4D Molecular Therapeutics, Inc. (FDMT) Earnings Call Transcript

Guys, we're getting started. Thanks for all being here today. I'm sorry for those online, we're running a couple of minutes late, but I 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 Kern, our Co-Founder, President and CEO.

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 4D Molecular Therapeutics. I've been in the industry for about 30 years as a physician scientist, a drug developer, a serial entrepreneur and CEO. So 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 the potential to establish a whole new treatment paradigm in wet AMD as you'll see today. So I'd like to start out with four key takeaways for you today that will 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 patients' 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, very interesting. They're all experts, but 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 here 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. So 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. So why can I say that definitively, well, I spent the last 5-plus years having hundreds of conversations with physicians, patients, their caregivers, clinic staff, and I hear over and over and over again. It's not good enough. So why do we think it's not good enough? Well, 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 and over again for the rest of their life. So why is that a problem? Well, wet AMD is chronic, it's continuous. It's relentless. It doesn't take a day off. So 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. And 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 of this burden and cost on the system, patients still lose vision. So let me say that again, patients in the United States of America with wet AMD, the majority will lose vision many will still go blind. And outside of the United States, where treatment is not available to the extent that it is here, the problem is much, much worse. So this simply isn't a good enough situation and patients deserve better. So what could the future look like? Well, our vision is that 4D-150 can serve as the backbone therapy for all patients with wet AMD, again, not the most, just the most severe. What does that look like? Single routine injection in the clinic, continuous disease treatment potentially for the rest -- we believe for the rest of the patient's life, a significant reduction in treatment burden and most important, since treatments on board at all times, 24 hours a day, 7 days a week, 365 days a year. We believe we're going to want 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 goal in years. So 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. So when we started the company over 10 years ago, the first order of business was to invent a novel capsid, and 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, in particularly the macula very, very efficiently with the single injection, so we could get our treatment right to the site of disease where it needed to be. And we wanted to design this vector to minimize any sort of risk of significant toxicities or inflammation. And 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. Now the vector is just a delivery vehicle. The actual treatment here is [ aflibercept ] in an RNAi for VEGF-C. So we hit 4 VEGF family members. Let's remember, aflibercept is the market leader in wet AMD over the last decade. It's been used in over 64 million doses in humans, 64 million, and it's shown great efficacy and a very excellent safety profile. That's our treatment. So that's completely derisked. What we're doing is delivering it in a much better way. And that is having expressed from the retina itself, right at the site of disease, continuously 24 hours a day, 7 days a week, 365 days a year for the rest of the patient's life. It's a fundamentally better way to use this amazing molecule Okay. So with that background, I'd love to invite Dr. Arshad Khanani on 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're thrilled to have him here. Arshad?

