Hey, guys. We're getting started. Thanks for all being here today. Sorry for those online, we're running a couple minutes late, but just want to make sure folks filtered in. My name is Julian Pei. I'm the Head of Investor Relations for 4D Molecular Therapeutics, and we're really excited to have you here today for our first ever Investor Day.
We're going to handle Q&A today via the QR code, so please scan that on your devices and submit those questions, and we'll get to those at the end with our great panel we have for you today. As usual, I'll remind you of our forward-looking statements. If you want to see more details, please go to our investor relations website or the SEC. With that in mind, it is my distinct pleasure to welcome to the stage Dr. David Kirn, our Co-Founder, President, and CEO.
All right. Thanks, Julian. Well, it's a pleasure to be here, and welcome. Thanks for being here. We really appreciate it. I'm Dave Kirn, Co-Founder, CEO, and President of 4D Molecular Therapeutics. I've been in the industry for about 30 years as a physician scientist, a drug developer, serial entrepreneur, and CEO.
We started 4D a little over a decade ago with a clear and compelling vision, and that was to boldly innovate and execute to bring great genetic medicines to millions of patients. Standing here today, it's remarkable to say that we are on the cusp of achieving that vision today with 4D-150. And we believe that 4D-150 has potential to establish a whole new treatment paradigm in wet AMD, as you'll see today.
I'd like to start out with four key takeaways for you today that we'll work through the course of the presentations. First of all, we believe that 4D-150 can be a backbone therapy for all patients with wet AMD, not just the most severe. What do we mean when we say backbone therapy? What we mean is a continuous, lifelong therapy after one single injection, with supplements being used as needed for supplementation of patient's care.
Number two, our target product profile addresses the two most important needs in this disease today, preservation of vision and treatment burden reduction, with the added opportunity for some patients to, in fact, be injection-free for many years, if not lifelong. Number three, we believe our clinical data, our phase III design, and our phase III execution has positioned us for great success in 2027 and beyond.
And finally, what you'll hear from us today is that our stakeholders, our patients, physicians, and payers, we believe, have come together and given us great confidence in our ability to commercialize this product broadly and see broad adoption. These are today's speakers. I think you're going to find them very interesting. They're all experts.
They've been selected very carefully to give very diverse perspectives on the opportunity for 4D-150. So we think that you'll walk away from here today with a much more holistic understanding of the opportunity in front of us. This is our agenda. It's going to follow that flow I started with in the beginning with the four key points. Let's just take a step back and say, why are we here today? We're here today because the current treatment paradigm in wet AMD is simply not good enough.
Why can I say that definitively? Well, I spent the last five plus years having hundreds of conversations with physicians, patients, their caregivers, clinic staff, and I hear over and over again, "It's not good enough." Why do we think it's not good enough? Let's start with the way treatment is currently administered. It's episodic.
It's bolus treatment where patients are beautifully treated for a finite window of time, and then they're left fundamentally untreated and have treatment lapses repeatedly over and over again for the rest of their life. Why is that a problem? Wet AMD is chronic, it's continuous, it's relentless. It doesn't take a day off. Imagine having this very serious disease in your retina that's not being treated in repeated blocks throughout the rest of your life. That just doesn't make sense. Number two, high treatment burden.
The burden on patients, their caregivers, and on the medical system is enormous with these repeat injections, as you'll see today. Finally, I'd like to leave you with the most important point is that because of this episodic treatment being mismatched with the disease biology, and despite all this burden and cost on the system, patients still lose vision.
Let me say that again. Patients in the U.S. with wet AMD, the majority will lose vision. Many will still go blind. Outside of the U.S., where treatment's not available to the extent that it is here, the problem is much worse. This simply isn't a good enough situation, and patients deserve better. What could the future look like? Our vision is that 4D-150 can serve as the backbone therapy for all patients with wet AMD.
Again, not just the most severe. What does that look like? Single routine injection in the clinic, continuous disease treatment, potentially, we believe, for the rest of the patient's life. A significant reduction in treatment burden, and most important, since treatment's on board at all times, 24 hours a day, seven days a week, 365 days a year, we believe we're going to preserve patients' vision. What's the result of that? They will be liberated.
They will be free to go off and live their life and spend their time with loved ones and family, and really enjoy their golden years. I'd like to briefly remind you how we can achieve this paradigm shift. It's not magic, and it's certainly not luck. This is by design. When we started the company over 10 years ago, the first order of business was to invent a novel capsid.
We wanted that capsid, that delivery vehicle, to have the following characteristics. We wanted to be able to deliver it by routine injection in the clinic, just like a bolus anti-VEGF. We achieved that. We wanted to use a very low dose, so we had low cost of goods and lower risk of any toxicities. We achieved that.
We wanted a vector that targeted the retina, particularly the macula, very efficiently with a single injection, so we could get our treatment right to the site of disease where it needed to be. We wanted to design this vector to minimize any sort of risk of significant toxicities or inflammation. I think as you see today, from the data that we've generated in the clinic, we believe we've achieved that with this proprietary and unique vector. The vector's just a delivery vehicle.
The actual treatment here is aflibercept and an RNAi for VEGF- C. We hit four VEGF family members. Let's remember, aflibercept is the market leader in wet AMD over the last decade. It has been used in over 64 million doses in humans. 64 million, and it has shown great efficacy and a very excellent safety profile. That is our treatment.
That is completely de-risked. What we are doing is delivering it in a much better way, and that is having it expressed from the retina itself, right at the site of disease, continuously, 24 hours a day, seven days a week, 365 days a year, for the rest of the patient's life. It is a fundamentally better way to use this amazing molecule. With that background, I would love to invite Dr. Arshad Khanani to the stage. Arshad has been with us through this entire journey, from inception to the treatment of the first patient with 4D-150, and we are thrilled to have him here. Arshad? Good to see you, man.
Thank you, David. Good morning, everybody. It is great to see you. I am Arshad Khanani, I am a Medical and Surgical Retina Specialist based out of Reno, Nevada. I have been involved with over 150 clinical trials as a PI, and I have been involved with many gene therapy programs throughout this journey. I have been in practice over 16 years. Today is a very emotional day for me, because when I started the journey with 4D, it was in December 2021.
I had the honor and pleasure to inject the first human patient. At that time, I do not think we would get a full room like this about a gene therapy. We have gone through a lot of learnings for gene therapy, and it is so exciting, as David said, that we now have pivotal data reading out next year from two global phase III trials looking at naive patients with neovascular AMD.
My goal today in the next five minutes or so is to take you through the journey of wet AMD patients and what we are seeing in clinic with those patients. I think in numbers and graphs, we actually miss the patient perspective.
Before I get started, I want to ask the audience, how many in the audience have been to a retina clinic beside the doctors? None. How many of you have somebody that actually suffers from a chronic, relentless, heterogeneous, blinding disease? That is what it is. I think the perspective of patients, the fear in the eyes of patients, the anxiety they have every time they come in our clinic, the emotions that we see or our staff sees on a daily basis when they get the news that you have a chronic disease that can blind you.
A chronic disease that can blind you, and you have to come to this clinic, sit for the doctors for 3 hours, get this injection in your eye, be out of commission for 24 hours because of irritation. I think in these graphs, we don't see that. I think this is something that excites me as a physician.
When you have a single intravitreal injection in clinic that can eliminate the need for injections or reduce that burden, it's a huge achievement for the field. This is a monumental, paradigm-shifting treatment that we hope we can deliver to the patients in the near future. David covered the problem at hand. We're treating a chronic disease with bolus injections, and they work great. I was in training when anti-VEGFs came out.
I had a patient who was blind in one eye from wet AMD, had a dog and a cane while her other eye was still seeing, but she had wet AMD. She said, "I know what this disease is going to do to me. I'm getting ready to go blind." Then came out the anti-VEGF, and she didn't go blind. This is what anti-VEGF did for those patients. But we know the real problem.
Bolus injections are not an answer for a chronic disease that needs sustained delivery, and this episodic treatment is a problem long-term. We will treat the patients, they'll gain the vision, and then life comes in the way. They fall and break a hip. They're in rehab for six months. What happens? They come back, and they're blind. We start treating them. We cannot recover the vision.
We are trying to change this with 4D-150. Real-world outcomes, many of you have seen these graphs. Me and many of our colleagues in the audience have published on it. Behind each number is a patient that went blind. Behind this number is a patient that has to be taken care of by their family. They have to navigate, they have to do groceries, they have to cook for themselves.
I think this is what we are missing. I think we want all of these patients not to lose vision. The number of injections go down over time. They're not sustainable. I think what we need to do is come up with something that can give them that backbone treatment so that if they miss injection, if life comes in the way, I have very motivated patients.
They don't want to miss an appointment, but they end up with a broken hip. They get into a car accident. They have a heart surgery, and now they're in rehab. They just cannot come. Or I have patients who live four hours away. There's nobody to drive them. I think having something that can give us assurance that there is treatment on board is super crucial.
Then we know why patients drop out. Everybody's trying to say, "Well, let's not have patients drop out." As I said, it's not possible. They need a ride. They have other health problems. Finances are a problem. Sitting in clinic is a problem. Missed work is a problem. In real world, we have 40% of patients dropping out, and you see this graph. That continues over time. It's not that patients don't want to get treatment.
It's not that patient don't want to keep their vision. The first thing they ask me, "Am I going to go blind? Can I drive? Will I lose my driving license? Will I need somebody to cater to me?" I think those are the questions. For me, it's personal. Seeing the results, what we have seen, treating dozens of patients in PRISM, and being at this moment, I think it's very, very exciting.
It's just not me, it's the whole community. If you look at ASRS PAT survey, what is the number one unmet need? Long-duration therapy. What are people excited about the most? Excitement is with gene therapy. I think we have come a long way, and this is not possible without delivering data from PRISM study, where we have seen long-term durability, efficacy, as well as good safety profile.
Now, sustained delivery is not new. Me and all the doctors in the audience have been involved with Port Delivery System or Susvimo. This is the seven-year data that I presented at EURETINA last year. What do we see? Going from LADDER phase II to PORTAL extension, we see maintenance of vision over seven years in a prospective clinical trial setting.
