The Promise of Gene Therapy
The one-and-done promise of gene therapy could rattle the field once again. Trials presented at the ASRS24 showed a drastic reduction (from 85% to 95%) in the number of anti-VEGF and complement treatments needed following gene therapy injection, improving patient vision while relieving them from the stress of monthly injections.
But researchers are still debating the optimal corticosteroid regimen that is required for reducing the inflammatory response associated with the administration of gene therapies, especially those that use viral vectors. The main controversy is whether systemic immunosuppression is necessary or if local therapies, such as topical and intravitreal administration, can suffice.
Results presented at the meeting suggest that local therapies alone can be effective, potentially reducing the need for systemic immunosuppression.
The LUNA trial evaluated the efficacy and tolerability of ixoberogene soroparvovec, a therapy that delivers an anti-VEGF gene into the eye. Investigators included various prophylactic regimens, including local corticosteroids with and without oral prednisone. They found that local corticosteroid therapy alone effectively reduced inflammation.
Biopharma company 4DMT conducted the PRISM study, which examined a dual transgene therapy for neovascular AMD. Patients in this trial received a 20-week topical steroid taper. Only one patient (of 39) required a 6-week extension of steroid therapy. No patients experienced clinically significant intraocular inflammation, indicating that local corticosteroid therapy was effective in managing immune responses.
Currently, gene therapy clinical trials are designed for patients who have failed standard therapy or require frequent injections. “Once we figure out possible long-term side effects and how to deal with inflammation, [gene therapy] could reach many more patients,” Dr. Olmos de Koo said.
New Approaches Enter Pipeline
While gene therapy brings excitement to the field, it might not be for everyone, experts agreed at the ASRS24. New agents are being evaluated to offer a broader range of treatment options with longer-lasting efficacy. Results from early-phase trials presented at the meeting show favorable safety and efficacy signals.
“Finally, after a long time, we have a lot of exciting drugs for geographic atrophy in the pipeline that seem to be safe, with many studies also showing a functional outcome in addition to anatomical outcome,” Dr. Skondra told this news organization.
Current FDA-approved treatments for GA focus on inhibiting the humoral arm of the immune system through C3 and C5 inhibitors. However, a new approach targets both the humoral and cellular arms of the immune response by inhibiting macrophages that release pro-inflammatory cytokines. The goal is to convert these macrophages to a “resolution state,” potentially reducing the release of inflammatory cytokines and offering a more comprehensive treatment for wet and dry AMD, said Rishi Singh, MD, a retina surgeon at the Cole Eye Institute, Cleveland Clinic.
AVD-104, a sialic acid–coated nanoparticle developed by Aviceda Therapeutics, is a promising candidate in this approach. This 100-nm-in-diameter particle, which is only as heavy as 20 hydrogen atoms, is designed for better tissue penetration and has a pharmacokinetic profile lasting 3-4 months after a single intravitreal dose.
AVD-104 aims to repolarize macrophages into a resolution phenotype and decreases complement factor overamplification through direct binding to complement factor H, which downregulates C3 production in immune cells. This dual-action approach could offer a more effective and long-lasting treatment option.
Dr. Singh, who presented the phase 2/3 SIGLEC clinical trial assessing AVD-104, said a single dose resulted in significantly slower rates of disease progression as early as 1 month post-treatment and a notable decrease in junctional zone hyper-autofluorescence.
In addition, about 40% of patients gained vision, which was unexpected but a pleasant surprise, Dr. Singh said. “This is a small study. I don’t want anyone to walk away with the conclusion that we’ve figured out how to improve visual acuity in GA. But it’s promising.”
Other researchers are tackling GA by focusing on therapies that aim to intervene before the complement system is activated.
ONL1204 is a novel agent designed to inhibit the activation of the tumor necrosis factor FAS receptor, which is activated and upregulated in a disease state and is implicated in multiple cell death and inflammatory pathways.
Multiple preclinical models of AMD have shown that ONL1204 preserves retinal cells and inhibits inflammation by inhibiting the FAS receptor. Phase 1 trial results presented at the meeting showed that ONL1204 was safe and showed strong efficacy signals as early as 6 months after treatment initiation.
“We need to be cautiously optimistic,” Dr. Skondra said. “Larger studies will tell us if these signals are real. But it’s a very exciting time. I’m happy to see different mechanisms of action besides the complement because we can attack the disease from multiple fronts.”
Dr. Grewal declared interests with Eyepoint, Iveric Bio, Regeneron, Alumis, Apellis, DORC, and Genentech. Dr. Muth declared interests with Bayer, Canon, and Roche. Dr. Olmos de Koo declared interests with Alcon and Pixium Vision. Dr. Singh declared interests with Gyroscope, 4DMT, Aviceda, Eyepoint, Alcon, Bausch and Lomb, Novartis, and Regeneron. Dr. Skondra declared interests with Biogen, Iveric Bio, Allergan, and Trinity Health Science. Dr. Talcott declared interests with Bausch and Lomb, Eyepoint, Regeneron, REGENXBIO, Zeiss, Apellis, Genentech, Alimera, Outlook, and Iveric Bio.
A version of this article first appeared on Medscape.com.