Thank you. Thank you, David. Good morning, everybody. It's great to see you. I'm Arshad Khanani, I'm a medical and surgical retina specialists based out of [ Reno ], Nevada. I've been involved with over 150 clinical trials as a PI. And I've been involved with many gene therapy programs throughout this journey. I've been in practice over 16 years. And 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 don't think we'll get a full room like this about a gene therapy. So we have gone through a lot of learnings for gene therapy, and it's 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 5 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 missed the patient perspective. So 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? Okay. How many of you have somebody that actually suffers from a chronic relentless heterogeneous blinding disease. And that's what it is. So 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. And I think in these graphs, we don't see that. So 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 shift in treatment that we hope we can deliver to the patients in the near future. David covered the problem at hand. We are treating a chronic disease with bolus injections, and they were great. I was in training when [ anti-VEGF ] came out. I had a patient who was blind in one eye from wet AMD, had a dog in a cane while the other eye was still seeing, but she had wet AMD. And she said, "I know what this disease is going to do to me. I'm getting ready to go blind." And then came out the anti VEGF, and she didn't go blind. So 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 their life comes in the way. They fall and break a hip, then rehab for 6 months. What happens is they come back and they're blind. We start treating them, we cannot recover the vision. So 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 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. And 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 hard surgery and now they're in rehab. They just cannot come. I have patients who live 4 hours away, there's nobody to drive them. So I think having something that can give us assurance that there is treatment on board is super crucial. And then we know why patients drop out. Everybody is 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. So in the 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 patients don't want to keep their vision. The first thing they asked me, am I going to go blind. Can I drive Will I lose my driving license? Will I need somebody to cater to me? And I think those are the questions. So 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. And it's just not me. It's the whole community. If you look at ASRS patch survey, what is the #1 unmet need, long duration therapy. And 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 Board delivery system or SUSVIMO. And this is the 7-year data that I presented at [ U Retina ] last year. What do we see going from ladder Phase I to portal extension we see maintenance of vision over 7 years in a prospective clinical trial setting. Now of course, for a 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 2 to 5 letters or a period of 7 years. It's unbelievable what we have seen with sustained delivery. Now imagine replicating this with a simple in-office injection of 4D-150. And being part of this program has really taught me about that fear patients have, the anxiety patients have. These are my happiest patients, 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. So I think that's the perspective. So bottom line is we see this real-world decline in vision, patients lose independence. They essentially lose their lives. I mean you ask somebody if you cannot drive, cannot see to cook, cannot read, they don't want to live. So 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? So I hope we get there. Obviously, we have to wait for the data. So 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.

Thank you, Arshad. I'm Carl Awh. I am the President of Tennessee Retina, a 15-physician retina-only practice in Nashville. As Arshad mentioned, I'm the past President or a past President of the American Society of Retina Specialists. And I've 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've been an active clinical investigator for quite a while, over 130 clinical trials. I've been PI on more than 50. And 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. And my mother who's now diseased was actually my patient for more than a decade with wet AMD. And so I understand this as a physician, as a family member, and I'm delighted to be here to talk about this data because it's so compelling. I think the company has done a fantastic job sort of setting the stage for Phase III. Phase I, they looked at in I/IIa, the most recalcitrant eyes, really challenging eyes to treat that helped establish safety and efficacy. Phase IIb, which is what I'll talk to you about a bit, tells us a lot, I think, about what we hope to see in Phase III. And there's a Phase IIb subgroup of recently diagnosed eyes that I think really parallel very well the patients that are being enrolled in the Phase III program. So let's talk about Phase IIb. And here are 3 critical results that we want to see about anatomy, vision and treatment burden. So 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, right? Barely any slope, stable vision after the intravitreal injection. And we achieved this with tremendous treatment burden control. So 46% of eyes had no additional injections for 2 years and 2/3 of eyes needed two or fewer injections over 2 years. There was no control group in this. So if we compare to an idealized aflibercept injection every 8 weeks, this represents a 78% reduction in treatment burden. So now let's look at this recently diagnosed population. So these were eyes diagnosed within 6 months and the majority of them had only 1 prior injection. So in this group of patients, again, tremendous maintenance of anatomy and visual acuity and now an 87% reduction in treatment burden. 2/3 of the patients received no additional injections after that initial single intravitreal injection of gene therapy and almost 90% had 2 or fewer injections to control their disease over 2 years. So tremendously exciting results. And of course, this has to come with acceptable safety. And so what we see here are the outcomes for every eye that was injected in Phase I and Phase II with the dose that's been using in the Phase III study. So in all these eyes, there were only 2 eyes with the lowest level of inflammation, anterior chamber or vitreous cells that resolved with topical therapy. And these have all occurred during the first 28 weeks. There were no other cases of inflammation for up to 4 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. So this is tremendously reassuring and compelling data. So with 4D-150, we see stable vision and anatomy, a tremendously robust reduction in treatment burden, that favorable safety profile, and this sets the stage nicely to move into the Phase III programs. And I'm delighted to now introduce Dhaval Desai, who will go over those programs with you.

