Latest / BioSpace / When vision fades: Rethinking wet AMD and the durability gap
Transcript
- speaker-0: Hi, my name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denecit. In this episode, I talk with Dr. Philip Jacob Rosenfeld, Professor of Ophthalmology at the University of Miami Health System and Bascom Palmer Eye Institute, and Wesley Jackson, Chief Science Officer at Valator. We talk about the eye condition called wet age-related macular degeneration, or AMD, the limits of anti-VEGF therapy, and the push for true durability. To change a patient's life. Phil and hi Wes, thank you so much for joining this episode of Denatured. Really excited to be talking about this topic, what AMD. And ⁓ if you can go ahead and start off and introduce yourselves. Let's start off with you, Phil. speaker-1: I'm Phil Rosenfeld. I'm an ophthalmologist and I'm a retina specialist and I'm based here in Miami at the Bascom Palmer Eye Institute, which I'm proud to say is the number one eye institute in the country. speaker-0: Perfect. Res go for it. speaker-2: Great. ⁓ my name is Wesley Jackson. I'm a bioengineer based in Berkeley, California. I started a company called Valator ⁓ several years ago, and we have a focus on developing retinal medicines that can act for a long duration and provide ⁓ many benefits to to patients as a result. ⁓ I was thrilled to get to meet Phil several years ago and really glad to have him here helping describe some of the indications we're targeting and ⁓ our technology. speaker-0: Perfect. All right, so let's go ahead and dig in. So for our listeners that are new to AMD, can you describe the condition and how do lifestyle and systemic factors influence when and how the disease develops? speaker-1: So I've been here at the Baskin Palmer Institute for 30 years. And from the very beginning, I've been focused on patients with age-related macular degeneration. You'd say Florida's the epicenter for maculegeneration because it comes on later in life. It's a form of retinal degeneration, and it's the most common cause of irreversible vision loss as we get older. And when I say vision loss, I don't mean Total blindness, I mean losing the most important vision that you have. And that is the reading vision, the driving vision, the ability to recognize people. And this results in 2200, or worse vision, legal blindness as patients get older. Now, when I say older, usually I can diagnose the condition. Once someone's in their 50s, usually they tell me one of their parents had macular degeneration. So it's a genetic condition that comes on later in life, but there are environmental factors that can greatly influence when it really kicks in and the symptoms become apparent to patients. So one of the most important modifiable risk factors, things that you can change to slow down disease progression, is smoking. Smoking is like throwing gasoline on a fire. Also, overall cardiovascular health. influences the progression of the disease if you have high blood pressure, abnormal lipids in the circulation, and your overall physiology, if you're overweight, significantly obese, then that can cause a worsening of the macular degeneration. Simply put, it's a disease of the macula, which is the central part of your retina. And the most important thing you can do when this starts in is eat a diet rich in green leafy vegetables and there are vitamins that you can take. So in some way it's a complex disease, it's genetic, and there's certain things you can do to help slow down the progression of the the disease. speaker-0: Things that ⁓ physicians have been telling us for years, really, to be healthy, to avoid these kind of medical conditions. speaker-1: What's good for the heart and good for the brain is good for the eyes. speaker-0: There we go. That's a great soundbite right there. Wes go ahead and let's get your perspective. speaker-2: I think from my perspective, what really surprised me as I as I started working in this space was that until fairly recently, there was really limited treatment options for patients who who were diagnosed with particularly the wet form of the disease where the real vision loss can occur. And and for these patients, once they started progressing down the wet AMD pathway, blindness was fairly inevitable. Is is that right, ⁓ Phil? speaker-1: That is correct. When I started thirty years ago, all the focus was on wet macular degeneration. It was basically an inevitable loss of vision that occurred over days and weeks. speaker-0: Wow, that's soon. That's scary. So let me ask you then that progression from dry to wet. How does that change both the biology of the disease and the patient's day to day vision? speaker-1: So as I tell my patients, the disease is macular degeneration. It always starts off as dry macular degeneration, and that can proceed for decades. Patients do complain. They complain of difficulty in dim light. They complain they can't drive at night. They have trouble with glare and going from a bright outside to the inside and vice versa, from inside to outside. So these are the Quality of life issues that come up before they actually lose vision. And I should also tell you that macular degeneration starts as dry macular degeneration. And that's to be contrasted with this wet form of the disease that can cause you to lose vision over a period of days and weeks. But that only happens in about 15 to 20% of patients with dry macular degeneration. So the underlying disease, I think of it as dry. Dry MacAnder degeneration is a slowly degenerative process. Dry turns to wet. But now with our new therapies, our anti-VEGF therapies, we take the wet and convert it back to dry. But the underlying dry MacAr degeneration progresses. Even when we're treating the wet, it's continuing to progress. speaker-2: I'll just comment. Phil said 10 to 15% of patients progress to wet AMD, but this is a very high prevalent disease. And and so even at that small percentage, the incidence of patients through transitioning to wet is still quite large. And and as I started working in this space, developing therapies in this space, I was amazed at at how many people I knew would start telling me about their their wet AMD and and their experience with with the disease and treatments. So so it really does affect quite quite a number of people. speaker-1: And one of the issues that really affects