Newer Therapies for AMD and Supporting Data

Arshad Khanani, MD: If faricimab is approved and available, I will initially use it in patients who are already on treatment but cannot have it extended, or if they have persistent fluid despite monthly injections of anti-VEGF agents. And once I see the efficacy that we have seen in clinical trials, I’ll translate faricimab into naïve patients with neovascular AMD [age-related macular degeneration] as well as diabetic macular edema [DME]. Faricimab—based on the durability and efficacy data that we have seen as well as the comparable safety data that’s available—appears to be an agent that can be utilized in the first line in patients with neovascular AMD as well as diabetic macular edema.

In terms of other agents in the pipeline, I think this is an exciting time for physicians as well as patients because we have many ways to target this disease, and now in-clinic agents as well as surgical implants or delivery to help our patients. When you look at injectables, KSI-301 is a large antibody biopolymer conjugate that has an anti-VEGF molecule attached to a large biopolymer. It has shown great durability in the phase 2b trial in patients, naïve patients with wet AMD, RVO [retinal vein occlusion], and DME. Those pivotal trials in neovascular AMD, the DAZZLE study as well as GLEAM and GLIMMER in DME as well as BEACON in RVO, are ongoing, again to see how durable KSI-301 is compared with aflibercept. Another molecule that is in phase 3 trial is conbercept. It is approved in China for wet age-related macular degeneration. It has a very similar design to aflibercept, but it has some differences with additional domains which may translate into better durability, but we don’t know that data yet. The PANDA-1 and PANDA-2 studies are ongoing, and we expect to see the data soon. There are other agents in the pipeline; OPT-302, that’s an add-on agent that blocks VEGF-C and -D. This is a second injection on top of anti-VEGF injections in phase 2, which was a large program, that showed that patients treated with the dual injection action gained more vision than patients who just receive an anti-VEGF agent. That program is going to start phase 3 programs soon. Looking at gene therapies, intravitreal gene therapy with ADVM-022 has shown great durability. The majority of the patients treated in the OPTIC trial received 1 injection and did not need supplemental treatment. As gene therapy is a new space, there are some patients with inflammation, especially in the high doses, and we are learning what’s causing it. But the good news is patients were managed with topical drops. There’s surgical gene therapy approaches with Regenxbio’s RGX-314 that has shown excellent safety profile as well as longer-term durability, but this is done in the operating room. There have been some patients with pigmentary changes, and we’re still learning about what that means. That program also now is in suprachoroidal, in-clinic approach. We don’t have any data from the AAVIATE and ALTITUDE studies, but we should later this year. Then with the port delivery system, we had very positive phase 3 trial data from the Archway trial last year showing most of the patients in the phase 2 LADDER study go about 16 months before their refill of the port, which is placed in the OR. In Archway, they had mandatory 6-month refills, but patients had noninferior vision or equivalent vision compared to monthly gold standard injections. It’s a surgical procedure, so there’s been some conjunctival erosions, retractions, and a high rate of endophthalmitis compared to injection. We’re still learning about it. Overall, when I look at the pipeline, I think the good news is that 3 or 5 years down the road, our patients with retinal vascular diseases will have excellent options to maintain their visual acuity long-term, which is a challenge currently. I think many of these approaches should be approved, so we can decrease the treatment burden for our patients with retinal vascular diseases.

Whenever a new agent is approved, we still need to collect real-world data to see if the efficacy and the safety of the agent is similar to what was seen in the trial. Recent experience with brolucizumab has been an eye-opener for all of us where safety has really been paramount. We saw cases, rare events, but we saw cases of retinal vasculitis and retinal artery occlusion that were not really picked up in the clinical trial. I think any agent that’s new, of course there’s reservation to utilize it to make sure that we are not harming our patients. But the good news is that FDA approval is a rigorous process, and once the FDA approves a drug, I am pretty confident using it, but of course while paying attention to the data. Because you may have 2000 or 4000 patients across multiple indications in these clinical trials, but once you have 10,000, 20,000, 30,000 or 50,000 patients treated in the real world, you can really see the signals of safety that were not there in the clinical trial. I am open to trying any new approved agent quickly, but I’m very careful in evaluating the safety as well as efficacy in my personal practice compared to clinical trial. If it pans out to be the same or better, then of course that agent will be used a lot more in our practices compared to if there are new signals of safety, then of course people will not utilize the agent. The bottom line is we have good agents that work, so it’s a much higher bar for any new treatment that comes in. The treatment has to be the same or better in terms of efficacy, but it has to be comparable in terms of safety.

I think these are exciting times for physicians who treat retinal diseases as well as for patients. With impending approval hopefully for faricimab soon, we’ll have an option that can decrease treatment burden in our patients. I’m still looking for long-term, 2-year and 3-year and longer, data to see if we can actually maintain vision in our patients with neovascular AMD by decreasing fibrosis and other vision-threatening, long-term events. As far as the pipeline, I’m also very excited about gene therapy and sustained delivery with port delivery systems, and we’ll learn more about these approaches as time goes on. Overall, these are good times to be involved with all the clinical trials to advance care for our patients with retinal vascular diseases. I want to thank you for your attention.

Transcript Edited for Clarity