Thanks, Carl. And thank you to everybody that's here in person and online for joining us today. My name is Dhaval Desai, and I'm the Chief Development Officer here at 4DMT. Over the past 2 years, our teams have been busy developing and delivering the Phase III wet AMD program for 4D-150. Today, I'm excited to be here to share with you why I think that program is designed to win. The 4FRONT program consists of 2 nearly identical studies, 4FRONT 1 and F4FRONT 2. Both are fully enrolled, randomizing 523 and 531 patients, respectively. 4FRONT one 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's defined as receiving up to 4 prior injections and being diagnosed within the last 6 months. Why did we choose this predominantly treatment-naive patient population? It's for 3 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. And 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 treatment injection-free, we think is going to shift the way retina specialists treat wet AMD. Moving back to the design. Primary endpoint of the study is noninferiority in BCVA at week 52 versus a comparator, a gold standard comparator of aflibercept 2 milligrams given every 8 weeks, with both arms receiving 3 loading doses right upfront. 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 4Front 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 maximized -- 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. And 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. Even as a single in-office intravitreal injection, 4D-150 stands to be the potential treatment of choice for any and all wet AMD patients. And to give us more perspective on that and the potential of 4D-150 in wet AMD, I'd like to invite Dr. 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. So 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. And so 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. So we want to get to it early because if the fire truck pulls up and does the job properly, you don't get what's burned down back. You're just saving what's left. And so the buckets of water are 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. And 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 sort of things have under control -- 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. So that's, I think, the real compelling promise of gene therapy and continuous delivery.

Arshad?

Well, I think I already showed about the real-world outcomes and number of injections. And I was closely involved with the [indiscernible] program. And I lead the TRuKI and tau studies, which are real-world studies looking at outcomes and what the second-generation drugs have done. So if you look at the data, we have added 2 weeks to patients who are POC treated on 2 milligrams of aflibercept. And you see, obviously, the need is so high that even that 2 weeks in PSC treated made [indiscernible] blockbuster. So 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 2 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 are in the business of saving vision. And I think our goal is to keep that vision long term. So I think that's what it is all about, Dhaval, from my perspective.

And then you treated some of the -- 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's why I said it's personal for me because after treating the first patient in 2021, I've treated over 45 patients in PRISM. And I've been through many different gene therapy programs. And what 4D-150 brings is 3 things we have to keep in mind, the vector. It's a [ retinotropic ] vector. IVT gene therapy had adverse events in other programs because the vectors go to the front. They don't go to the back. And that's 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. So the 3E10 dose is the lowest dose in a pivotal program that is being studied. And part of it, it works so well, as David presented, is because of the R100 vector. And the third is prophylaxis. Having the right prophylaxis, it's important, and we learn from other programs and we optimize the prophylaxis. So 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. And when I offer gene therapy for a patient, this was during PRISM time, telling that patient that my experience shows that there's a 50% chance that you will not need injection for a chronic disease or a 50% to 75% chance that you're going to go from getting 6 or 8 or 10, many of the patients in Phase I, as Carl presented, were high patients requiring injections every 4 to 6 weeks. Taking that patient to 1 or 2 injections in a year, it's been groundbreaking from my perspective and from the patient's perspective. So bottom line, Dhaval, is that it's very consistent in my experience in PRISM treating over 45 patients.

Carl, anything for you, additional?

No. I think if we can see in Phase III, what we've seen in Phase II, Dhaval, has made the benefits crystal clear. I think it will be I think tremendous for our patients.

And then maybe, Carl, can you talk a little bit about your PDS experience and how this parallels to that?

Right. So as Dhaval showed, we have seen the best long-term vision outcomes with the port delivery system, which has to be refilled every 6 months in the office with drug. But when we refill at 6 months, there's still lots of drug left in it. So the drug level never goes to 0. And so that is why we see this tremendous maintenance of vision, a little bit of water on the fire all the time. And I think that, that's what we should see with gene therapy. It relieves a lot of anxiety for me as a 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. And that's when things can really suddenly get worse. So I don't have that anxiety with PDS and nor will I with gene therapy because there'll always be some drug there helping keep things under control.

