4D Molecular Therapeutics Investor Day 2026 - 4D MOLECULAR THERAPEUTICS INC

Hey guys, we're getting started. Thanks for all being here today. I'm 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 am 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. David Kern III, Co-Founder, President & CEO of Investor Relations Thanks, Julian. Well, it's a pleasure to be here and welcome. Thanks for being here. We really appreciate it. I'm Dave Kern, co-founder, CEO, and president of 4-D Molecular Therapeutics. I've been in the industry for about 30 years as a physician scientist, a drug developer, serial entrepreneur, and CEO. So we started 4-d 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. Being here today, it's remarkable to say that we are on the cusp of achieving that vision today with 4150. And we believe that 4150 has potential to establish a whole new treatment paradigm in what AMD is 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 4150 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 three design, and our phase-three 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 gonna 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 4150 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 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 what AMD is simply not good enough so 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 and again it's not good enough. So why do we think it's not good? 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 ever again for the rest of their life. So, why is that a problem? well what 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 this burden and cost on this 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 And outside of the United States, where treatment's 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 4150 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 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, 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. 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 ten years ago, the first order of business was to invent a novel capsid, and we wanted that capsid to have 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 achieve that. we wanted a vector that targeted the retina and particularly the macula very very efficiently with a 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 the delivery vehicle. The The actual treatment here is Aflibircept and an RNAi for VEGF-C. So we hit four VEGA family members. Let's remember Aflibirecept 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 de-risked. what we're 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's a fundamentally better way to use this amazing molecule okay so with that background I'd love to invite Dr. Arshad Kanani to the stage. Arashad has been with us through this entire journey from inception to the treatment of the first patient with 4150 and we're we're thrilled to have him here. Arsad? Good morning everybody. It's great to see you. I'm Arshadd Kanani. I am a medical and surgical retina specialist based out of Reno, Nevada. I've been involved with or 150 clinical trials as a PI and I've been involved with many gene therapy programs throughout this journey I've in practice or 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 would 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 three 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. So before I get started I want to ask the audience how many in the audience had 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 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 diseases that can blind you and you have to come to this clinic sit for the doctors for three 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 shifting treatment that we hope can 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 were 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 and you know she said I know what this disease is gonna 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 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 so we are trying to change this with 4150 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 they 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 thing 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'm 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 our patients who live four 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 you know they need a ride they have other health problems finances are a problem sitting in clinic is a problem miss work is a problems 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 wanna keep their vision the first thing they asked me am 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 prison, 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 Path Survey, what is the number one 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 poor delivery system or sasvimo and this is the seven year data that i presented at uretina last year what do we see going from ladder phase two to portal extension we see maintenance of vision over seven years in a prospective clinical trial setting now of course poor 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 or 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 and 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 4150 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 invasion 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 4D150 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 you know obviously we have to wait 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 in 2021. Carl is unbelievable and a role model for me. Carl. Thank you, Arshad. I'm Carl O. I am the president of Tennessee Retina, a 15-physician retina-only practice in Nashville. As Arshada 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 P.I. on more than 50, and going to David's presentation, 64 million doses ago, ago the first human eye ever injected with a flibrocept was in our office in the phase one so we really have seen the world change and my mother who's now deceased 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 done a fantastic job sort of setting the stage for phase three phase one they looked at and one to a the most recalcitrant eyes really challenging eyes to treat that helped establish safety and efficacy phase 2b 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 three and there's a phase 2 B subgroup of recently diagnosed eyes that I think really parallel very well the patients that are being enrolled in the phase three program so let's talk about phase 2b and here are three 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 all 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 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 a flibrocept injection every eight weeks. This represents a 78% reduction in treatment burden. Now let's look at this recently diagnosed population. So 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, and this is a very high rate of 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 and so what we see here are the outcomes for every eye that was injected in phase one and phase two with the dose that's been using in the phase three 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 have 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, carotid 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 4D150 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 three programs