent with previous gene therapy trials, there were four posterior microneedle perforations when the needle was advanced too far into the vitreous cavity, one subretinal cannulation, and one mild suprachoroidal hemorrhage. There were two patients that had proximal perforations that underwent a root cause analysis and it was found that there was an S bend in the cannula that did not allow for the needle to be retracted prior to cannulation.
The FOCUS study is currently ongoing and patients in both the traditional pars plana approach and the Orbit Subretinal Delivery System are currently being followed. During the discussion Dr. Eichenbaum discussed that optimizations to the device through animal testing are still ongoing with a goal to reduce complications. He also discussed the benefits the device could have over traditional vitrectomy for future cell-based therapies.