Now, of course, Port Delivery System is surgical. You have an implant in your eye long-term. There's obviously surgical risk associated, so that's why it's not a huge uptake. But it does proof of concept for what sustained delivery can do. We're losing two to five letters over a period of seven years. It's unbelievable what we have seen with sustained delivery. Now, imagine replicating this with a simple in-office injection of 4D-150.
Being part of this program has really taught me about that fear patients have, the anxiety patients have. These are my happiest patient. So are the gene therapy with 4D-150. They're different people when they come to clinic because they know they're not getting injection every time they're coming in. I think that's the perspective.
Bottom line is, we see this real-world decline in vision. Patients lose independence. They essentially lose their lives. You ask somebody if you cannot drive, cannot see to cook, cannot read, they don't want to live. Our goal is that with 4D-150, we are able to close that gap. Gene therapy as a field has that potential to close that gap. The blue thing you see here is we lose vision in the real world. Can we get stable vision after gaining it?
Can we control the disease long-term for these patients? I hope we get there. Obviously, we have to wait for the data. I want to introduce the next speaker. Carl and I have a special relationship. He was ASRS President when I got the Young Investigator Award in 2021. Carl is unbelievable and a role model for me. Carl.
Thanks, Arshad. Thank you. All right. Thank you, Arshad. I am Carl Awh. I am the President of Tennessee Retina, a 15-physician retina-only practice in Nashville. As Arshad mentioned, I am the past president or a past president of the American Society of Retina Specialists, and I have been at this a bit longer than him. I was practicing before we had anti-VEGFs, so I really understand how amazing the advent of anti-VEGF treatment was for our patients.
I have been an active clinical investigator for quite a while, over 130 clinical trials. I have been PI on more than 50. Going to David's presentation, 64 million doses ago, the first human eye ever injected with aflibercept was in our office in the phase I. So we really have seen the world change. My mother, who is now deceased, was actually my patient for more than a decade with wet AMD.
I understand this as a physician, as a family member, and I am delighted to be here to talk about this data because it is so compelling. I think the company has done a fantastic job setting the stage for phase III. Phase I they looked at, and phase I/II-A, the most recalcitrant eyes, really challenging eyes to treat, that helped establish safety and efficacy.
Phase II-B, which is what I will talk to you about a bit, tells us a lot, I think, about what we hope to see in phase III. There is a phase II-B subgroup of recently diagnosed eyes that I think really parallel very well the patients that are being enrolled in the phase III program. Let us talk about phase II-B. Here are three critical results that we want to see about anatomy, vision, and treatment burden.
Central subfield thickness is how thick is the macula. Swelling of the macula, we think of as a proxy for disease control. So we see beautiful control of this disease after that initial single intravitreal injection of gene therapy. Most important, visual acuity. So that is that slope that Arshad said is our desired. All right. Barely any slope. Stable vision after the intravitreal injection.
We achieve this with tremendous treatment burden control. So 46% of eyes had no additional injections for two years, and two-thirds of eyes needed two or fewer injections over two years. There was no control group in this, so if we compare to an idealized aflibercept injection every eight weeks, this represents a 78% reduction in treatment burden. Now let us look at this recently diagnosed population.
These were eyes diagnosed within six months, and the majority of them had had only one prior injection. So in this group of patients, again, tremendous maintenance of anatomy and visual acuity and now an 87% reduction in treatment burden. Two-thirds of the patients received no additional injections after that initial single intravitreal injection of gene therapy, and almost 90% had two or fewer injections to control their disease over two years.
So tremendously exciting results, and of course, this has to come with acceptable safety. What we see here are the outcomes for every eye that was injected in phase I and phase II with the dose that has been using in the phase III study. So in all these eyes, there were only two eyes with the lowest level of inflammation, anterior chamber or vitreous cells, that resolved with topical therapy.
And these all occurred during the first 28 weeks. There were no other cases of inflammation for up to four years, and certainly no serious adverse events. No hypotony, endophthalmitis, vasculitis, choroidal effusion, the sort of things we worry about with a new treatment like gene therapy. This is tremendously reassuring and compelling data.
With 4D-150, we see stable vision and anatomy, a tremendously robust reduction in treatment burden, this favorable safety profile, and this sets the stage nicely to move into the phase III programs. I am delighted to now introduce Dhaval Desai, who will go over those programs with you.
Thanks, Carl. Thanks, Carl. Thank you to everybody that is here in person and online for joining us today. My name is Dhaval Desai, and I am the Chief Development Officer here at 4DMT. Over the past two years, our teams have been busy developing and delivering the phase III wet AMD program for 4D-150. Today, I am excited to be here to share with you why I think that program is designed to win. The 4FRONT program consists of two nearly identical studies, 4FRONT-1 and 4FRONT-2.
Both are fully enrolled, randomizing 523 and 531 patients respectively. 4FRONT-1 was conducted in North America and enrolled 100% treatment-naive patients. 4FRONT-2 is our global study and allowed up to 40% previously treated patients. That is defined as receiving up to four prior injections and being diagnosed within the last six months. Why did we choose this predominantly treatment-naive patient population?
It is for three main reasons. The first is a favorable administration and safety profile. Administered as a single in-office intravitreal injection with the safety profile that Carl just showed you, we believe that retina specialists would see the potential of 4D-150 and enroll the only phase III program that has predominantly treatment-naive patients.
The second is a regulatory precedent. Nearly every phase III study in AMD that has resulted in an approval has treated treatment-naive patients. Moreover, trials that have used that patient population have resulted in the broadest label possible: treatment of wet AMD, full stop. Finally, the ability to show paradigm-changing efficacy. We know what these treatment-naive patients do at 52 weeks in terms of vision and anatomy.
Matching those results with previously unseen treatment burden reduction, and for the first time ever, having proportions of patients be injection-free, we think is going to shift the way retina specialists treat wet AMD. Moving back to the design.
Primary endpoint of this study is non-inferiority in BCVA at week 52 versus a comparator, a gold standard comparator, of aflibercept 2 mg given every eight weeks, with both arms receiving three loading doses right up front. In terms of the regulatory agencies, we have alignment through RMAT designation with the FDA, PRIME with the EMA, and through multiple interactions with the PMDA in Japan, and are robustly powered to a global standard of non-inferiority margin of roughly four letters.
In addition to our own expertise, we've engaged with global thought leaders on the forefront studies to ensure that we deliver a program that has the potential for not only worldwide approvals, but worldwide adoption. When we think about clinical trial design, some important aspects are highlighted here in the green box. What's critical about patient selection and about response criteria is that both have been selected to maximize visual acuity without altering the expected outcomes at 52 weeks in this patient population.
Another important aspect of clinical trial design is when and from what reference point patients get supplemental injections. Those can be found here in the green outlined box and have both been established to protect best corrected visual acuity. Because first and foremost, our highest priority is protecting patients' vision. Only then does treatment burden reduction become relevant.
What does a relevant outcome look like, you might ask? Well, historically, what we've seen is an incremental reduction in treatment burden over 52 weeks, with no patients in any of these studies being able to remain injection-free.
What we believe is that if we can match the visual acuity and anatomic response that we're expecting to see at 52 weeks with the magnitude of treatment burden reduction and the proportion of patients that are injection-free, that the 4FRONT data set stands to be one of the most impactful data sets we've seen in AMD since ANCHOR and MARINA. As a potential backbone therapy, 4D-150 has the potential for continuous disease control. By providing lifelong expression of anti-VEGF, it has the opportunity to show us long-term vision preservation and unheard-of treatment burden reductions, all with a potentially best-in-class safety profile.
Given as a single in-office intravitreal injection, 4D-150 stands to be the potential treatment of choice for any and all wet AMD patients. To give us more perspective on that and the potential of 4D-150 in wet AMD, I'd like to invite Doctors Khanani and Dr. Awh to join me up on the stage. Thank you, gentlemen, and thank you for joining us. Why don't we jump right in and start maybe with where we're at today. What's working and what needs improvement? Carl, maybe I'll start with you.
Well, we have a very effective treatment for wet AMD, anti-VEGF drugs. The problem, as Arshad showed in the real-world data, is that we can't really administer these drugs as frequently and consistently as they need to be given to our patients. We need a better way to deliver the same sort of therapeutic benefit.
I talk to my patients about wet macular degeneration a little bit like managing a house on fire. We want to get to it early, because if the firetruck pulls up and does the job properly, you don't get what's burned down back. You're just saving what's left. The buckets of water are our injections, putting the fire out. But you never completely put it out with wet AMD.
There are these embers there, and our goal is to think about when to put the next bucket of water on to keep things under control. The problem is, as Arshad mentioned, someone breaks a hip, there's a winter storm, someone comes back late, and the house catches on fire, and you lose a little bit more. With continuous therapy, whether it's with the Port Delivery System, which we've seen, or with gene therapy, imagine that we're always putting a little water on the embers, always.
So yes, the disease tends to fluctuate a little bit, just as the heat can rise, but you feel way more secure knowing that you've things under control with a bit of drug always there that may be adequate to control it for a lifetime, but that you may supplement as needed with an extra injection. That's, I think, the real compelling promise of gene therapy and continuous delivery.
Thanks, Carl. Arshad?
Well, I think I already showed about the real-world outcomes and number of injections. I was closely involved with the Vabysmo program. I lead the TRUCKEE and TAO studies, which are real-world studies looking at outcomes and what the second-generation drugs have done. If you look at the data, we have added two weeks to patients who were previously treated on 2 mg of aflibercept. You see, obviously, the need is so high that even that two weeks in previously treated made Vabysmo a blockbuster.
Here, we are actually trying to do is that we are helping patients long-term, as Carl said. We are not trying to just go a week or two beyond what it is. We are actually trying to shift the paradigm of treatment that we can have optimal outcomes and so that patients don't go blind. We're in the business of saving vision, and I think our goal is to keep that vision long-term. I think that's what it is all about, Dhaval, from my perspective.
Then you've treated probably one of the top enrollers in the PRISM program. What have you seen from that program that makes you feel confident that 4D-150 can fill those needs?
Well, I think that is why I said it is personal for me because after treating the first patient in 2021, I have treated over 45 patients in PRISM. I have been through many different gene therapy programs. What 4D-150 brings is three things we have to keep in mind. The vector, it is a retinotropic vector. IVT gene therapy had adverse events in other programs because the vectors go to the front. They do not go to the back. That is what led to adverse events.
