Gene Therapy for Wet AMD Near an Inflection Point: Arshad Khanani, MD

Phase 3 data for the first wave of gene therapies in neovascular age-related macular degeneration (wet AMD) are expected to begin reading out by the end of this year, a milestone that could make durable, potentially injection-free disease control a reality for patients within the next few years, said Arshad M. Khanani, MD, MA, FASRS, managing partner and director of clinical research at Sierra Eye Associates, in an interview with The American Journal of Managed Care^® (AJMC^®).

Khanani explains why long-term phase 1/2 data have eased earlier safety concerns around intravitreal gene therapy and how lower doses, more retinotropic vectors, and refined prophylaxis regimens have narrowed the risk. He also breaks down which patients with wet AMD stand to benefit most and makes the case for offering gene therapy broadly rather than reserving it only for the highest-need patients.

Khanani weighs the trade-offs between subretinal, suprachoroidal, and intravitreal delivery routes, discusses what manufacturing and scaling will need to look like for an equitable rollout, and explains why he doesn't expect gene therapy to face the kind of restrictive access controls that once shaped CAR T-cell therapy in oncology. He closes by addressing what last year's phase 3 failure of sozinibercept means for the future of targeting VEGF-C and -D in wet AMD.

This interview has been lightly edited for clarity.

AJMC: You've been the lead investigator across multiple gene therapy programs for wet AMD. From where you sit as the person running these trials, how close is gene therapy to becoming a real, scalable option rather than just a clinical trial result?

Khanani: Being involved with gene therapy for the past decade, I'm really excited that we'll be looking at phase 3 data reading out for gene therapies, starting with RGX-314 [surabgene lomparvovec; REGENXBIO] at the end of this year, and then ixo-vec [ixoberogene soroparvovec; Adverum Biotechnologies] and 4D-150 [4D Molecular Therapeutics] next year.^1-3

I think gene therapy is very close to becoming a reality, because now we also have long-term data from the phase 1/2 trials for all the ongoing programs, and what we've seen is long-term efficacy. Safety was an initial concern with intravitreal gene therapy, but we've learned that using lower doses, more retinotropic vectors, and the correct prophylaxis regimen can minimize the safety risk. I think it's an option that should be available to all patients, if the physician and patient think it's appropriate for them, as long as the long-term efficacy and safety data from the phase 3 trials continue to look as good as what we've seen in the phase 1/2 portion of these programs.

AJMC: How do you think about patient selection for these therapies? Could every patient with wet AMD potentially be a candidate, or are there specific patients you'd prioritize first as the most eligible?

Khanani: One thing I want to highlight is that we're not replacing a gene. We're using gene therapy as a drug delivery platform to create a biofactory of anti-VEGF in the eye. Patients are very heterogeneous: some need injections every 4 to 6 weeks, while others need them every 3 to 4 months.

When I think about gene therapy, obviously patients who have a high treatment burden with injections every 4 to 6 weeks or even 8 weeks are the priority. If there's a chance that half of them won't need injections again, based on the data to date, that's very promising, and even if they do need injections, they'll need fewer. I think there's a case to use gene therapy in pretty much all patients because of that benefit. Even for a patient on anti-VEGF every 3 to 4 months, if they can go injection-free for the rest of their lives after gene therapy, there's a good reason to consider it. It's going to depend on the safety profile and, of course, payer coverage, but what we've seen is that we can implement gene therapy as a maintenance option in the majority of patients if the efficacy and safety continue to look good.

AJMC: There are a variety of gene therapy delivery routes: subretinal, suprachoroidal, and intravitreal. What are the real trade-offs between these approaches, and do you think one route will end up winning out, or will different routes serve different patients and disease stages?

Khanani: I think you need to look at the route that can help most of your patients. Anything done in clinic is much more adaptable than going to the operating room, so intravitreal or suprachoroidal routes will be able to help a lot more patients than subretinal. Subretinal gene therapy [RGX-314] will be the first to have phase 3 data and is likely to be the first approved, and the surgery itself is simple, but it still requires the operating room, so it’s not for all patients, but, if approved, I expect to offer it to a majority of my patients who need frequent injections.

The differences by route of delivery really come into play with prophylaxis and safety events. With subretinal gene therapy, we don't really need prophylaxis. We've seen with the RGX-314 subretinal program that a post-op regimen alone is good enough, and we don't see immune-related events. With intravitreal or suprachoroidal gene therapy, we'll need topical steroid prophylaxis for those patients, and anywhere from 3 to 6 months in most cases.