So maybe shifting to the Phase III. Can you maybe just talk a little bit about like what are your expectations out of the Phase III?

Yes. I think -- can I make a comment on? Yes, sure. So 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 or the PDS patients versus Bema patients. So just to keep in mind, the sustained delivery, when patients miss visits, they didn't lose vision, didn't have massive bleeds and all this end-stage things. So 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 risk. So 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. So Phase III, Dhaval, I think Phase III are designed for regulatory success. And we take the learnings from Phase I and II and implement them in Phase III. So I think the most important thing for me is that the data that Carl showed is recently diagnosed patients, we have the highest number of injection-free and significant reduction in treatment burden. So going to naive in 4FRONT 1 and majority naive and 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 1 week. But in 1 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. And those are the patients sometimes can get vision outcomes that are not optimal in clinical trials and can drive the overall visual acuity down. So excluding those patients with the response criteria and capping the CST, which 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. So 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. So 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. So I think those are some of the things that have optimize the trial design in my mind as a clinical trialist involved with many of the clinical trial design.

So -- and based on that, Carl, maybe I'll ask you, like 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...

I've learned not to make predictions. 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 it has been around safety. And so can you talk a little bit about expectations safety-wise?

If we see the sort of 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. And so I think that if we're looking at something that's very manageable by a predictable course of topical steroids with a onetime 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.

Anything additional from you?

No, I think Carl said it well. This is a onetime treatment. So imagine you are reducing injections by 50% or 75% or eliminating injection. So each injection has a risk of infection, each injection has certain other risk. And here, you're doing just one injection. So I agree. I think what physicians don't like is chronic inflammation. Physicians don't like unexpected inflammation and physicians don't like inflammation leading to irreversible vision loss. So based on the data that you showed, Carl, if you're going to have mild transient inflammation, during the initial period, and you don't have to have the fear of something bad happening down the road, which we have seen in the data. I think that's the most important thing in my mind is that with the 20-week steroid, we expect that patients -- almost all patients will not require anything else. And I think for the audience there, it's always like this fear of something is going to happen down the road. And I'll tell you this, if something is going to happen down the road, we actually have signs early in those programs. It's just that either they're not shared or they're not observed. So in 4D-150, being involved with all gene therapy, I've been carefully looking for everything I can find that is changing. And my experience has been very positive based on the totality of the inflammation data. It's mild, it's transient. It happens early, and then you don't have to worry or be fearful about something happening down the road.

Yes. And maybe in this last question for both of you. Let's assume we're 2 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'll 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've got. I think that will be the natural sort of first wave of treatment. But I think that with port delivery system, which I have more experience than most, I have found that, that's how that launched. But now I have patients who need injections every 6 weeks, every 8 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 8 or 10 weeks, that's really great. Think about it, how many of you are overdue for your 1-year physical exam, right? So it's really tough sometimes to make one appointment. Imagine that you've got to go every other month or bring someone every other month. If we can change that for our patients, that's really tremendous.

Arshad?

Well, I agree with Carl. I think somebody who has not done gene therapy and is new to them, they're probably going to go to their high-need patients. But for me, treating over 45 patients in PRISM and enrolling patients in all of the cohorts, right, the first high need, broad and then recently diagnosed. And I have had experience with all 3 of those. So my perspective is a little biased because I have firsthand seen the efficacy, the durability and the well-tolerated safety. So from my perspective, I'm actually getting patients ready. There is hope in the future, right? A lot of patients ask like what's coming in the future, either can't get these injections. So 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. So my perspective is that it's 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... And now I'd like to invite to the stage a very good friend of mine and a long-time colleague, our Chief Commercial and Chief Business Officer, Chris Simms.