people's lives is it turns from dry to wet, and we can treat it with anti-veg F therapy, and we can't predict how many injections into the eye patients are gonna need. And we can control the wet, but it's a ticking time bomb. At any moment that dry can convert back to wet. So we have to follow these patients closely. And intervene with a treatment, which is an injection into the eye, as soon as the wet macro degeneration comes back. So it's not a treatment that solves the wet macro degeneration problem. It just prevents the severe vision loss, but vigilance is needed, and we need to monitor these patients constantly. speaker-2: And I wanna just take a step back because cause I I wanna highlight how much of a miracle these anti-VEGF drugs are. Cause as ⁓ Phil alluded to earlier, the disease is quite complex. There's a lot of genetic and environmental factors that go into the disease and the progression to wet AMD is is fairly not well understood. But what we do know is is there's one signaling factor, this vascular endothelial growth factor that drives the wet phenotype and drives the vision loss. And so regardless of the complex etiology underneath the disease, blocking this one factor is highly effective for most patients to to control the vision threatening elements of of of the wet phenotype. And these are the therapies that have only been available for patients in the last 20-ish years. And it has totally changed the management of this disease from pretty much certainty that the patients would be blind in a matter of weeks to ⁓ trying to preserve the vision for the rest of the patient's life. speaker-0: But there is a caveat because we know that there's frequent injections with the with the VEGF treatments. So what are some of the biggest challenges that patients face in real world adurance? speaker-2: You describe what your your patient's experience is, Phil. I think this is really interesting. speaker-1: So in clinic, a patient will come in and complain of distorted vision, waviness to their vision, a blur in the center of their vision. And I have to explain to them that their macula degeneration is now wet macular degeneration, and that's when new blood vessels grow into the back of the eye. And that's where this vascular endothelial growth factor comes into play, because it's the cytokine, it's the stimulus that causes the blood vessels to grow. So now we inject. into the eye. And let me tell you, when I first have to explain to a patient that we're going to stick a needle in their eye, and it's just the first injection of many injections, they require a little discussion, a little comforting, a little appreciation that we do this all the time, that we numb up the eye, but we still have to stick a needle in the eye. And most patients over a period of months do get somewhat Comfortable with the injection. No one really accepts it, but they become understanding that it's necessary or they're going to lose their vision. So we have to explain how we prepare the eye. There's a risk. There's a risk you can get an infection in the eye. So we have to prepare the surface of the eye so that no bacteria get into the eye. But that risk is still around 0.02% in someone who has experience giving the injection. In many institutions, they do it. around the world in an operating room. We do it in the clinic and patients tolerate it very well. I explained that they're good they're gonna need to go home, take a nap, their eyes very irritated, but they shouldn't have much discomfort after that that first day. But they come back. There's a regular follow-up at first it's every month, and then we can extend it to every six weeks, then eight weeks, but they're spending a lot of time with us and we're monitoring them. At around the time that anti-BEGF therapy was developed, we had another revolutionary development, and that's optical coherence tomography. This is a method that allows us to image the back of the eye and detect if any fluid is re-accumulating. So we manage patients one of two ways. One is called treat and observe, and the other is treat and extend. The average patient. comes in a month after their first injection, gets another injection, probably two or three a month apart. And then we slowly extend the interval, treat and extend every six weeks, eight weeks, ten weeks, and so on until the fluid goes away. But sometimes the fluid doesn't always go go away and w and we have to revert back to an every four or six week injection just to keep the macula fluid free. So the goal here is to eliminate all fluids from the macula because it's the growth of these abnormal blood vessels and the leaking of this fluid that causes visual loss. speaker-2: I think new perspective on on the patient experience because my my mom was diagnosed with with the wet form of the disease last year and she is a needle phobe. So I had to do quite a bit of coaching in order to get her comfortable going in and getting the injections. And and I remain very vigilant to make sure she is getting her redosing on schedule because I I know how important it is not to let that affect Fluids start accumulating because the ability for the disease to continue generating damage in the eye happens when the anti-veg F dose wears off and those disease mechanisms are restored again because the the veg F becomes active. And so then when the patient waits too long and goes in, gets the dose after the substantial fluid's been. accumulated in the eye, there can be damage that now has been done in the retina and limits how well they're able to come back to to the previous level of of visual acuity. So I think one of the challenges for clinicians and for patients is to make sure the the patients are staying compliant, they're staying on protocol, and ideally minimizing the the number of opportunities that patient has to go off protocol by finding the the most durable, the longest lasting therapies to to treat the patients. speaker-1: When I look at the spectrum of my patients and who's willing to accept an injection, women are much more accepting of doing anything around their eyes because I think they're used to applying makeup and having some type of manipulation around their eyes. Men are very reluctant to have an injection in the eye. But it's not just the patient accepting the injection. It's the whole need to come in on a frequent basis in a situation where you can't drive. 