Number two is the dose. The dose is super important. What we have seen is gene therapy, you have to have the lowest dose where you can balance efficacy and safety. The 310 dose is the lowest dose in a pivotal program that is being studied. Part of it works so well, as David presented, is because of the R100 vector.
The third is prophylaxis. Having the right prophylaxis, it is important, and we learn from other programs, and we optimize the prophylaxis. I think using those three things, Dhaval, and treating over 45 patients in PRISM, the data is very consistent. Majority of the patients are injection-free, and those who are not injection-free have significant reduction in treatment burden.
When I offer gene therapy for a patient, this was during PRISM time, telling that patient that my experience shows that there is a 50% chance that you will not need injection for a chronic disease or a 50%-75% chance that you are going to go from getting six or eight or 10. Many of the patients in phase I, as Carl presented, were high-need patients requiring injections every four to six weeks.
Taking that patient to one or two injections in a year has been groundbreaking from my perspective and from the patient's perspective. Bottom line, Dhaval, is that it is very consistent in my experience in PRISM treating over 45 patients.
Carl, anything from you additional?
No. I think if we can see in phase III what we've seen in phase II, Dhaval's made the benefits crystal clear. I think it will be something tremendous for our patients.
Then maybe, Carl, can you talk a little bit about your PDS experience and how this parallels to that?
Right. As Dhaval showed, we have seen the best long-term vision outcomes with the Port Delivery System, which has to be refilled every six months in the office with drug. But when we refill it six months, there is still lots of drug left in it. The drug level never goes to zero. That is why we see this tremendous maintenance of vision. The little bit of water on the fire all the time.
I think that is what we should see with gene therapy. It relieves a lot of anxiety for me as the treating physician too, because with bolus injection, you know that there is at times no drug in the eye if the patient goes long enough. That is when things can really suddenly get worse. I do not have that anxiety with PDS, nor will I with gene therapy because there will always be some drug there helping keep things under control.
Yeah. Maybe shifting to the phase III, can you maybe just talk a little bit about what are your expectations out of the phase III, Arshad?
Yeah. Can I make a comment on that?
Yeah, sure.
During COVID, the patients who actually didn't lose vision, and just like Carl, I was a big enroller in the Port Delivery System programs for the PDS patients or Susvimo patients. Just to keep in mind the sustained delivery, when patients miss visits, they didn't lose vision, didn't have massive bleeds and all these end-stage things.
I think that's something to keep in mind that we have this experience, but obviously it's a surgical procedure with a device in the eye with long-term risks. I still use it on a very small number of patients. But obviously the difference here is this is intravitreal treatment that it can be done by anybody around the world. Phase III, Dhaval, I think phase III are designed for regulatory success.
Sure.
We take the learnings from phase I and II and implement them in phase III. I think the most important thing for me is that the data that Carl showed is recently diagnosed patient, we had the highest number of injection free and significant reduction in treatment burden. Going to naive in 4FRONT-1 and majority naive in 4FRONT-2, I think that's number one.
Number two is controlling the patients who are outliers, right? When you have patients that are not controlled with monthly injections, looking at the response at a month versus a week, I think that's important because you are excluding patients because everybody essentially has a response at one week, but in one month you're going to exclude the patients who actually have high disease activity.
These are your patients that you can identify right away that are going to need monthly injections going forward. Those are the patients sometime can get vision outcomes that are not optimal in clinical trials and can drive the overall visual acuity down. Excluding those patients with the also helps because there are patients with large pigment epithelial detachments. Those can have very high CST and can lead to chronic need of treatment.
I think when you look at the criteria, and then the lastly is supplemental criteria. You have to tighten that up so that you give treatment and preserve vision for your patients. I think as you said, this is something we designed based on input from global colleagues, global experts, and keeping vision in mind for patients. I think those are some of the things that have optimized the trial design in my mind as a clinical trialist involved with many of the clinical trial designs.
Based on that, Carl, maybe I'll ask you. Based on that trial design and based on the fact that you're an investigator, what are your expectations for results? What looks good to you in terms of what happened?
Well, I've learned not to make predictions. But I would just say that the phase II results are so compelling, and I think a lot of thought has been put into the design of phase III, and I would love to see outcomes very similar to what we've seen in phase II.
So maybe digging on that a little bit. Historically, gene therapy, the big conversation around that has been around safety. Can you talk a little bit about expectations safety-wise?
If we see the minimal inflammation in phase III that we've seen in phase II, that will be completely acceptable to me. In fact, I would be willing to tolerate probably a little higher percentage even of inflammation. When I operate to fix someone's retinal detachment, they always have some inflammation afterwards. We put them on drops.
We control that. I would never not fix a retinal detachment because I'm worried about a little post-surgery inflammation. I think that if we're looking at something that's very manageable by a predictable course of topical steroids with a one-time treatment in someone's life to give them lifetime benefit, then what we've seen with the safety profile so far, I think will be acceptable to every retina specialist.
Arshad, anything additional from you?
No, I think Carl said it well. I think this is a one-time treatment. Imagine you are reducing injections by 50% or 75% or eliminating injection. Each injection has a risk of infection. Each injection has certain other risks. Here you are doing just one injection. I agree. I think what physicians do not like is chronic inflammation. Physicians do not like unexpected inflammation. Physicians do not like inflammation leading to irreversible vision loss.
Based on the data that you showed, Carl, if you are going to have mild transient inflammation during the initial period and you do not have to have the fear of something bad happening down the road, which we have seen in the data, I think that is the most important thing in my mind, is that with the 20-week steroid, we expect that almost all patients will not require anything else.
I think for the audience here, it is always like this fear of something is going to happen down the road. I will tell you this, if something is going to happen down the road, we actually have signs early in those programs. It is just that either they are not shared or they are not observed.
In 4D-150, being involved with all gene therapy, I have been carefully looking for everything I can find that is changing. My experience has been very positive based on the totality of the inflammation data. It is mild, it is transient, it happens early, and then you do not have to worry or be fearful about something happening down the road.
Yeah. Thanks. Maybe in this last question for both of you, let us assume we are two years down the road and 4D-150 is now in your hand. How do you think about utilization of it when it becomes available? Carl, maybe I will give it to you first.
Well, we tend to use new therapies on the toughest cases because we so much want something better than we have got. I think that will be the natural first wave of treatment. I think that with Port Delivery System, which I have more experience than most, I have found that that is how that launched, but now I have patients who need injections every six weeks, every eight weeks, every 10 weeks, who are delighted to have that because it really changes their life in terms of frequency of visits and their mindset of that security of knowing they always have a little treatment.
People talk about, "Well, if you make it eight or 10 weeks, that is really great." Think about it. How many of you are overdue for your one-year physical exam? It is really tough sometimes to make one appointment. Imagine that you have got to go every other month or bring someone every other month. If we can change that for our patients, that is really tremendous.
Yeah, Arshad?
Well, I agree with Carl. I think somebody who has not done gene therapy and it is new to them, they are probably going to go to their high-need patients. For me, treating over 45 patients in PRISM, and enrolling patients in all of the cohorts. The first high need, broad, and then recently diagnosed. I have had experience with all three of those. My perspective is a little biased because I have firsthand seen the efficacy, the durability, and the well-tolerated safety.
From my perspective, I am actually getting patients ready, that there is hope in the future. A lot of patients ask, "What is coming in the future? I can get these injections." Going from high-need patients who may not be all injection free, but reducing their burden, going to moderate or low-need patients who are going to be injection free. My perspective is that it is much broader in my patient population than how it gets started in the community.
Well, gentlemen, thank you very much. We could stay here and probably chat for another 30 minutes, but we have to move to the next session. Thank you for taking the time and thank you for sharing your opinions.
Thank you, Dhaval.
Yeah.
Thank you. Now, I'd like to invite to the stage a very good friend of mine and a longtime colleague, our Chief Commercial and Chief Business Officer, Chris Simms. Good job.
Thank you, Dhaval. Good morning, everyone. Thank you for being here. I am really excited to have the opportunity to share more detail about the commercial potential of 4D-150, and what we believe success could look like following regulatory approval, of course, for patients, retina specialists, their clinics, payers, and the overall market.
It just came to me, actually, as I was preparing for this presentation that 13 years ago this month, I started at Genentech. Shortly thereafter, I met Arshad and Carl. Arshad looked a lot younger then. Carl looks the same as he does right now, actually. But I was so impressed, being new to this therapy area, about the impact that Lucentis had on patients and vision. As Arshad talked about earlier, patients would get this diagnosis of wet AMD, and for many, it probably felt like a death sentence.
They knew that the eventuality of that was potentially going blind, and then a medicine like Lucentis comes to market, and all of a sudden, they had hope. That hope was followed by actually the regaining of vision and how transformative that was for them. Unfortunately, as we have seen in the real world since then, the data that Arshad showed earlier, while that vision gain occurred, it was not sustained.
We think it is time, 20 years, it is 20 years ago this year, I think, since Lucentis was launched. We think the market is prime for the next transformation. Today, we are going to discuss the commercial opportunity. Please remember that this reflects our current assumptions and our estimates. 4D-150, as you know, remains in phase III development, and of course, we cannot guarantee trial results, regulatory approval, or eventual commercialization.
That said, as we think about preparing for commercialization, we start with trying to fully understand who the key stakeholders are. For us, there are four key stakeholders, and we are going to ground the next portion of the presentation today in going through the needs of those four groups. You have patients, of course. You have retina specialists.
It is really important that we think through how a therapy like this could get incorporated into a very busy retina clinic, so we are going to spend time unpacking that as well. Of course, there are payers. Underpinning all of this is the need, as we have talked about earlier, to shift the treatment paradigm. Today, the treatment paradigm is defined by episodic disease control, bolus therapies at different frequencies. We believe the future needs to shift towards continuous, steady disease control.
We think that results in better outcomes for patients, and we think that is the core definition of what a backbone therapy means. 85% of retina specialists, when we survey them, they agree with that approach as well. Dhaval showed earlier what we view as our simple target product profile.
I am not going to take you through it all again, I think it is pretty straightforward, but I will draw your attention to the last bullet on this screen, because I think it has really important practical application for commercial success. The last thing on this screen points to the fact that 4D-150 was designed to be a single intravitreal therapy injection. What are the commercial implications of that? They are quite simple, but they are also really important. That means that 4D-150 can be delivered in an in-office setting.