Thank you, Dhaval. Good morning, everyone. Thank you for being here. I'm 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 than 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, right? 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. And that hope was followed by actually the regaining of vision and how transformative that was for them. Unfortunately, as we've seen in the real world since then, the data that Arshad showed earlier, while that vision gain occurred, it wasn't sustained. And we think it's time 20 years, it's 20 years ago this year, I think, since Lucentis was launched. We think the market is primed for the next transformation. So today, we're 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. And for us, there's 4 key stakeholders, and we're going to ground the next portion of the presentation today and going through the needs of those 4 groups. You have patients, of course, you have retina specialists. It's really important that we think through how a therapy like this could get incorporated into a very busy retina clinic. So we're going to spend time unpacking that as well. And of course, there's payers. Underpinning all of this is the need, as we've 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's the core definition of what a backbone therapy means and 85% of retina specialists when we survey them, they agree with that approach as well. [indiscernible] showed earlier what we view as our simple target product profile. I'm not going to take you through it all again. I think it's 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 the 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're actually -- they're quite simple, but they're also really important. Well, that means that 4D-150 can be delivered in an in-office setting. Carl, Arshad, Sara, David, clinics can administer 4D-150, we believe, the same way that we administer bolus anti-VEGF therapies today. There's no surgery required. Your process that you use, we think we can support that. So fitting into that seamless -- 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 very familiar with. So 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. And 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. So 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 4 key stakeholders that I 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 it's 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 2 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 the space, right? Most recently, the medicine of Vabysmo brought from Roche/Genentech, it provides the potential for incremental durability. We've 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. And just for reference, in 2021, the average treatment interval, the real-world data was about 55 days. We use 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. So the incremental change in that 5-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. The BYSil itself 3 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. So 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 I can paint the picture from the patient lens as the size of this market. This -- let me just start with wet AMD itself. So 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 incidents. 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 can 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 incidents driven by an aging population is really high in this space and projected to continue to be so, okay? So 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. So we've 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's important to actually spend time looking specifically at the perspective of the patient and what really matters to them. And to walk us through that, I'll invite Cat Pajak on my team to come up.

Thanks, Chris. My name is Catherine Pajak. I'm the Vice President on the commercial team at 4DMT. Professionally, I've been working in this space, commercializing innovative medicines for over 2 decades. Personally, I've seen my professional and personal lives kind of collide over the past few months as my dad has just started taking anti-VEGF injections. So with that, I want to impart 3 things on to 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. So I'm going to start with the treatment cycle. It's a big slide. It's overwhelming. So we'll break this down and look at each step of the process quickly. First, there's anticipation of appointments. I think 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's not just the patient themselves going to the injection, it's more often than not with a caregiver. Then 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 United States have a retina specialist. Then patients get to the office, and they have to go through an evaluation process of imaging and having their vision checked. What we've 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're in and out of there under an hour. Other times, it'll take 3 hours. So patients aren't 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. And one of the reasons there's so much anxiety with the injection is that the recovery can differ patient to patient. And what we've 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'll have visual disturbances, pain, itchiness that last for over a day. So this whole burden of process repeats and repeats and 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. So why do patients go through this? It's actually quite simple, and Arshad alluded to this. They don't want to go blind. Patients fear vision loss. These are close to 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. So I've talked about the patient experience on a high level. And now I'd like to introduce you to Judy. Judy is a patient living with wet AMD, but I had an opportunity to spend some time with last month. She's active. She's independent. And I think her video story that I'm about to share right now really brings home both the hopes and the fears that patients have today. As Arshad pointed out that more than 40% of patients go off therapy end of year that 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 health care challenges. And if they end up in the hospital or in rehab, they're simply unable to get their injections. So imagine what a world with 150 could look like for these patients. We did some market research, and we showed our patients -- our profile to patients. And 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 they were -- that was compelling to them. The other was this emotional burden relief. It was going to take away the anxiety of having to feel clear 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. So 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. And to share more about the patient perspective, I'd like to invite Dr. Sara, now on the stage to tell us more about the patients that she sees. 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 how the patients that come to you from all over. So maybe we can start and talk a little bit about the patients you see in your practice.

