Dr Christine Kay
A gene therapy that aims to increase levels of two key proteins that enable the growth of new blood vessels in age-related macular degeneration (AMD) was shown to stabilize vision with a low rate of ocular side effects while reducing the need for intraocular injections by 81% through 9 months, researchers have found.
The PRISM trial evaluated three doses of the therapy, 4d-150, and found that the two highest doses — 1 x 1010 (1e10) and 3 x 1010 (3e10) vector genes (vg)/eye — were most effective at maintaining best-corrected visual acuity (BCVA) and restoring retinal central subfield thickness (CST) through 36 weeks, said Christine Kay, MD, director of retinal genetics at Vitreoretinal Associates in Gainesville, Florida, who helped conduct the study. The phase 1/2 trial enrolled five patients in each dosing cohort for a total of 15 patients.
“In the high-dose 3e10 group, 80% of patients didn’t need any supplemental injections out to week 36,” Kay, who presented the findings at the American Society of Retina Specialists (ASRS) 2023 Annual Meeting, told Medscape Medical News. “One patient had a dense cataract, and without that person the rate would’ve been 100%.”
Dual Transgene Approach
4D-150 is a dual transgene therapy designed to activate production of the proteins aflibercept and vascular endothelial growth factor-C (VEGF-C) RNAi, both of which maintain retinal vascular integrity and inhibit new vessel formation in neovascular AMD. The treatment is injected directly into the vitreous of the eye in the office and does not require ocular surgery to place a gene vector below the retina, which is the delivery vehicle for other investigative gene therapies for retinal disease.
“BCVA was stable,” Kay said. “The 3.6-letter reduction in the high-dose group was irrelevant, but CST [central subfield thickness] did show a dosing response.” The 3e10 group experienced a 92 (± 49) µm reduction in CST, a key anatomical biomarker of retinal integrity, from baseline, Kay said. “There is a dose-response here,” she said.
No treatment-related adverse events were reported across all three dosing cohorts, Kay said. “There was no hypotony, the uveitis outcomes were excellent — zero in all patients — and one patient had trace cells that resolved transiently,” she said.
None of the patients required treatment with oral, topical, or injectable steroids for post-injection intraocular inflammation, Kay said. All patients received topical durezol drops after the injection, which were tapered over 20 weeks.
In 10 of 11 samples, transgene expression of aflibercept was detected at 12 weeks post-injection, Kay said. The high dose rendered the highest concentrations of aflibercept in the aqueous humor, greater than 200 vg/eye 12 weeks after injection, compared with less than 100 vg/eye for the intermediate 1e10 dose and about 20 times greater than the low 6 x 109 vg/eye dose.
“The log difference in the low dose versus the medium dose was a 1.7-fold difference, and between middle and high dose it was a threefold difference,” she said.
“Everything is pointing to the 3e10 dose,” Kay said. The dose expansion phase of the phase 2 PRISM trial will evaluate the 3e10 and 1e10 doses in comparison to aflibercept injections. The trial is fully enrolled (n = 50), she added.
“The important thing about the 4D vector is that it’s ‘retinotrophic'”, meaning it is attracted to the retina itself, Kay said. “Because of that steep gradient when you are injecting it into the eye, it is designed to go into the retinal choroid,” she said. “That’s the optimization of the vector and the capsid.”
Potential for Gene Therapy in AMD
Dr Aleksandra Rachitskaya
Gene therapy for AMD has the potential to meaningfully reduce the frequency of intravitreal injections, often monthly or every other month, that these patients must endure — a concept known as treatment burden — said Aleksandra Rachitskaya, MD, a vitreoretinal specialist and associate professor at the Cole Eye Institute at the Cleveland Clinic in Ohio.
“They have such a burden of neovascular age-related macular degeneration, our population is aging, the numbers that are projected are quite significant, so I think gene therapy in general for neovascular AMD is something we’re very excited about,” Rachitskaya told Medscape Medical News.
“The interesting thing about the PRISM trial is that they’re encoding not only for aflibercept, but they’re also encoding for mRNA sequencing anti-VEGF-C, so that’s a slightly different approach than was taken in the past,” she said.
The intravitreal platform also has potential, she said. The subretinal and suprachoroidal platforms, both of which are being investigated with RGX-314, are “more challenging.” With subretinal delivery, “the patient has to go to the operating room and there’s only a subset of retina specialists who can do it. You have to be vitreoretinal-trained; it’s not something that can be done by a medical retina specialist,” Rachitskaya said, whereas intravitreal injections can be administered in the office.
The PRISM data are “encouraging,” if early stage, she said. “If this approach works it could really be something that would effectively treat our patients,” she said. “The relative ease of administration and the potentially significant effect on disease control are noteworthy.”
Kay has reported being a consultant to and investigator for trial sponsor 4D Molecular Therapeutics and having relationships with Gyroscope Therapeutics/Novartis and REGENXBIO. Rachitskaya has reported no relevant financial relationships.
ASRS 2023 Annual Meeting. Presented July 29, 2023.
Richard Mark Kirkner is a medical journalist based in the Philadelphia area.
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