Carl, Arshad, Sara, David's clinics can administer 4D-150, we believe, the same way that they administer bolus anti-VEGF therapies today. There's no surgery required. Your process that you use, we think we can support that. Fitting into that retina operating model seamlessly is going to be critically important.
The other implication for that, as we'll go through in more detail, is that how this product would be reimbursed, we believe today it would be similar to the same reimbursement model called buy and bill because it's primarily Medicare Part B that retina clinics know all too well and are very familiar with. That's a simple point in our TPP, but it has direct implications for how we think a clinic could incorporate a therapy like this. We also recognize, as many of you do as well, that this is a very competitive space.
In a few slides, I'm going to talk about the size of this market. The market has showed continued growth that attracts lots of interest, and of course, we recognize there's lots of unmet need that still exists that attracts a lot of new entrants into the category. We believe 4D-150 is very different in this competitive space. In fact, our difference is by design.
Simply put, the many bolus therapies that exist today and the many bolus therapies that are in development all share the same limitation, which is finite durability. 4D-150 was designed and developed for a different objective: continuous disease control and long-term preservation of vision. Today, this is the plan for the balance of the presentation.
I'm going to spend a few minutes talking about the market, just reminding us about the opportunity and the size of the market, and then we're going to go through the insights for each of these four key stakeholders that I've referenced: patients, retina specialists, clinic operations and economics, and then payers. Let's quickly remind everyone of the size of the market.
Again, probably not a surprise, this is a large market valued globally at about $16 billion. 60% of that is in the U.S. and is anchored by the two primary indications of wet AMD and DME, as you see here. The market has grown an average of 5% over the last 10 years. That growth has been driven by two factors.
One, there has been new innovative products that have come to market that we'll talk about, and of course, we have an aging population, so increasing the amount of prevalence and a high incident rate continues to grow the market as well. Arshad just referenced this earlier, but we have seen innovative new therapies come to this space.
Most recently, the medicine of Vabysmo, brought from Roche Genentech. It provides the potential for incremental durability. We actually did some interesting analysis, I think, with our own data, with our own team, and we said, "Hey, since 2021, during the introduction of more longer-acting agents, what's been the real-world extension of treatment interval?" Just for reference, in 2021, the average treatment interval with real-world data was about 55 days. We used this database called Vestrum to do this work.
In 2026, the average treatment interval, again, we're covering the period where longer-acting agents have become available. That average treatment interval is 67 days. The incremental change in that five-year period, it's there. It's about 12 days.
We think that's fairly modest. But despite that modest change, we know that these medicines have had large commercial success. Vabysmo itself, three years after launch, is about a $4 billion brand. It speaks to the importance of durability. We hear this time and again. Doctors tell us, patients tell us, "Reduce treatment burden, give me something that can help maintain my vision." This again references that.
However, what's interesting, and we think points to the massive opportunity that remains is that despite the innovation of these new bolus therapies, 0% of them provide a patient with the possibility of continuous disease control, and 0% of them provide a patient with the potential of being injection-free. Again, we think this is just more evidence of the size of the market opportunity that remains. Of course, the market is not just growing in terms of value.
It's also been growing, as I referenced, in terms of volume. I'm going to walk you through just some of the numbers to help you can paint the picture from the patient lens as to the size of this market. Let me just start with wet AMD itself. Today in the U.S., we estimate about 600,000 patients receive regular therapy, regular injections for wet AMD.
Space has a pretty high rate of incidence. It's important when we think about the potential in the future to recognize that. About 160,000 of those 600,000 patients that are on therapy this year are new to therapy in the last 12 months. Further, the rate of bilateral disease we estimate to be between 30% and 40%. So those 600,000 patients actually translates to about 800,000 eyes that are being treated, again, just for wet AMD, just in the U.S. So a large market.
By 2030, we expect that to continue to grow, and we estimate there will be about 900,000 eyes under treatment, again, just for wet AMD in the U.S. by 2030. I won't walk you through all the details for DME. The dynamic is similar. You have a higher rate of bilateral disease. You have fewer numbers of patients that are diagnosed and treated.
But all of this together, if you think about what this market could look like in terms of size, in terms of number of patients, by 2030, we estimate there will be about 1.7 million eyes in the U.S. under treatment between wet AMD and DME by 2030. And if you add up the new to treatment in that time period, about 550,000 of them will be new to treatment in 2030.
We share these numbers. I know it's a lot of moving pieces, but the key takeaway, large market continuing to grow. The rate of incidence driven by an aging population is really high in this space and projected to continue to be so. Okay. Underpinning all of this is patients. From a commercial perspective, we don't do much before we understand what truly matters to patients. It's foundational.
We have done some work to better understand what patients care about, what are the motivations, what are they concerned about, what are their lived experiences. Arshad and Carl already alluded to some of this, but we think it is important to actually spend time looking specifically at the perspective of the patient and what really matters to them. To walk us through that, I will invite Kat Pajak on my team to come up.
Thanks, Chris. My name is Catherine Pajak. I am the Vice President on the commercial team at 4DMT. Professionally, I have been working in this space commercializing innovative medicines for over two decades. Personally, I have seen my professional and personal lives collide over the past few months, as my dad has just started taking anti-VEGF injections. With that, I want to impart three things onto you today. One, to paint further the holistic burden that Arshad and Carl both alluded to of what these patients are going through now.
Two, what motivates patients. And three, how we see these things coming together for the potential commercial adoption of 4D-150. I am going to start with the treatment cycle. It is a big slide. It is overwhelming. We will break this down and look at each step of the process quickly. First, there is anticipation of appointments. I think this was alluded to earlier today.
Patients are scheduling their appointments out months ahead of time so that they can ensure that they have transportation. It is not just the patient themselves going to the injection. It is more often than not with a caregiver. Patients have to get to the actual injection, and for many patients, this can be hours and hours at a time. In fact, less than 10% of ZIP codes in the U.S. have a retina specialist.
Patients get to the office and they have to go through an evaluation process of imaging and having their vision checked. What we have heard in our patient market research is that this process can vary depending on how busy the clinic is. I know with my dad, sometimes we are in and out of there under an hour. Other times it will take three hours.
Patients are not really sure what to expect, and this also adds to anxiety and makes logistical planning more difficult. Then comes the injection. This is the shortest part of the journey, but also filled with the most anxiety. One of the reasons there is so much anxiety with the injection is that the recovery can differ patient to patient. What we have also seen is that the recovery for patients, in particular, one experience might stand out.
They might have one experience where the injection took longer, and it took longer for their vision to be restored. They will have visual disturbances, pain, itchiness that lasts for over a day. This whole burden of process repeats and repeats, and the anxiety and the dependence and the emotional burden associated with each step of this process cumulatively adds to the burden that both patients and their caregivers feel.
Why do patients go through this? It is actually quite simple, and Arshad alluded to this. They do not want to go blind. Patients fear vision loss. These are quotes from market research about patients not wanting to go blind, what their biggest fear is. They want to continue being independent and doing things that matter to them.
I have talked about the patient experience in a high level, and now I would like to introduce you to Judy. Judy is a patient living with wet AMD that I had an opportunity to spend some time with last month. She is active, she is independent, and I think her video story that I am about to share right now really brings home both the hopes and the fears that patients have today.
[Presentation]
I think Judy's story really highlights the emotional impact of the disease and the motivation that patients feel to get treatment. They know what's at stake. They know what at stake if they lose their vision. But in reality, we know, as Arshad pointed out, that more than 40% of patients are going to drop off of therapy by the end of year one.
The reasons are obvious, from the emotional and the physical and the logistical burden of treatment. Another thing that Arshad alluded to, which is important to point out, is that many of these patients have other healthcare challenges, and if they end up in the hospital or in rehab, they're simply unable to get their injections. Imagine what a world with 4D-150 could look like for these patients. We did some market research, and we showed our profile to patients.
You won't be surprised to know that they were very receptive. I think two things really stood out to me in the research. One was the practicality of the vision preservation. That was compelling to them. The other was this emotional burden relief.
It was going to take away the anxiety of having to fear getting to treatment. It was going to take away the burden that they felt they were giving to their care providers. But more than just being motivated about the profile, they wanted to ask about it, so that 90% of patients wanted to ask their physician about 4D-150. We really believe that this patient receptivity, this patient motivation, their fears, this is going to be very, very important in the commercial trajectory of 4D-150.
To share more about the patient perspective, I'd like to invite Dr. Sara Haug onto stage to tell us more about the patients that she sees.
Thanks, Kat.
Thanks, Sara. I think Arshad started off today asking how many people here had actually been into a retina clinic, and I found it so compelling just spending a day in your office and seeing the patients that come to you from all over.
Yes.
Maybe we can start and talk a little bit about the patients you see in your practice.
I am a Retina Surgeon and Medical Retina Doctor, obviously, in Southwest Colorado. We are a multi-specialty group, but we have two retina surgeons in my practice. We are the only retina surgeons between Albuquerque, Salt Lake, and Denver. We have a huge catchment area. We are nine doctors, and three of those are optometrists. We have six surgeons. But it's a very unique place to practice. The town is Durango, Colorado. It is a hippie cowboy town, I like to say. But then we get a lot of patients from the more rural areas. I have true cowboys in my clinic. And we also service the Navajo Nation.
When you talk about that wide geography-
Yes
How far are patients coming?
Yeah. We have patients coming four to six hours, one direction, just driving. That does not even include the visit or the time that it takes just to like It is a whole day. There was a retina group up in Grand Junction, which is three and a half hours away, and they just closed, so we have this huge bolus of patients that are being transferred to our practice. One thing I want to say, we have all talked about what a revolution this was in 2006 with the advent of Lucentis and how patients did not go blind from wet macular degeneration. But 20 years on, we are weary. The clinics are full.
Yeah. Tell us a little bit more about that. I know you are here today. What are you going home to? How many patients are you going to see on Friday?
Friday will be upward of 100. We have three offices. Our main site is our Durango clinic. That is where we run our clinical trials. That is where we have our premier equipment, et cetera. Then we have our satellite clinics in Farmington, New Mexico, and Cortez, Colorado. My patients, I think, affectionately call it the stab and go. We will see upwards of over 100 patients, but a lot of them are the routine injections. Theoretically, it can go a little bit quicker.