So I am a retina surgeon and medical retina doctor, obviously, in Southwest Colorado. We are the only retina -- 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. So we have a huge catchment area. We are 9 doctors, but 3 of those are optometrists, not but and 3 of those are optometrists. So we have 6 surgeons. But it's a very unique place to practice. The town is Durango, Colorado. It is a hippy Cowboy town, I'd 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 Naval nation.

So when you talk about that wide geography, how far are patients coming?

Yes. So we have patients coming 4 to 6 hours one direction just driving. That doesn't even include the visit or the time at the -- that it takes just to -- like it's a whole day, there was a retina group up in Grand Junction, which is 3.5 hours away, and they just closed. So we have this huge bolus of patients that are being transferred to our practice. And one thing I want to say, we've all talked about what a revolution this was in 2006 with the advent of Lucentis and how patients didn't go blind from wet macular degeneration, but 20 years on where [indiscernible] the clinics are full.

So tell us a little bit more about that. I know you're here today, what are you going home to? How many patients are you going to see on Friday?

So Friday, it will be upward of 100 Yes. So our clinics are -- so we have three offices. Our main site is our Durango clinic. That's where we run our clinical trials. That's where we have our premier equipment, et cetera. But 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'll see upwards of over 100 patients, but a lot of them are the routine injections. So theoretically, it can go a little bit quicker.

And so when you start a patient on wet AMD treatment, what is your treatment goal? And what does that paradigm look like?

So it was interesting. My treatment goal with wet macular degeneration. So first of all, when patients get this diagnosis, there are tiers. They all know people getting the injection therapy. They say, "Oh, does this mean injections? " and I try to reassure them that this isn't the disease it was when your parents went through it. We have good treatments for them. But of course, I don't follow up with the data showing that it's very hard to maintain this treatment schedule. But my goal is to try to reduce the burden of visits and injections on patients. So I try to minimize the amount of injections patients get while still maintaining the vision and anatomy.

So 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. So I push it and tell truly the patients failed treatment then they say, oh, you need to be on 8 weeks. In preparation for this, Cat had asked me how many of my patients are still on a 4- to 6-week schedule in light of these newer therapeutics that have more durability. And it's kind of doing back of the napkin sort of math. My staff estimated 50% to 60% of my patients are still on every 4- to 6-week treatment.

And you have patients coming that 4 to 6 hours every [indiscernible].

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 wash cloth 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's very -- she has to be every 4 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. I mean these are -- it's a true burden on not just the patients, but then also our clinic, we are crushed.

And what about discontinuation? Are you seeing -- are you feeling that you're paying?

No. 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. And 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, it drops off a little bit in the winter, although not so much anymore. And so I don't -- 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.

You're not lacking patients tends [indiscernible].

Well, that's the thing. I mean, what am I going to do? And it's interesting when we talk about patients that it's a real problem patients break a hip and they're in rehab for 2 months and then trying to get them back in clinic when my schedule is already completely triple booked, if they get off the schedule, it's really hard to get them back in.

Yes. So what question are your patients most asking you?

So I actually asked Cat to ask me this because I hear it every single day. How many more injections do I need? And the answer is, forever. They -- at least our current treatment paradigm for wet macular degeneration today to maintain vision is that these patients need this medicine forever. And what I tell them, though, is that the way we deliver it is going to be very different. So just hang in there until these new therapies come to market if and when, because it is going -- the way we think about wet macular degeneration and how we treat it is going to be very different in 3 to 5 years, I hope.

And you've also been an investigator in our forefront program. So what has been the reception to gene therapy from those?

No. It's interesting. I wondered -- so Durango has a very -- of course, it runs the complete gamut from very educated. We have Colorado State 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. And 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 of injections. So like I've been getting this for 5 years, why can't I sign up and they ask me every single time, when is it coming? When is it coming and it's never soon enough. So the reception has been very, very positive. I've had very few people expressed concern about this gene therapy.