'Cause after an injection, it's not recommended that you drive. So patients either have to Uber lift in by themselves or a family member needs to take time out of their schedule, bring in their parent, and it's really disruptive to their whole life in in in general. Yeah. speaker-0: Yeah, and and on that point, let me ask you then, Wes. I mean, so what is the core limitation in current anti V Vegev therapies? And it sounds like this frequency is definitely a a big one. So what ers Valatortoin trying to address in this aspect? speaker-2: I think since the ⁓ anti-VEGF therapies have come to the market and they've demonstrated their power in treating the disease, there's there's been a desire to try and extend the dosing interval. But I think inherently one of the challenges is the type of therapeutic, these are antibody biologic, large molecule therapy, is difficult to package in a way that can either provide a slow release or a reservoir type strategy to provide that long duration of therapy. So ensuring that they remain stable and being able to get enough drug into the injection volume that's acceptable for the eye has been kind of the challenge to make sure we can get enough drug in to to really meaningfully extend the durability of of the products. And I think what we've done at Valator is identify a platform technology that takes a an original approach to to try and solve this problem of durability. And so rather than having a slow release reservoir, we've developed a drug compound that inherently is able to be eliminated from the ocular tissues at a much slower rate than the typical antibody. And as a result, we can keep the drug in the ocular tissues at higher concentrations longer and therefore extend that interval that we get effective treatment for for the patients. And the way we do it is using a biopolymer called hyaluronic acid. Which is actually one of the main components that makes up the the extracellular matrix in the ocular tissues. It forms these really large, elongated, hydrated structures that are eliminated quite slowly from the eye. We follow kind of the natural recycling routes that that occur for these biopolymers in in the eye. ⁓ so we've got this vehicle that enables us to define a slow elimination rate from the ocular tissues. And we conjugate to these biopolymers multiple copies of small anti-VEGF biologics that give us the specificity of inhibiting the VEGF that we want for the disease. And we've also designed these constructs to be highly stable in the back of the eye so they can maintain their anti-VEGF activity for months to even a year after administration. ⁓ So our goal is to have the exact same administration protocol that Phil has used for all the previous generations of anti-bedge Fs. ⁓ but we want to have a therapy that can be reliably administered only twice a year for all the patients and get them on a reliable frequency. that I think most patients are used to, for example, going to the dentist twice a year. And I think that matches kind of the the frequency that that Phil would like to be seeing his patients. ⁓ and and if we can align that with when they get their anti VIGF dose, ⁓ then I think we've put them on a better trajectory for better treatment in the lung. speaker-1: What I like to say is we want a treat and release injection regimen where we know definitively this patient is going to be stable for four or five, ideally six months, so we can get into this twice a year injection regimen. The eye is a great injection vehicle, drug delivery system, because it's a hollow ball and we pump drug into it and we pump drug into it at a level that would cause significant side effects if it was systemically administered. But we can get a high dose in the eye for s allow for this sustained release capability. And and and there are other strategies that are being developed, but none of them allow this treat and release phenomena because the other strategies have other issues going going on with them. They they cause inflammation, they cause pressure to go up. Gene therapy is a hot area of investigation. But the patients still have to come back frequently and get monitored. What's so nice about this hyeronic acid polymer delivery system is that hyeronic acid is normally in the eye. It doesn't cause inflammation. And we know that these VEGF binding proteins are safe. So you put it all together with this twice-a-year strategy where patients don't have to come in and be monitored. speaker-2: And I I want to go back to something you said earlier because it's a little bit subtle, but for for a given patient that comes in, you don't necessarily have a fixed administration cycle. You're trying to extend the interval as much as possible. So there's a lot of monitoring and finding what frequency makes sense for that patient based on how responsive they are to the drug. And I think some of the current generation anti-VEGFs or treatments for WET AMD really try and highlight. how long the most responsive patients are able to go on a single dose. So some of them get to three months or four months between dosing, but that's only the patients who are responding the best. Same. And and I think what we're seeing and and what we're targeting, because we have this much slower elimination rate, is we're focusing on the patients who will be focusing on the patients who are responding the the least well to to the therapy. And getting those patients to it at least six months. Many of the patients who are better responders may be able to go longer than that. But from our perspective as the drug developers, we're going to leave that between Phil and his patients. We want to set a reliable dosing frequency ⁓ that all patients can reliably get that treat and release therapy that Phil's referring to and make make it easier for the patients to stay compliant to that. speaker-0: Well, thank you so much, Phil, and thank you so much, Wes, for talking about this. I am definitely slightly less squeamish about the eye now, I have to say. So thank you very much for that alone. But ⁓ this has been a very interesting podcast. And if you'd like to listen to more episodes of Denatured, please turn to biospace dot com or shoot me an email at jennifer.smith hyphenparker at biospace dot com to send me a pitch. Thank you so much, both of you. speaker-1: Thank you.