When you start a patient on wet AMD treatment, what is your treatment goal and what does that paradigm look like?
It was interesting. My treatment goal with wet macular degeneration. First of all, when patients get this diagnosis, there are tears. They all know people getting the injection therapy. They say, "Oh, does this mean injections?" I try to reassure them that this is not the disease it was when your parents went through it.
We have good treatments for them, but of course, I do not follow up with the data showing that it is very hard to maintain this treatment schedule. My goal is to try to reduce the burden of visits and injections on patients. I try to minimize the amount of injections patients get while still maintaining the vision and anatomy.
What does that look like in practice? How often are you giving?
I'm sure you all are aware of this treat and extend protocol. So what we try to do is we do a number of loading doses until we think things are stable, vision and anatomy are stable, and then we slowly inch the patient out so that we try to increase the treatment interval between injections. Now, one thing Carl said when we were just having a discussion is that this implies failure.
I push it until truly the patient's failed treatment, then I say, "Oop, you need to be on eight weeks." In preparation for this, Kat had asked me how many of my patients are still on a four- to six-week schedule in light of these newer therapeutics that have more durability, and kind of doing back of the napkin sort of math, my staff estimated 50%-60% of my patients are still on every four to six week treatment.
And you have patients coming that four to six hours every four to six weeks.
It's a huge burden, and part of the reason I'm so excited to talk about this is just to impart what my patients go through. A lot of my patients, the injection itself is the easy part. It's going home and putting the washcloth on their eyes. It's driving over Wolf Creek Pass. It's getting her neighbor to bring her in. "Oh, I don't want my son to have to take another day off work."
These are really true concerns. I have the cutest little lady who's like, her children drive her crazy. But she's 90, and her kids want her to come out to Oregon for Christmas. And so I think in July she had her calendar because she has to be every four weeks, otherwise she loses vision.
And so we mapped out all of her injection appointments between July and Christmas so her kids could get her the plane ticket to go home to Oregon. It's a true burden on not just the patients, but then also our clinic. We are crushed.
Yeah. What about discontinuation? Are you seeing, are you feeling that your patients-
I know. I wish. I have no sense of it. So one thing about Durango, and one thing especially about my younger seniors, is they are on the go. So we have a lot of patients come through, they're like, "I'll do one injection for them a year," and then they move along.
So, and we have a ton of snowbirds, so summer is our busy season. People come from Arizona, Florida, Southern California to Durango for the summer. So our census gets really high in the summer, drops off a little bit in the winter, although not so much anymore. And so when patients don't follow up, I just assumed that they went on to their next space. But we are not tracking it at all, and I think that's something, as a profession, we could do a better job of.
But you're not lacking patients to see.
Well, that's the thing.
Yeah.
What am I going to do? It's interesting when we talk about patients that it's a real problem. Patients break a hip and they're in rehab for two months, and then trying to get them back in the clinic when my schedule is already completely triple booked. If they get off the schedule, it's really hard to get them back in.
Yeah. What question are your patients most asking you?
I actually asked Kat to ask me this because I hear it every single day. "How many more injections do I need?" The answer is forever. At least our current treatment paradigm for wet macular degeneration today to maintain vision is that these patients need this medicine forever. What I tell them, though, is that the way we deliver it is going to be very different. Just hang in there until these new therapies come to market, if and when, because the way we think about wet macular degeneration and how we treat it is going to be very different in three to five years, I hope.
You have also been an investigator in our 4FRONT program. So what has been the reception to gene therapy from those
It is interesting. I wondered. So Durango has a very, of course, it runs the complete gamut from very educated, we have a Colorado Stat e University in our town, to my ranchers who live middle of literally nowhere with 500 head of cattle, coming in with the hat and the boots. I wondered how the term gene therapy was going to sit with them, and the reception is off the charts amazing.
Patients actually are upset since we only enrolled treatment naive or patients who have only received a couple injections. They are like, "I have been getting this for five years. Why can't I sign up?" They ask me every single time, "When is it coming? When is it coming?" It is never soon enough. So the reception has been very, very positive. I have had very few people express concern about this gene therapy.
If you get a question about gene therapy, how do you explain it to
It sort of depends on the patient, but all you have to say is you get one intravitreal injection, and then your injection burden goes way down. You might just need a couple injections, or none at all, and that is all you need to say. Then they are just like, "Sign me up. I am in.
Yeah. If you think forward, you imagine a world where 4D-150 becomes approved, how do you see it changing your patients' lives, your clinic?
Yes. There is this worry that retina specialists have become so used to just being the, I am going to go and I am going to do 100 patients today. There is a benefit to us using these drugs consistently. At least where I am, I am an early adopter of new technology. In my clinic, I do not see that there is a wet macular degeneration patient that would not benefit from this technology. But to echo what Carl said, as a field, we do tend to start a little bit slowly.
There have been other drugs that have come to market that have not had the response that we were looking for, and so we want to get used to it before we really broadly apply this. Yes, we will probably start with the patients that are every four to six weekers. But I do not think there is a way to over-treat wet macular degeneration, so I think this product would benefit all of my wet macular degeneration patients.
That is great, Sara.
Yeah.
Well, thank you so much for sharing your perspective with us today.
Yes, thank you. It's a pleasure.
Yes. With that, I'd like to ask Chris to come back to talk to us more about the retina specialist perspective.
Yeah. Thank you, Kat. Thank you, Kat and Sara, and thank you, Judy, for sharing her experience in the video. We're going to spend the balance of time going through the other three key stakeholders. Retina specialists, we talked about the clinics, we talked about payers and reimbursement. The retina specialty physician community is super interesting for a lot of reasons, actually.
One of the things that we think is interesting about this community that has direct commercial implications is the fact that 1,250 of them, so roughly less than half at about 3,000, represent about 90% of all the patient volume. Of course, that relatively small community, as we've seen already, can drive pretty significant commercial success. With Vabysmo, largely, those numbers I shared earlier were driven by this community.
A couple of other key points that we think are relevant for our commercial setup is the fact that just 10 organizations within retina represent over 25% of patient volume. When we surveyed them, and you've heard commentary about this already, 40% would say that they have minimal to no capacity to see additional patients. We share these data points with you for two implications.
The first is that a small community can absolutely support, I think, large commercial blockbuster products. Importantly, when we think about commercialization and scaling that as a smaller startup biotech company, we can absolutely do this in a community of this size because of this dynamic. Personally, myself, Dhaval, and Julie Clark, our Chief Medical Officer, this is our third company together, I believe. We've launched two medicines in this space.
We launched one within the setting of a large pharma company, and the other was in the setting of a smaller biotech company, not that dissimilar from 4DMT. The size of the commercial investment, the size of the teams we had to build were pretty much identical in both of those settings. That has implications for how we think about preparing to commercialize.
The other point that's interesting that we think fits into our strategy and what 4D-150 can mean for a clinic is addressing this capacity issue. You just heard Sara talk about how she's going to be slammed on Friday. Most clinics fall into that category. This capacity issue is real, and truthfully, the incremental gains of longer-acting VEGFs that have been launched and those that are likely in development are not going to address this the way that it needs to be.
I think to fully address this, particularly in light of the fact that the patient population continues to grow, you need real innovation. You need a shift in the treatment paradigm. We think 4D-150 can affect that. In our research, it's not surprising that retina specialists are really eager for a backbone therapy like 4D-150.
These results actually mirror the enthusiasm that we showed earlier from the ASRS PAT survey, and retina specialists see a very meaningful role for 4D-150, with 75% indicating that they would look to prescribe it within the first year of approval. Further, as you heard from the conversation with Carl and Arshad, they don't see the potential for 4D-150 as being singular to the high-need patients. They see it actually as being an opportunity across a broad patient population, and we see this in our research as well.
Clearly, patients that have a higher healthcare burden would be the patients that are likely to be first prioritized. We pick up in our research the intent to actually prescribe to a treatment-naive patient population with time as well. We think this has direct implications and translates to adoption. A question that I get quite often is, how would 4D-150 be adopted in the commercial setting?
We recognize, and I think Carl also said this earlier, that the patients first considered are likely to be those patients that have high need. In our analysis, we define that as patients today that need eight or more bolus injections, and that accounts for about 25% of the eyes that are treated today in this area. However, we know that over time, and we hear this from physicians, once a couple of things are established.
First of all, it's a buy and bill model, so confidence in reimbursement is going to have to be established. There's also going to need to be the demonstration, of course, of real-world safety, and of course, patient demand can help accelerate that. But when those things start to come into play, we absolutely believe that patients with moderate burden, defined as about 45% of the eyes that are treated, and those with lower burden will be considered with time as well for a therapy like 4D-150.
We've also asked physicians and did additional work that said, "Well, what portion of patients would you consider?" We see results that we think are really encouraging. We see patients share numbers in the 30%-40% range, somewhat affected by the severity of the disease and the amount of burden that a patient will have today.
We even see numbers, about 20% of newly diagnosed patients that may be considered for a therapy like 4D-150. Of course, we recognize that this is early. This has all the limitations that come with market research, and it's subject to change, certainly as our data and our product profile becomes more established. We share it with you today to reinforce the unmet need.
We share it with you today to also reinforce the enthusiasm and the potential that 4D-150 could have. As Kat mentioned earlier, we know that patients are motivated to act. 90% say they would ask their physician about a product like 4D-150. In addition to that, we've done research with retina specialists, and we asked them if a patient were to inquire about a therapeutic like this, how would they respond?
We see a very similar response where 90% of doctors said they would do everything they can to support that patient request. The combination of those two factors, we think, could be a major accelerant for adoption in its commercial setting. Let's now switch to the clinic operations and the economics.
A question I get from many investors, many of you in the audience quite often, is the obvious statement. Sometimes it says, "Hey, this is a retina buy-and-bill model." Physicians and clinics make margin in that retina buy-and-bill model. Therefore, if you were to reduce treatment burden by X %, what would the effect of that be on the clinic operationally? Really important question. We actually think we have the potential to enhance it, but we need to explain to you and to the physician community as to how we believe that to be true.