How do you explain -- if you get a question about gene therapy, how do you explain it?

It sort of depends on the patient, but all you have to say is you get one [indiscernible] injection and then your injection burden goes way down, you might just need a couple of injections or not at all, and that's all you need to say. And then they're just like, sign me up. I'm in.

Yes. And so if you think forward, you imagine a world where 4150 becomes approved, how do you see it changing your patient's lives are [indiscernible]?

Yes. So there is this worry that retina specialists have become so used to just being the -- I'm going to go and I'm going to do 100 patients today. We do -- there is a benefit to us using these drugs consistently. At least where I am an early adopter of new technology in my clinic, I don't see that there's a wet macular degeneration patient that wouldn't benefit from this technology. But to sort of 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 haven't had the response that we were looking for. And so we kind of want to get used to it before we really broadly apply this. So yes, we will probably start with the patients that are every 4 to 6 weekers. But I don't think there's a way to overtreat wet macular degeneration. So I think this product would benefit all of my wet macular degeneration patients.

That's great, Sara. Well, thank you so much for sharing your perspective.

Thank you. It's a pleasure.

And with that, I'd like to ask Chris to come back to talk to us more about the retina specialist perspective.

Thank you, Cat and Sara, and thank you, Judy, for sharing her experience in the video. So we're going to spend the balance of time going through the other three key stakeholders, right? So retina specialists, to with the thing. We talk about payers and reimbursement. So the redness specialty physician community is super interesting for a lot of reasons, actually. But 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 had about 3,000 represent about 90% of all the patient volume. And of course, that's a relatively small community, as we've seen [indiscernible], can drive pretty significant commercial success. [indiscernible], those numbers I shared earlier was 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. And 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. So 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. But also importantly, when we think about commercialization and scaling that as a smaller start-up biotech company, we can absolutely do this in the community of this size because of this dynamic. Personally, myself, Dave and Julie Clark, our Chief Medical Officer. This is our third company together, I believe, we've launched two medicines in this space. We did -- we launched one within the [indiscernible] large pharma company and the other was in the setting of a smaller biotech company, not that dissimilar from for DMT. The size of the commercial investment, the size of the teams we had to build were pretty much identical in both of those settings. So 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 4,150 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, right? 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 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 40 and 150 can affect that. So when our research is not surprising that retina specialists are really eager for a backbone therapy like 4 150. These results actually mirror the enthusiasm that we showed earlier from the ASRS pad survey and retina specialists see a very meaningful role for 4150 was 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 40150 as being singular to the high-need patients. You 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 health care burden would be the patients that are likely to be first prioritized. But we pick up in our research, the intent to actually prescribe to a treatment-naive patient population with time as well. And we think this has direct implications and translates to adoption. So a question that I get quite often is, how would 4150 be adopted in the commercial setting. So we recognize, and I think Carl also said this earlier that the patients first considered it likely to be those patients that have high need. In our analysis, we define that as patients today that need 8 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 when 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 4150. And we've also asked physicians and additional work that said, what portion of patients would you consider? And we see results that we think are really encouraging. We see patient share numbers in the 30% to 40% range. somewhat affected by the severity of the disease and the amount of burden that a patient will have today. And we even see numbers about 20% of newly diagnosed patients that may be considered for a therapy like 4150. 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. We also reinforce the enthusiasm and the potential that 4150 could have. And as Cat mentioned earlier, we know that patients are motivated to act, 90% say they would ask their physician about a product like 4150, and in addition to that, when we did -- we've done research with threatened specialists, and we asked that if a patient were to inquire about a therapeutic like this, how would they respond. And 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 the commercial setting 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 that says, "Hey, this is a retina buy-and-bill model, right?" Physicians and clinics make margin in that retina buy-and-bill model. So therefore, if you were to reduce treatment burden by x percent, 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 the clinic purchases, the therapy that they're going to administer to their patient. They administer the inject in their offices, they then build a payer for reimbursement. And then with time, they'll