What Comes After Anti-VEGF in Wet AMD: Arshad Khanani, MD

A one-time gene therapy with a durable safety and efficacy profile is the single development most likely to reshape how wet age-related macular degeneration (AMD) is treated over the next 5 years, more so than emerging Wnt- or Tie2-targeting agents, 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®).

In part 1 of the interview, Khanani discussed how close gene therapy for wet AMD is to real-world use, weighing delivery routes, patient selection, and what an equitable rollout will require. In part 2, he turns to the next tier of the pipeline, addressing how Wnt signaling agonists and Tie2-targeting agents compare with gene therapy and with validated dual-pathway drugs like faricimab (Vabysmo; Genentech), and whether these newer mechanisms are likely to stand alone or pair with anti-VEGF therapy.

Khanani also makes the case for why payers should weigh gene therapy's long-term value, not just its price tag, in coverage decisions, and explains how insights from geographic atrophy research are shaping his thinking about patients with both wet and dry AMD. He closes by sharing the one development in wet AMD care he's most confident will happen within the next decade.

This interview has been lightly edited for clarity.

AJMC: The Wnt signaling pathway agonists and Tie2-targeting agents are new mechanisms that aim to restore and stabilize the blood-retinal barrier directly. How do you think about this mechanism class relative to everything else in the pipeline? Is barrier restoration a fundamentally different and complementary approach, or is it ultimately solving the same problem from a different angle?

Khanani: I think Wnt is an exciting target. Wnt agonism can be meaningful in patients with diabetic macular edema [DME]; I'm not sure it plays as big a role in wet AMD, but we're going to learn more. We have ongoing phase 3 trials that are going to read out comparing a Wnt agonist to ranibizumab [Lucentis; Genentech] monthly, so that will give us more information on how much of a role it plays in DME as well as disease control in those patients.

In terms of Ang-2/Tie-2 activation—Ang-2 inhibition leads to Tie-2 activation—faricimab [Vabysmo; Genentech] has already been approved for 4-and-a-half years now.¹ It's a bispecific antibody that blocks VEGF-A and Ang-2, and we've seen better disease control and durability by targeting two pathways, so that's already validated. We now have programs with more potent bispecifics combining Ang-2 inhibitors with higher-molar-dose anti-VEGF, as well as anti-VEGF with direct Tie-2 activation. I'm excited to see what those programs show. But Ang-2/Tie-2 has already been validated as a beneficial pathway for disease control, both in wet AMD and DME.

AJMC: If these barrier-restoration approaches prove effective in wet AMD, do you see them being used as standalone therapy or as an add-on to anti-VEGF treatment for patients who aren't responding adequately?

Khanani: The Wnt program currently in development is a monotherapy,² not an add-on to anti-VEGF, but we have Wnt agonist and anti-VEGF bispecifics going into clinical trials later this year. It's very hard for patients to tolerate multiple chronic injections, so my preference is usually a bispecific, like what we've seen with faricimab, which is widely adopted globally because one molecule targets 2 pathways.

I think the future of retinal vascular disease management will include molecules that are better than or similar to faricimab, or that target Wnt and anti-VEGF together. Most of the programs that will be relevant for patients come down to: can we go from a bispecific like faricimab to an even more potent drug that gives more durability and better disease control? I'm looking more at simultaneous inhibition in one molecule instead of add-on treatments.

AJMC: Is there something about how gene therapy and novel-mechanism trials are currently designed that you think needs to change to get better, faster answers?

Khanani: I think the current trials are designed based on what we learned from the phase 1 and 2 studies, where we're going much earlier into treatment-naive patients instead of chronic patients. What we saw in phase 1/2 is that recently diagnosed patients actually respond better, partly because they may not yet have elevation of other biomarkers like VEGF-C and -D, or tachyphylaxis to the anti-VEGF effect. Plus, healthier retinas may produce more drug when targeted with gene therapy.

The current trials are designed to position gene therapy as an early option instead of a salvage option, and I think we'll learn from these trials who the right patients are. But if it works well in early patients, we'll have proof of concept that this isn't just for chronic patients but for a much larger patient population. I think they're designed appropriately, and I'm anxiously waiting to see what the data shows in terms of efficacy and safety.

AJMC: Between gene therapy, VEGF-C/D inhibition, and Wnt- or Tie2-targeting agents, which do you think is most likely to actually change how most patients with wet AMD are treated in the next five years?