Let's first start with what the model looks like. You may be familiar with this. We commonly refer to it as the buy-and-bill model. In simple terms, what does this mean? It means that a clinic purchases the therapy that they're going to administer to their patient. They administer the inject in their offices.
They then bill the payer for reimbursement, and then with time, they'll get reimbursed for that medicine, usually on a basis of their average selling price of the medicine plus a percentage margin, depending a little bit on the payer. I just explained that in four easy steps. It sounds pretty simple, and for the most part, it kind of is. However, what's lost in this is a couple of things.
Doctors will tell us that for every one retina specialist in a clinic, they need four to five staff people behind the scenes to administer this process. Making this work in a busy retina clinic is incredibly complicated and requires a lot of overhead expense. The other reality, though, as you think about bringing new therapies to market, ideally, you seamlessly integrate into this.
Ideally, you do not cause a new workload or something that gets in the wheels of this that causes disruption. Of course, we think 4D-150 has an advantage there because you do not need to understand how a new surgery needs to be coded because it does not require a surgery. You also do not need to understand how reimbursement logistics and cash flow would flow in a surgery site of care.
While the buy-and-bill model certainly creates economic value, we want to actually also recognize that it also has the potential for value erosion. Because this is so important, we are going to walk through this with a little bit more detail. Today's reality of practice economics is built upon injection frequency. To make a couple of obvious statements, but it bears repeating, if there is no injection, there is no reimbursement today. If a patient falls off therapy, as many do, reimbursement stops.
If you have limited capacity to take on new patients, that limits your ability to grow and to see and to generate additional revenue into the future. What could tomorrow's opportunity with 4D-150 then look like? We think we could potentially amplify that value through one treatment. You capture that value up front. Of course, 4D-150 has adherence by design.
It is a lifelong therapy, and if you can reduce the treatment burden for a patient, you should be able to reduce the treatment burden for a clinic as well, and that has the potential to affect the capacity issue. We believe this to be so critical to understand that economic value that is generated for a clinic, that we actually created an illustration to bring it to life with a little bit more detail.
Bear with me if you will, but just follow the math here. We said, "Okay, what would 10 patients on therapy for five years result in terms of reimbursement potential?" So 10 patients on therapy for five years, if those patients are considered relatively adherent, they will get an average of six injections per year. So per patient, that is 30 injections over that five-year period.
Of course, we have 10 patients, so the total reimbursable injections would result in 300 events over a five-year period, again, for 10 patients getting six injections a year. Then we said, "Well, what would need to be true to make that potential real?" This is what would need to be true in today's treatment paradigm. For those 300 injections, you would need, of course, 100% of patients to stay on therapy for the five years. You would need 300 visits.
You would need 300 injections. You would need 300 potential benefits investigations and other amounts of back-office work. You would need 300 incidents of getting full and accurate and ideally timely reimbursement. If all of those things were true for 10 patients on therapy for five years, then you would realize 100% of the potential reimbursement.
We've heard today that we all know this does not happen in the real world, right? In fact, because of patient drop-off for a variety of reasons, and because not all patients are going to get that average of six injections per year, the reality is, as opposed to 300, is actually closer to 160. That's what we mean when we say value erosion in the current treatment paradigm today.
160 means that what should have been 100%, again, following that example, is more like 53% in the real world. So how could 4D-150 impact that? Well, we believe that by contrast, 4D-150, by treating those 10 patients, has the potential to capture multiple years of value with a single injection and the upfront value of reimbursement. Further, the difference in workload is dramatic. With the required 10 visits, 10 injections, 10 incidents of full reimbursement, and 10 benefits investigations.
And of course, that then creates the potential for 100% of that reimbursement value. And of course, while this figure is illustrative, it's not suggestion of a proposed price or reimbursement commitment. To put it all together, the potential value proposition, we believe, is not just simply fewer injections. It's not just upfront reimbursement and the capture of value that is otherwise lost.
It's fewer injection-related activities while seamlessly integrating into and possibly enhancing the economic model that is well known by retina clinics today. And of course, importantly, overlaying all of this is the potential for patients to have significant treatment burden reduction and hold onto their vision. The final section of the commercial strategy is about payers, the fourth stakeholder in the list that we shared earlier. Let's first talk about payers by looking at who the primary payer is.
So in this wet AMD market, because it's an older patient population, the primary payer is Medicare. In fact, today, about 90% of patients are reimbursed with a Medicare plan. 37% of those are reimbursed through CMS. It's on fee-for-service, so often referred to as straight Medicare. And 51% are on some Medicare Advantage plan. There's a variety of them. An important question often comes up is, well, what is the patient's out-of-pocket expense?
We've done some modeling, and certainly, there are expenses that patients have to pay out of pocket. But today, about 70% in the current treatment paradigm have zero incremental out-of-pocket exposure. We believe, based upon what we know today, that the reimbursement model for 4D-150 would be similar. It would be Medicare Part B, and also then fall within this overall payer landscape that we show here.
And the two implications of this for us is that, one, we believe it positions 4D-150 for broad patient access. And as I've already referenced, we think this allows 4D-150 to fit within the very familiar buy and bill reimbursement model that retina clinics use routinely. We also recognize that the cost of therapy today can be quite significant.
And for a patient on therapy for up to five years, depending upon what the therapy is, but if you're on a branded therapy for up to five years, that total cost can be as high as $73,000 for that therapy. And despite that, patients still have the risk of losing vision. So when we talk to payers, it's not overly surprising that payers recognize the challenges with existing therapies.
Three out of four would say that existing therapies have limitations, but 87% acknowledge the need for improved therapy in wet AMD, and 100% of payers agree that the goal of treatment in AMD should be the ongoing protection against vision loss. Similar to retina specialists and similar to patients, payers are also excited about the potential of gene therapy.
71% in our research would suggest that they view gene therapy as the mechanism that they believe has the most potential to address the unmet needs in AMD. Of course, the question that comes up often is: How do we view pricing? The truth of the matter is it's too early to discuss pricing. We still need to know more about our product profile. We still need to see what phase III data looks like.
However, as we do research with payers, they do support a broad range of pricing options and coverage and reimbursement for 4D-150 based on the profile we've shown them so far. Let me wrap it up. I'm going to finish where we started. We started by saying we are going to build our commercial strategy by building around the needs of the four key stakeholders: patients, retina specialists, retina practices, and payers.
Hopefully, you've seen how 4D-150 can address some of those critical needs of those stakeholders and, through that, shift the treatment paradigm to continuous disease control. We think it's important as well to understand how a therapy like 4D-150 can operationally be incorporated into a busy retina clinic, and to help us with that understanding, I'd like to invite Dr. David Eichenbaum to join me. Welcome.
Thanks, Chris. Happy to be here.
Great to have you. Have a seat.
Hi there. I'm David Eichenbaum. I'm a Director of Research at an eight-doctor retina practice in Florida. We're one of the highest volume 4FRONT investigative sites globally. I've been PI in over 130 clinical trials, and we see lots of patients with wet AMD.
You do. David and I know each other for a while. We go back probably when I joined Genentech years ago.
Lucentis
I spent 10 years on Lucentis. Sara mentioned earlier about the volume of patients in her clinic. Can you just share a few data points or just your clinic experience, just in terms of number of patients you guys see and what that could look like as well?
Yeah, sure. Our volumes are a little lower than Sara's volumes. We see, depending on the office and the doctor and the stage they're at in their career, probably between 45 and 75 patients per clinic day, plus clinical trial patients in addition to that. I'd say probably about two-thirds of the patients in the clinic are there for an injection.
Sure. That requires, as we just alluded to, I think, quite a significant amount of operational support. There is an advantage to the logistics around that. When you think about a therapy like 4D-150, how do you think about it in terms of how it fits into the operational flow of your clinic?
Yeah. We do intravitreal injections in the clinic. A lot of branded agents. The majority of our injections are branded. We have always been a heavily branded clinic, and we are very comfortable with buy and bill. We have a very well-supported buy and bill model. We do all of our billing internally with our own in-house billers, and we are access sensitive and we are reimbursement sensitive. But as long as a drug fits into our flow, it should be able to be integrated with our internal operations without a whole lot of reinventing of the wheel, which is important to us.
Yeah. I mentioned earlier, because this is a buy and bill model, that there is a need to ensure that you have the confidence that if you are going to inject a medicine that is expensive, that you feel confident that you will get reimbursed for that. Is that an accurate statement? And clearly in a 4D-150 world, how would that show up with your decision to use a therapy?
Yeah. The old saying is no margin, no mission. You've got to keep the lights on, and the medicines are by far the largest piece of revenue in the practice. They're also the largest cost in the practice, and if you don't have revenue to support your cost, all the rest of your revenue isn't going to make that up. It's very important that we have processes, which we've established over 20 years since the approval of Lucentis.
I can tell you, when I started in the practice in 2007, our processes weren't very good. But they've gotten a lot better in 20 years. And the processes are well supported, and if we have a drug that fits into those processes and we can support that particular product, then it can slot in wherever there's a clinical need and a clinical demand.
The importance of a medicine like 4D-150 to, in essence, fit within how you order the product, how you inventory it in your fridge and so on, that being similar to the process you use today is a critical feature for you, or would be an important feature for you.
Absolutely. It has to be able to not require special equipment, not require special handling. It has to be something that looks and feels like an Eylea injection, more or less.
Right. That's really helpful. We sometimes hear the question because, as Dhaval covered earlier, there is a prophylactic steroid regimen that patients would go on upon receiving 4D-150. And there's this question that comes around, well, how, one, will patients react to that, and how would you as a physician, if you had a patient on 4D-150 in the real world, how would you monitor them? Can you just speak more to what that would look like for you?
Yeah. From a clinical perspective, I really like what Carl said about that. Carl said, "If I have a patient with a retinal detachment," all four of your doctors here today are surgical retinal specialists. If I have a patient with a retinal detachment, I am not withholding their retinal detachment repair because they are going to have inflammation for four to eight weeks afterwards.
I am going to manage the inflammation with drops, almost all the time with drops, and they are going to get better. And I think that is a similar approach to what we would take with intravitreal gene therapy with 4D-150. It is a 20-week corticosteroid taper, so that is a little bit longer. But the principles of treating patients with episodic inflammation that we do all the time after a single surgery, or what we anticipate to be a single surgery, apply here.