get reimbursed for that medicine, usually on a basis of the average selling price of the medicine plus a percentage margin, depending a little bit on the payer. So I just explained that in 4 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. One, doctors will tell us that for everyone retina specialists in the clinic, they need 4 to 5 staff people behind the scenes to administer this process. making this work in the busy retina trend is incredibly complicated and requires a lot of overhead expense, okay? The other reality though, as you think about bringing new therapies to market ideally, you seamlessly integrate into this. Ideally, you don't cause a new workload or something that gets in the wheels of this that causes disruption. And of course, we think 4150 has an advantage there because you don't need to understand how a new surgery needs to be coded because it doesn't require a surgery. You also don't need to understand how reimbursement logistics and cash flow would flow in the surgery side of care. So while the buy-and-build model certainly creates economic value, we want to also recognize that it also has the potential for value erosion, and because this is so important, we're going to walk through this with a little bit more detail. So today's reality, a practice economic is built upon injection frequency to make a couple of obvious statements, but it bears repeating. If there's no injection, there's no reimbursement today. If a patient falls off therapy as many do, reimbursement stops. And 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, so what good tomorrow's opportunity with 4150 then look like, we think we can potentially amplify that value through one treatment, so you capture that value upfront. Of course, 4150 has adherence by design. It's 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's generated for a clinic that we actually created an illustration to bring it to life with a little bit more detail. So bear with me, if you will, just follow the math here, we said, okay, what would 10 patients on therapy for 5 years result in terms of reimbursement potential. So 10 patients on therapy for 5 years. if those patients are considered relatively aderenate, they will get an average of 6 injections per year. So per patient, that's 30 injections over that 5-year period. And of course, we have 10 patients, so the total reimbursable injections would result in 300 events over a 5-year period, again, for 10 patients, getting 6 injections a year. Then we said, well, what would need to be true to make that potential real. And this is what would need to be true in today's treatment paradigm. So for those 300 injections, you would need, of course, 100% of patients to stay on therapy for the 5 years. You would need 300 visits, you would need 300 injections. You would need 300 potentially benefits investigations and other amounts of back of work. And you would need 300 incidents of getting full and accurate and ideally timely reimbursement. If all of those things were true for 5 or 10 patients on to therapy for 5 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 patients 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 4150 impact that? Well, we believe that by contrast, 4150 by treating those 10 patients has the potential to capture multiple years of value 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 increases the potential for 100% of that reimbursement value. And of course, while this figure is illustrative, it's not a suggestion of a proposed price for reimbursement commitment. And 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 integrated 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 on to their vision. So 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 our own fee for service. So often we refer to it 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 has 0 incremental out-of-pocket exposure. We believe, based upon what we know today, that the reimbursement model for 4150 would be similar. It would be Medicare, 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 4150 for broad patient access. And as I've already referenced, we think this allows 4150 to fit within the very familiar buy-and-bill reimbursement model that retinitis used routinely. We also recognize that the cost of therapy today can be quite significant. And for a patient on therapy for up to 5 years, depending upon what the therapy is but a branded -- if you're on a branded therapy for up to 5 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, the payers -- excuse me, payers recognize the challenges with the existing therapies Three out of 4 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 long term -- the goal of treatment in AMD should be the ongoing protection against vision loss and similar to retina specialists and similar to patients, payers are also excited about the potential of gene therapy 1% 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. And of course, it's question that comes up often is how do we view pricing? The truth of the matter is it's too early to discuss pricing, right? We still need to know more about our product profile, we necessarily 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 4150 based on the profile we've shown them so far. So 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 4 key stakeholders, patients, retina specialists, retina practices and payers hopefully, you've seen how 4150 can address some of those critical needs of those stakeholders and through that shift to treatment paradigm to continuous disease control. We think it's important as well to understand how a therapy like 4150 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 a meat doctor retina practice in Florida. We're one 1 of the highest volume forefront investigative sites globally. I've been PI in over 130 clinical trials, and we see lots of patients with AMD.