Unmet Needs for Patients With AMD

Karl Csaky, MD, PhD: Jennifer, is the race over? Are we going to be able to crack the durability nut? Is that the only nut that we have left to crack? We have other drugs. We have the anti-VEGFCs and VEGFDs that are moving along, and we have other potential agents. In your mind, are there other unmet needs that will change our thinking about how we manage our patients?

Jennifer I. Lim, MD: That’s a great question, Karl. I believe the durability question has been addressed to some point, between the PDS [port delivery system] device and faricimab. Start with a drug that has longer action, and then if you need to, put that drug into a device and get extended durability. The efficacy end point still can be raised. When you say 30% to 40% improve 3 or more lines—granted, there’s a floor-and-ceiling effect—there’s still some unmet need to increase the efficacy. With a drug like the OPT-301, in minimally classic and occult CNV [choroidal neovascularization] it was able to raise that bar and in phase 2 get a whole line more. That’s 1 unmet need.

Another unmet need is the fibrosis picture when you get scarring. How do we stop the fibrosis from occurring? Lastly, how do we stop the atrophy? We have some answer for geographic atrophy, but how do we prevent that, the atrophy that follows the CNVM [choroidal neovascular membrane], which we see in treatments, and then maybe regenerative medicine to put that back in? It might be a tripartite treatment—treat the acute disease, prevent scarring, then put something in to regenerate the tissue so you don’t get the atrophy and you get healthier retina coming back.

Karl Csaky, MD, PhD: Nancy, what’s your thinking about the durability? What’s going to change? What are you thinking about? When you look at some of these other trials, and people are moving along and working on newer agents, what’s your hope that we have down the road, that we won’t have in the near term with our durability programs?

Nancy M. Holekamp, MD: Gene therapy is the long-term durability play. That has a much longer runway, those clinical trials are still early phase. To say 1 and done is too optimistic, but I like the idea, and I’m enthusiastic about gene therapy in this space. Just to be clear for our listeners, this gene therapy is a viral vector that delivers into the eye a viral particle that invades a cell, and we don’t care what cell it is. In some programs we’re not sure what cell is being infected, but it sets up a little bio factory that makes our anti-VEGF agents. That would be long-term expression of ranibizumab or aflibercept, and that’s exciting. That has a very long runway for these gene therapy clinical trials, but that’s the ultimate durability play.

Jennifer mentioned visual acuity. I almost throw up my hands and say we don’t control visual acuity. There’s no agent we’ve tested so far reliably, at least in phase 3, that produces superior visual acuity outcomes. Visual acuity is all about catching the disease early and treating it before irreversible loss has occurred.

When I think about unmet needs, I agree with what Jennifer said about fibrosis and treating geographic atrophy. We’ve also had some programs about preventing choroidal neovascularization, and those have not proven to be successful. Imagine a time where perhaps we can identify risk factors, possibly using artificial intelligence, using OCT [optical coherence tomography] biomarkers. If it’s possible to prevent vision loss, then that would be the ultimate futuristic play. That’s my hope.

Karl Csaky, MD, PhD: Carl, to you. Is the durability play over? Is there something else? When you think about where we want to be in 5 or 10 years, what are some of the additional attributes of agents that you would like to have in your hands as you take care of these patients? What are the things that you don’t see being directly met in our present and perhaps in the short-term near future armamentarium?

Carl Regillo, MD, FACS: We’re on the cusp of addressing the unmet need of greater durability for anti-VEGF therapy, no doubt about it. Whether we’ve solved it or we’re at the place we need to be, that’s an entirely different question. As we’ve pushed the envelope above and beyond the standard intravitreally injected anti-VEGF, we sometimes get some unforeseen consequences and adverse events that could be improved upon. The device looks good, but that could be improved upon. Maybe we want to put a bispecific in the device. In fact, that’s being tested at phase 1; a bispecific fragment is being used. Maybe that’s going to give us better efficacy, and then the device gives us the durability, for example.

You’ve already been hearing bits and pieces of all these things that we could do to make things better, and that includes better visual acuity. Nancy mentioned early detection. I want to put a plug in for that. With our first-generation anti-VEGFs, if you catch wet AMD [age-related macular degeneration] at its earliest stages, when the visual acuity is good—20/40 or better—you can keep the vision of 20/40 or better in over 80% of patients. Of course, you’re on top of the condition and patients are compliant with follow-up certainly. Preventing wet AMD? That’s huge. There’s nothing on the horizon that’s going to do that for us, so that’s an unmet need for sure.

Then there’s gene therapy. I’m still keen on it and very excited about it, but it’s early on, and my excitement has been a little tempered by some of the adverse events associated with that, both intravitreally and subretinally. There’s a new way to introduce gene therapy: the suprachoroidal is looking good. These are very limited, partial phase 1 data, so take that with a grain of salt. We didn’t even mention tyrosine kinase inhibitors [TKIs] with implants and injections, both suprachoroidal and intravitreal. It’s exciting, and it’s going to take 3, 5, or more years to sort these out, but we’re going to have some great choices for patients.

There’s not going to be 1 agent that stands out or 1 modality that stands out that’s going to work great for the majority of patients. That’s where we’ve been—a few drugs work great for everybody. The future is going to be, “This patient is ideally suited for a faricimab injection. This patient is ideally suited with a port. For this patient, maybe think about gene therapy or a TKI or whatever else is out there.” In some respects, it’s exciting because we’re going to start to meet these unmet needs to some degree, hopefully conquer them completely, and get great results in everybody. But that’s a little unrealistic. We’re going to have our share of frequent-flier patients who need a lot of injections, even 5 years from now with whatever agent, and we have to think of better ways to address all that. It’s exciting. Then again, there are going to be a lot of data, a lot of choices to make. It’s going to make our jobs a bit difficult but in a better way.

Karl Csaky, MD, PhD: Absolutely. I want to thank my good friends Jennifer, Nancy, Carl, and Lloyd for this great discussion about lots of topics. I want to thank our audience for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to the e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. With that, I’ll sign off. Thank you all.

This transcript has been edited for clarity.