Yeah. That is helpful. And I shared a few slides that talk about the potential economic value that 4D-150 could have for a practice. I think we recognize that how we derive that is different than maybe the current treatment paradigm. Did that resonate with you? Did that make sense? And anything that you would share about how important that would be?
Yeah. So I complimented you on those slides when we reviewed them, and I mean that sincerely. There is this drop-off, and just like Sara said, we are not good at following the attrition from clinic. But we know there is attrition because if we look at real-world databases, we see time and time again that there is attrition.
Of course, the clinical value of 4D-150, I think, is what is going to compel doctors the most. But there is this tremendous economic value. There is this economic gap that a patient has. If we start treating the patient, they begin to do well. We feel good about them and feel good about the result, and then they do not come in. The patient is not going to do well, and we are not going to have the economic benefit of that patient in our clinic.
You get all of that upfront with 4D-150, and as long as those economics look like what we expect the economics would be with intravitreal injections, I think it is a win-win for the clinics as well as the patients. And currently, in 2026, 2027, we expect the buy and bill model to exist now and in the at least near to midterm future exactly like it exists today. That may change over time. But right now, there is a lot of unrealized value that can be captured based on the model you presented.
Yeah. We asked you this question yesterday. I thought your answer was really interesting, which is, let's assume 4D-150 is commercially available in your clinic. You've had lots of experience via our clinical trial program. When you think about the patient or patients that you would consider upon commercial availability, can you just describe what that would look like and how you'd go about making those decisions?
Sure. Certainly. So they'd have to be patients who have good access, who early on, they'd be original Medicare with supplement patients. Aside from that, clinically, I'd start it in the higher need patients because there are a bunch of those that we have in our clinic. That's the obvious first place where the drug would go. Another place where I would put them is probably because of the clinical trial experience and probably because I'm a bit of a futurist, and I believe the best is always yet to come.
I would use it in treatment-naive patients right from the get-go. I like to test drive new drugs in a population as close as I can get in my clinic to what we saw in the clinical trials, just to see if they work. I think there are a lot of doctors who, when they see the data and they see the stage development process, would do that for at least a proportion of their patients.
Yeah. We hear that as well. We hear certainly, I think, the higher need patient is probably the one that first comes to mind.
Yep.
But we hear more and more from physicians, with the caveat that you just made, of course, reimbursement, and you have to have confidence that the right reimbursement profile is there. We're about to wrap up, but I'd love just to maybe take a step back and say, based upon everything that you know about 4D-150, what we believe the potential could be for your clinic and for your patients, what gives you the greatest confidence that a product like 4D-150 can become a key part of the future treatment paradigm?
The greatest confidence I have is the existing data set. The existing data set combined with what we know about Port Delivery System, and Arshad and Carl and I were all deeply involved starting in phase II with Port Delivery System. We see what that looks like.
It's a great treatment because it's ongoing therapy, but it requires this surgery and this indwelling device. If you can combine that with something that has a similar safety profile to intravitreal injections and a similar delivery method to what we do every day, you've got this perfect storm of things that physicians, patients, clinics, and it sounds like payers are all aligned for.
I think it's the data combined with the alignment gives me a lot of excitement about 4D-150, and that's what I see as the biggest lever we have is the unification of these different stakeholders pushing this therapy closer to the first line over time.
Well, David, we're about out of time, but let me just say thank you. You were one of the first retina specialists that I got to know 13 years ago.
Sorry.
No. I'm still here.
Should have met Arshad.
Eventually, you can meet all of them.
Yeah.
But you've, through that time period, been full of insight and always an advocate for, I think, advancing science and for what's best for patients. So thank you for that support. Thank you for being here today. With that, I'm going to move to the next section.
Pleasure. Thank you.
Thanks for being here.
Thanks for having me. Nice to see you.
You too. To bring us home, I would like to invite our CEO, David Kirn, back to the stage. David.
Thank you, Chris. All right. Thanks, David, for those incredible insights, and Sara, for your insights as well. As Chris said, I am going to bring us home and try to make this pretty efficient and get on to our Q&A session. I want to start by reminding you that we have assembled a phenomenal team at 4DMT. I am very, very proud to be working with these people, all deep experts in their own fields.
Importantly for today, they have deep expertise in retina therapeutics development, in retina therapeutics commercialization, and in manufacturing regulatory affairs. We are set up for great success. Second, I want to acknowledge we have a number of board members here. Thank you for attending. We have a phenomenal Board of Directors. In particular, they are particularly well-suited for where the company is today and where we are going.
They have deep experience in commercialization, scaling of companies, and I think they are going to be very, very instrumental in helping to guide the next evolution of 4DMT into a commercial stage company. So thank you. This is our catalyst calendar. We have had a very busy and robust and successful 2026. We are set up for success in 2027 with two very important readouts.
4D-150, our first phase III trial, will read out in Q1, Q2, excuse me, of 2027. 4D-150 will read out in the second half of 2027. It is going to be a very important and transformative year. We are fortunate to have a very strong financial position, as you can see here on the slide, and this gives us a cash runway into the second half of 2028. Again, come back to the four key takeaways at 4D.
You will notice there is a theme of four of everything. At any rate, number one, 4D-150 has the potential to become the backbone therapy for wet AMD in all patients eventually with wet AMD. Number two, the target product profile that we have developed and that the product shows addresses the most important unmet needs for patients with wet AMD: vision preservation and treatment burden reduction with the potential for long-term freedom from injections.
Number three, our clinical data, our design of phase III and execution on phase III positions us for great success in 2027 and beyond. Number four, all stakeholders, including patients, physicians, and payers, their enthusiasm gives us great confidence that we have an incredible potential here for robust broad commercial adoption. I would like to end by thanking our amazing KOLs for your attendance today and your insights. Thanks to the 4DMT team.
You did a phenomenal job making us successful today. Thank you for that. Thank you to our board of directors for being here. Thanks to all of you for your time today. We really, really appreciate it. With that, I would like to invite our speakers back up to the stage, and now we will take on some of your questions. Thank you. All right. Thank you. You guys do an incredible job like stage management here. It is impressive.
Okay. There we go. All right. We got a lot of questions in the queue, so we will try to get to as many as possible, but if there are further questions, please find us after the reception. The first question comes from Josh Schimmer at Cantor. What kind of BCVA change do you expect from the day one to 52-week BCVA non-inferiority analysis? What do you expect in the aflibercept arm? Is a change from week minus five baseline a pre-specified sensitivity analysis in the analysis plan and will appear in top line?
Okay, so thanks for the great question. I am going to turn that over to Dhaval, and then you can also share it with some of our key opinion leaders.
Yeah. I will take it in the first part of that question first. You heard me reference this treatment-naive patient population and what we would expect to see out of that. If you go back to every single phase III study that has been done, you see that visual acuity show up somewhere around six to eight letters.
Where it exactly is dependent upon what the starting visual acuity is, but we picked this population because that is where we expect this outcome to wind up, in that six to eight-letter frame, really dependent upon where the baseline visual acuity is. On the second question, as it relates to the week minus five analysis, I am not going to comment specifically on what is or is not in the SAP.
What I will comment on is this concept that part of the reason that we picked this patient population was to be able to lay these results down next to TENAYA and LUCERNE, PULSAR, and every other phase III study that has been done. Those studies measure visual acuity from the first loading injection. In order to make that same comparison, we will have an analysis, showing from the very first injection.
Yep. There was a follow-up question on this in terms of most 4FRONT-1 patients are now past the 20-week taper period. On a pooled masked basis, has any patient restarted steroids? Dave, do you want to actually take it?
Sure. I think we have reported that data, and we are very thrilled with what we are seeing in terms of overall safety and also just completion of steroid drops on time. I think it sets us up for commercial success.
Yep. I just want to comment that we are in a blinded study, so in order to protect study integrity, we are not commenting on blinded safety events in the phase III trial. Second question comes from Mayank Mamtani's team at B. Riley. We talked about the aflibercept response criteria as a way to reduce variability in 4FRONT.
Could you speak to how that has played out operationally screening, whether you can characterize what share of screened patients did not make it and what their prior injection frequency like? It is a treatment-naive study, so there should not be a prior treatment injection frequency, but yeah.
Yeah, perfect. Why don't we start with Dhaval and then maybe hear from Arshad as well?
Yeah, I think the question is asking how many patients were screened out due to the aflibercept. Again, not commenting on exact results on an ongoing masked trial. But in concept, if you think about the general response criteria and where these patients start, these treatment-naive patients, you typically show up at around 350 or so microns, and your first injection gives you about 100-micron reduction.
Recall that our response criteria for aflibercept was a 15% response, so 15% of 350 is significantly smaller than 100. When I made the comment that the criteria were put in place and specifically, the response criteria were put in place as to maximize the visual acuity outcomes but not fundamentally alter the week 52 expectations, that's what we're talking about. We don't expect a ton of patients to be screened out by this, but I won't comment on the exact number. Arshad?
Yeah, no, I agree with you. I think the other criteria that's in there is complete resolution of fluid. A lot of time, we are seeing patients who come in earlier stage of their disease, and they get one injection, and they get dry.
The whole idea behind these criteria is to, as I said earlier, is to make sure that we don't get those patients who at one month have "no response," that will show a response at one week and then they'll have recurrent fluid. We are inclusive. We have not really designed this to exclude a large number of patients, but that small subset of patients that are just difficult to treat, that drive vision down in many of the studies, including TENAYA and LUCERNE.
Great. The next question is from Daniel Giraldo at Bank of America. How are you thinking about the potential for re-dosing or bilateral dosing? What data are we collecting for that?
Yeah, that's a great question. Maybe I'll start with Dhaval from the technical side, and then Chris and some of KOLs can weigh in on the commercial opportunity there.
The question is just re-dosing in same eye or fellow eye?
Bilateral. Yeah.
Bilateral.
Bilateral.
Yeah. We know that a lot of these patients do have bilateral disease, and the ability to treat patients bilaterally is going to be important. As part of any development program in gene therapy, the regulatory agencies here in the U.S. and in Europe and worldwide require you to do a fellow eye program. We've put on clinicaltrials.gov that that program is currently underway. We fully expect at the time of launch to be able to administer 4D-150 to patients bilaterally.