If you have somebody with glaucoma, or somebody who's had high [intraocular] pressure in response to steroids in the past, those are patients we can't use those gene therapies on, because we don't want chronic high pressure in the eye. Some patients will have increased pressure because of the steroid prophylaxis, which we can control with eye drops, but patients who can't administer eye drops are also a concern.

I think it's good to have different options to serve a heterogenous wet AMD patient population.

AJMC: Gene therapy in particular raises a manufacturing and access question that injectable drugs don't. What do you think the first few years of real-world rollout will look like, and who is likely to get left behind in that rollout?

Khanani: I think the main thing is that when a new treatment comes out, you try to use it in your highest-need patients first to establish safety, just like in the trials. In phase 1, we enrolled high-need patients to establish safety because gene therapy is irreversible. In terms of scaling and manufacturing, I think it's much better now than it was 10 years ago; I'm seeing much better production and scaling of gene therapy.

In real-world practice, we'll start with the patients who are in high need and require chronic, frequent injections, and then transition into patients who are better controlled. I hope manufacturing and scalability are addressed before these gene therapies are approved. That's a big regulatory consideration before any new treatment is approved. Hopefully we won't have issues once they're available for our patients in the next few years.

AJMC: In oncology, with CAR T-cell therapies, we initially saw Risk Evaluation and Mitigation Strategy programs tightly control where a therapy can be delivered before the FDA removed that requirement.⁴ Could something like that play a factor in the gene therapy space as well?

Khanani: No, I don't think so. What we've seen is that these are injected in a routine retina clinic. Obviously, you have to follow the biohazard safety guidelines, but other than tthat,we don't have to worry about it. Cell therapy would be different, where it's much more controlled and will likely require centers of excellence. I think gene therapy is for the masses, the way it's being done in a routine clinic or operating room setting. Remember, gene therapy is not a gene replacement therapy; it's a drug delivery platform using AAV vectors, and they are non-pathogenic.

Of course, we have to follow what's called Institutional Biosafety Committee approval before we do trials, so some sort of approval is needed, but I don't think we have to worry about risk mitigation or anything else, because the side effects we have seen to date aren't lethal. It's just chronic inflammation, which obviously we don't want.

AJMC: Sozinibercept, which targets VEGF-C and -D, failed to show a superior-vision benefit in phase 3 trials last year.⁵ Given that, is there still a role for targeting VEGF-C and -D in the treatment of wet AMD, and if so, which patients stand to benefit most?

Khanani: Superior vision on top of VEGF-A was a very high bar for the sozinibercept phase 3 trials, but we all know that VEGF-C and -D are elevated in patients who are chronically treated with VEGF-A suppression. I think it's still important to address VEGF-C elevation if we can, expecting that we're not going to see better vision, but we may see better disease control and durability.

Speaking of gene therapy, 4D-150 has a dual mechanism of action, producing aflibercept in the eye as well as interfering RNA for VEGF-C. Blocking VEGF-C on top of aflibercept production may benefit patients' disease control at the lower dose used in the 4D-150 trials [3×10¹⁰ vg/eye]. I still believe there's a benefit; we just know we're not going to see superior vision if we block VEGF-C.

References

1. REGENXBIO announces pivotal program for surabgene lomparvovec in diabetic retinopathy. News release. REGENXBIO. August 7, 2025. Accessed August 5, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-announces-pivotal-program-surabgene-lomparvovec
2. Adverum Biotechnologies initiates ARTEMIS phase 3 study evaluating ixo-vec for wet AMD. News release. Adverum Biotechnologies. March 3, 2025. Accessed August 5, 2026. https://www.globenewswire.com/news-release/2025/03/03/3036018/0/en/Adverum-Biotechnologies-Initiates-ARTEMIS-Phase-3-Study-Evaluating-Ixo-vec-for-Wet-AMD.html
3. 4DMT completes enrollment for 4FRONT-2 global phase 3 clinical trial of 4D-150 in wet AMD. News release. 4D Molecular Therapeutics. June 29, 2026. Accessed August 5, 2026. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-completes-enrollment-4front-2-global-phase-3-clinical-trial
4. McCormick B. FDA expands access to approved CAR T-cell therapies by eliminating REMS. Am J Manag Care. 2025;31(Spec. No. 9):SP578-SP579.
5. Harp MD. Opthea phase 3 clinical trial, COAST, in patients with wet age-related macular degeneration fails to meet primary endpoint. Ophthalmology Times®. March 24, 2025. Accessed August 5, 2026. https://www.ophthalmologytimes.com/view/opthea-phase-3-clinical-trial-coast-in-patients-with-wet-age-related-macular-degeneration-fails-to-meet-primary-endpoint