and I'm delighted to now introduce Devil Desai who will go over those programs with you. Thanks Carl, thanks Carl and thank you to everybody that's here in person and online for joining us today. My name is Devil and I am the chief development officer here at Ford EMT. Over the past two years our teams have been busy developing and delivering the phase 3 wet AMD program for 4150. Today I'm excited to be here to share with you why I think that program is designed to win. The forefront program consists of two nearly identical studies, Forefront 1 and Forefront 2. Both are fully enrolled, randomizing 523 and 531 patients, respectively. Forefront one was conducted in North America and enrolled 100 percent treatment-naive patients. Forefront 2 is our global study and allowed up to 40 percent previously treated patients. That's 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's 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 believed that retina specialists would see the potential of 4D150 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 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 Afliricept two milligrams 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 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 forefront data set stands to be one of the most impactful data sets we've seen in AMD since anchor in marina as a potential backbone therapy 4150 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. And as a single, in-office, intravitreal injection, 4150 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 4150 in wet AMD, I'd like like to invite Drs. Kanani and Dr. Rao 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 our shot 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 talked to my patients about wet macular generation 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 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 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 a compelling promise of gene therapy and continuous delivery. Thanks. Arjun? Well, I think I already showed about, you know, the real-world outcomes and number of injections. And, you now, I was closely involved with the Pabaisamo program, and, you know, and I lead the Truckee and Tahoe 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 two weeks to patients who were POC-treated on two milligrams of Aflipiracet. And you see, obviously, the need is so high that even that two weeks on POC treated made Vabaisamo a 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 two beyond what it is, we're 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. So I think that's what it is all about, Davo, from my perspective. And then, you know, you've 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 4D150 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, you know, I've been through many different gene therapy programs, you now, and what 4D 150 brings is three 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 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 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 prophyaxis, it's important, and we learn from other programs and we optimize the prophylexis. So I think using those three things, Davil, 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 the 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 gonna go from getting six or eight or 10. Many of the patients in phase one, as Carl presented, high-need patients requiring injections every four to six weeks taking that patient to one or two injections in a year it's been groundbreaking from my perspective and from the patient's perspective so bottom line double is that it's very consistent in my experience in prison treating over 45 patients Carl anything from you additional no I think if we can see in phase three what we've seen in phase two you know doubles made the benefits crystal clear I think it'll be a something tremendous for our patients and then maybe Carl can you talk a little bit about you know your PDS experience and how this parallels to that right so as double 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 at six months there's still lots of drug left in it so the drug level never goes to zero and so that is why we see this tremendous maintenance of vision you know the 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 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 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 three can you maybe just talk a little bit about like what are your expectations out of the phase 3. yeah i think can i make a comment yeah sure so during COVID, the patients who actually didn't lose vision, and just like Carl, I was a big enroller in the poor delivery system programs, were the PDS patients versus FEMA patients. So just to keep in mind the sustained delivery, when patients missed visits, they didn't loose 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 risks so I still use it on a very small number of patients but but obviously the difference here is this is intravitreal treatment that it can be done by anybody around the world so phase three double I think phase three are designed for regulatory success and we take the learnings from phase one and two and implement them in phase three so 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 so going to naive in front for a forefront one and majority naive in forefront two 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 and those are the patients sometime 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 optimized the trial design in my mind as a clinical trial list 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 you know the phase two results are so compelling and I think a lot of thought has been put into the design of phase three and I would love to see outcomes very similar to what we've seen in phase two so maybe digging on that a little bit you know historically gene therapy the big conversation around that 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 three that we've seen in phase two 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 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? I think Carl said it well. This is a one-time treatment. So imagine you are reducing injections by 50 or 75 percent or eliminating injections. 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 lack 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 gonna have mild transit 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 here, it's always like this fear of something is gonna 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 observed so in 4150 being involved with all gene therapy I've been carefully looking for everything I can find that is changing and I and you know my experience has been very positive based on the totality of the inflammation data is mild transient it happens early and then you don't have to worry or be fearful about something happening down the road. Yeah, thanks. And maybe in this last question for both of you, let's assume we're two years down the road and 4150 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'll be the natural, you know 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 six weeks every eight weeks every ten 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 you know people talk about well you know if you make it out eight or ten weeks that's really great you know think about it how many of you are