Khanani: I think having a gene therapy that has a good safety and efficacy profile and that payers approve will be a paradigm shift and will be widely adopted. As long as these are reasonably priced—and payers understand that a one-time treatment with a 50% chance of not needing any more injections is a huge paradigm shift—they will be welcomed by both patients and physicians.

AJMC: Speaking of payers, we often see step therapy requirements before patients can access newer treatments. Beyond the clinical trial data, is there anything that could help make the case that gene therapy should be a first-line option or covered differently?

Khanani: From my perspective, we know that real-world outcomes for patients with wet AMD are much worse than what we see in clinical trials, in part because patients can't keep up with frequent injections. Repeated injections also allow for recurrent disease activity and fluctuations in central subfield thickness, or fluid on imaging, which leads to long-term vision damage. My hope is that with sustained delivery from gene therapy, we'll control the long-term disease well, without missed visits or treatment burden lapsing into disease reactivation.

From both a payer and a physician perspective, having long-term disease control will optimize vision much better than what we see currently, which leads to better quality of life for patients, including fewer falls, fewer accidents, and lower cost of care. I believe payers need to look at this data as a long-term benefit, both to patients and to payers, because repeated injections also carry a cost over a patient's lifetime. If gene therapy is appropriately priced, it should be a much earlier option for our patients, so that payers benefit, physicians can optimize vision, and patients can keep their independence.

AJMC: You've been closely involved with geographic atrophy research. Does anything you've learned from the dry AMD side of the field change how you think about sequencing or combining therapies for patients who have both wet and dry disease processes occurring together?

Khanani: When we look at the data for geographic atrophy drugs, many are being used in patients who already have wet AMD and are losing vision because of dry AMD. It was a huge milestone for the field to have 2 drugs approved for geographic atrophy,^3,4 which is a very hard disease. Those drugs slow the progression, but they don't stop or reverse it.

We have a huge pipeline of gene therapies, cell therapies, and other modalities looking at helping patients with geographic atrophy.⁵ I'm really excited about the potential of stem cells, because that's our only chance to restore vision for these patients. Other programs are also important. A 1-time gene therapy that slows progression, instead of the currently approved agents injected every month or every other month, would be beneficial. There are also programs looking at treating wet and dry AMD at the same time in a bispecific fashion.

There's a lot of excitement in the field of geographic atrophy. The unmet need is very high, and we're working hard to help these patients. With all the research and trials going on, I'm hopeful that in the next 5 to 10 years, we'll have better solutions for our patients with geographic atrophy.

AJMC: Looking at where wet AMD treatment stands today—with indefinite monthly or bimonthly injections—to gene therapies and barrier-restoration mechanisms that can potentially eliminate that burden, what's the one thing you're most confident will happen in the next decade?

Khanani: I think gene therapy is going to be a reality. It's not science fiction anymore. It's going to be a reality for wet AMD, diabetic eye disease, and likely geographic atrophy from dry AMD. We're using this as a drug delivery platform, so whatever drugs have helped our patients so far, we can now package them in gene therapy, relieve that treatment burden, and have continuous production of these drugs in the eye.

I think when people think of gene therapy, they assume it's not a reality for the eye yet, or they worry about side effects. But over the last decade we've done so much development and learned so much that I think we're now at a point where it's going to be a reality even sooner than 5 years for wet AMD, in my opinion.

References

1. Joszt L. FDA approves faricimab to treat wet AMD and DME. AJMC. January 31, 2022. Accessed August 5, 2026. https://www.ajmc.com/view/fda-approves-fariximab-to-treat-wet-amd-and-dme
2. Merck and EyeBio announce initiation of phase 2b/3 clinical trial for Restoret for the treatment of diabetic macular edema. News release. Merck. September 4, 2024. Accessed August 5, 2026. https://www.merck.com/news/merck-and-eyebio-announce-initiation-of-phase-2b-3-clinical-trial-for-restoret-for-the-treatment-of-diabetic-macular-edema/
3. Joszt L. FDA approves first treatment for geographic atrophy. AJMC. February 17, 2023. Accessed August 5, 2026. https://www.ajmc.com/view/fda-approves-first-treatment-for-geographic-atrophy
4. Bonavitacola J. FDA approves new treatment for geographic atrophy. AJMC. August 7, 2023. Accessed August 5, 2026. https://www.ajmc.com/view/fda-approves-new-treatment-for-geographic-atrophy
5. Uzorka B, Randolph J. The therapeutic pipeline for geographic atrophy. Retinal Physician. March 1, 2026. Accessed August 5, 2026. https://www.retinalphysician.com/issues/2026/march-april/the-therapeutic-pipeline-for-geographic-atrophy/