Yeah. The only comment I would add is that commercially, as I showed earlier, 30%-40% of wet AMD patients will develop disease in their fellow eyes. We think that's a significant opportunity just from a commercial perspective. When their fellow eye is treated, I think will be up to doctor discretion. Maybe one of the KOLs can speak to when they would be comfortable treating the fellow eye. Certainly, the amount of opportunity there considering the bilateral rate is quite significant.
David, do you want to start?
Sure. Yeah. I am involved in the bilateral study from the phase II patients, and we're waiting on the results from that. But in principle, assuming we have good safety and efficacy from that in the real world, I'd probably treat the second eye as I was towards the end of the corticosteroid taper for the first eye. I would be comfortable treating at that point.
A lot of the patients are going to want it in the second eye. I can tell you, when you talk to patients about a durable treatment in one eye that has a continuous release that will reduce their injection burden or eliminate it, if they're a bilateral patient, they want that treatment in the other eye. With surgery, we do bilateral surgery for vitreous opacities.
I typically wait until the drops are done for the first eye until I do the second eye. Usually, it's about on to two months. I think that principle would translate to 4D-150. I think bilateral treatment is common in retinal disease because people tend to be somewhat symmetric, more or less. My feet are almost the same size left to right. I would be totally comfortable assuming we have the data to support it to treat the second eye as I get through that corticosteroid taper period for the first eye.
Okay. Carl, you had a comment too, I think.
Well, PDS is a great example. I have a number of patients who have PDS in both eyes because they have it in one eye, they're getting injections in the other, so they really can compare the difference. What will be nice about gene therapy, though, with an intravitreal injection is PDS, we still are doing the refills every six months. So my goal, if I operate on the second eye, is to do the timing so that their refills can be the same day. That means I really have to do the surgery close to the time of one of the refills, so it constrains me a little bit. That wouldn't be a constraint with an intravitreal injection for gene therapy.
Yeah. No, I agree. I think I have the same experience with numerous patients with bilateral PDS. But being part of PRISM and having so many patients, everybody with the fellow eye is asking for it. Now, of course, we are part of the fellow eye study, and not everybody can get in.
But every single patient is asking that, "I want this in my other eye." Because if you think about it, you are getting every four to eight weeks on average, injections every four to eight weeks in both eyes. You do one eye, but the other eye still has that treatment burden, visit burden, right? Just like David said, after you treat one eye, you are off the steroids, everything looks great, you treat. So within three to six months after the initial injection would be my timing.
Awesome. Thank you. I think the next question is around really the phase III design in terms of supplemental criteria and how supplemental criteria should be thought of. So, Dhaval, you talked about the retreatment rules. How do these compare across different trials, and how should we think about that?
Yeah. Why don't you kick it off, Dhaval, and then we can hear from some of the investigators on the study.
Yeah. So when you think about retreatment criteria, it's really based upon the patient population first that you're treating, and then the second consideration there is the therapeutic that you're using. So I don't know that you really can compare across trials one rescue criteria versus the other. I think what we can comment on is for this trial and this patient population, we have optimized our retreatment criteria to protect visual acuity and safeguard the primary outcome, because that is the singular most important thing in the 4FRONT program with a secondary emphasis on treatment burden reduction. Arshad?
Yeah, I think I've been part of numerous trials, as you know, and I think what we have learned is that sometime you do end criteria only, which actually doesn't have patients who have worsening anatomy and then boom, they lose a lot of vision because we didn't treat them. For example, if it's 75 microns and five letter loss, you may have patients who actually are 75 or 100 microns on disease activity.
They have real disease, but they don't qualify for an injection because the vision is not down yet. Then you have to wait for that five letter loss, and by the time you supplement them, it's too late to recover that five letter, or they suddenly have an episode of bleeding or some other irreversible vision loss.
You have all seen the criteria for 4FRONT program is both anatomy and vision at 50 and five. We have anatomy by itself and then, of course, retinal hemorrhage. I think in this program, as Dhaval said, the goal is to protect the vision and the primary outcome. Because if you don't meet the primary outcome, then it is irrelevant how much treatment burden reduction is there, how many patients are injection free. I think this program has been designed very thoughtfully based on the learnings from many of the programs that all of us have been involved with.
Okay. Great. Next question's really around steroids. This is for the KOLs from Lisa Walter at RBC. How challenging do you think it will be for patients to manage the 20-week topical steroid taper? Also, how concerned are you about patients developing cataracts due to this level of steroid use?
Sara
In our clinic for a steroid taper, we actually have a whole checkbox sheet that we give them. You can't monitor them at home for adherence, but I haven't had too much of a problem having patients adhere to the schedule. Obviously, this is an older patient population, so in my mind, of course, steroid can accelerate cataract, but a lot of my patients who haven't had cataract surgery yet at this point in their life already have somewhat of a cataract. And so, cataract surgery is an inevitability. It's not something that would make me worried about using steroids in this situation.
Carl?
I tell my patients for other reasons, cataracts are inevitable and cataracts are replaceable. Your macula is not replaceable. We are always going to prioritize what is best for your macula or your retina. It would be nice if we did not have that as a side effect, but it is not something that would constrain me in the least.
Yeah, because we are used to using steroids for diabetic macular edema. We use steroid topically for uveitis. We know that 20% or 30% of patients will have increase in pressure, but I have not had to stop anybody on steroids because we can control pressure with other eye drops. I think I want the audience to put themselves in the situation of a patient.
If you have three options, you have either surgery to decrease your burden, you have just continue the way you are doing injections four to eight weeks for the rest of your life, or take 20 weeks of steroids topically at home. I think all of you are going to pick the third option. Or most of the people are going to pick the third option.
Now, of course, patients who cannot take steroids because of glaucoma or they just do not have compliance issues, sometimes elderly patients can put it. We have other options. In real world, we have other options of steroids. We have sub-Tenon's injection of steroid. We have intravitreal steroids we can give. I think we will adapt, but I think in my experience, steroids have not been an issue in my practice based on my PRISM experience and my experience with other gene therapy trials.
I would say the key is based on the data we have so far from phase II, it is episodic. This is not chronic inflammation that requires ongoing steroids as far as we can tell to date. As long as it remains essentially episodic, it is something that we can deal with clinically.
All right. I think we're kind of running out of time, so I'll take one last question. The last question is from Matthew Caufield at H.C. Wainwright. For the potential adoption of 4D-150 in wet AMD, how could you see uptake playing out in the first one, three, and five years? How quickly could you see real world use expand beyond those first high burden patients we talked about earlier today?
Well, thanks, Matthew. Chris, you want to take that?
Yeah, sure. Thanks, Matthew, for the question. I guess I showed earlier, I think the initial adoption is primarily from that higher need patient population, which by the way, is not an insignificant number of patients. 25% of eyes fall into that, what we would deem as a higher need category. The exact timing as to when patients or when physicians would consider a broader population, I think, is going to be dependent upon a couple of things.
I think the first thing is demonstration of real world safety. We've seen that with other drugs that we've launched. My experience, it happens somewhere in the 6-1 2-month period. The other key factor is actually not clinical at all. It's actually about confidence in reimbursement. The key thing, I think, in a buy and bill model that drives that is you get a permanent J-code.
Once you get a permanent J-code, reimbursement usually works a little bit smoother. It comes a little bit faster. What we usually model in a commercial setting is about nine months from the time your medicine is approved to the time you get your permanent J-code. So those factors, we think, cause the adoption to get broader beyond that higher need patient population. I think that happens. I think, for rough modeling, we think, 9- 12 months is when you would start to see that graduation occur.
Fantastic. Anything you guys want to add to that?
Yeah. I would say that the first year, exactly what Chris said, is testing the waters for reimbursement. You have a miscellaneous J- code. I think the penetration into the market in the first year will be low. I think after you have the J- code and you have the initial experience and you're beginning to get Medicare Advantage plans on board, talking about years two to four, you'd probably see an uptick.
And I'd probably say at that point, I would use it in 20% - 25% of the patients in my clinic would actually have access, have need, and be able to pay for it. And following that, you have, I guess, market maturity. And I'm not sure how much more you would get, but it would be some number more than that.
You would have later adopters coming online, you would have folks who are in academic institutions coming online, and things like that. But I think that you'd begin to see a significant penetration following that first year, following the initial experience and the reimbursement with the anonymous code.
Yeah, I actually think what'll be different with this is that we're going to have tremendous demand by patients. Half of my patients don't really know what I inject. They just know I'm injecting something, maybe it's a different drug, and they see little differences in their experience.
But patients who have this new gene therapy and now are not needing injections understand they've gotten something really different, and that's a story that's easy to tell and easy for other patients to understand. I think that we'll actually see much more of a drive of patients coming into the office saying, "I've heard about this gene therapy, why can't I get that?" Much more so than we do with different intravitreal injections.
Yeah. It happens now in the waiting room, right? Like, "Oh, I got this thing, I don't have to get shots." And then patients come in and say, "I want that stuff, I don't want these injections." This is very common, and it has happened with clinical trials, it happened with Port Delivery System. And I think
It's happened with Vabysmo.
Yeah.
The ads for Vabysmo drove tremendous demand.
I think I totally agree. I think from my perspective, I think payers, right? The number of patients in my clinic who have straight Medicare, as Chris called it, is about 40%. Those are the first group of patients that I'm going after. Of course, we'll have to figure out co-pay assistance and other things, but those are the patients that don't need auth, right? These are the branded drug markets.
If you look at the translation of branded drugs, that's where the gene therapy will be used initially because these patients have coverage, and that's about half the market, right? These are the potential patients. But as I said earlier, I think high need or patients who need frequent treatments are going to be the one. We'll do studies like TRUCKEE where we share the real world experience.
We have done the SUMMIT study with Port Delivery Systems, and it's very similar to what the outcomes we saw obviously in the clinical trial. I think the field will evolve, but I think this is not a 5% or 3% of the market. I think this is because it's in clinic, it has safety and efficacy and durability, hopefully that's highlighted in the phase III. Of course, we have to wait for the data. I think we have to think about broader market. This is not for a specific small number of patients. Part of it is the delivery, part of it is the data of efficacy and durability, and part of it is safety.
Perfect. All right, David, you can sum up.
All right, well, thank you all for being here. We're going to have a reception afterwards. We look forward to networking with all of you. Again, thanks all for your time.