overdue for your one-year physical exam all 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 yeah well I agree with Carl I think somebody who has not done gene therapy and it's new to them they're probably going to go to their high need patients but for me treating over 45 patients in prism you know and enrolling patients in all of the cohorts right the first high need broad and then recently diagnosed and i've had experience with all three of those so my perspective is a little biased because i have first hand seen the efficacy the durability and the and the well-tolerated safety so from my perspective i'm actually getting patients ready that they there is hope in the future right a lot of patients ask like what's coming in the future i 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 it's much broader in my patient population than then then how it gets started in in the community well gentlemen thank you very much you know 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 thank you thank you and now uh i'd like to invite to the page a very good friend of mine and a long time colleague our chief commercial and Chief Business Officer, Chris Simms. Good job. Thank you, Davil. 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 4150. 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. Arshada 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, 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 Lucentus was launch we think the market is prime 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 4150 as you know remains in Phase three development and of course we cannot guarantee a trial 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 four key stakeholders and we're going to ground the next portion of the presentation today and going through the needs of those four 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 All of this is the need, as we've talked about earlier, to shift the treatment paradigm. Today the treatment paradigms 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 percent of retina specialists, when we survey them, they agree with that approach as well. Davos 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 that it has really important practical application for commercial success. The last thing on the screen points to the fact that 4D150 was designed to be a single intervitreal therapy injection. What are the commercial implications of that? They're quite simple, but they're also really important. Well, that means that 4D150 can be delivered in an in-office setting. Carl, Arshad, Sarah, David's 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 the retina operating model seamlessly is gonna 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 4D150 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 boles therapies that are in development all share the same limitation, which is finite durability. 4150 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 gonna spend a few minutes talking about the market, just reminding us about the opportunity and the size of the market. And then we're gonna 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 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, right? Most recently, the medicine of Vivizemone brought from Rose Genentech, it provides the potential for incremental durability. We've actually did some interesting analysis, I think, with our own data, with 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 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. So the incremental change in that five-year period, it's there. It's about 12 We think that's fairly modest But despite that modest change we know that these medicines have had large commercial success The bismu itself three years after launch is about a four billion dollar brand It speaks to the importance of durability. We hear this timing 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 that despite the innovation of these new bolus therapies, 0% of them provide a patient with a possibility of continuous disease control, and 0% have then provided 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 volume. I'm gonna walk you through just some of the numbers to help you paint the picture from the patient lens as to the size of this market. This, let me just start with wet AMD itself. So today in the US, we estimate about 600,000 patients receive regular therapy, regular injections for wet AMD. Space has a pretty high rate of incidence, and it's important when we think about the potential in the future to recognize that. About 160,000 of those 600,00 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 US. So a large market by 2030, we expect that to continue to grow. And we estimate there'll 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 US 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 the 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. 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 their motivations, what are they concerned about, and what are the lived experiences. Our shot in Carl's 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 Kat Pajak on my team to come up. Thanks, Chris. My name is Katherine 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 two decades. Personally, I have 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 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 4D150. 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, as I 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 three hours. the 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 lasts for over a day. So 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. 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 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. 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 that 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. I always say if I'm not having a good day, it's my own fault. I need to make it a good. So I find some activity that I like to do, whether it's going up to Lake Tahoe and hiking around up there or going swimming. I don't want to just sit around. When I was first diagnosed with macular degeneration, I decided I've got to do something about this and I've gotta do something right away. I don' want to go blind. When I think about losing my vision, I'm most afraid of losing my independence. My ability to drive, my ability to do things for other people was very upsetting to me. I saw what happened to my mother. She was driving at that time still and she called me and she said, I just hung up my keys and I said, why? She said I was driving and I stopped to talk to who I thought were my neighbors and they were the mailboxes. My biggest goal was to be able to live independently and be able see and do the things that I wanted to do and not have this get any worse. but I never realized how fast this disease grew. My doctor came in the room and he says, you have macular degeneration, I wanna start giving you injections in your eyes. And I said, no, no hold on here, what's going on? Then another doctor came and he said, this has gotten worse, you need to start taking the injections and I did. When I leave my house it's five hours before I get back. It's a long process and sometimes I get needles in both eyes on the same day. You need to really understand the value of your vision. It's everything. Your hearing is one thing. If you lose your teeth, that's another thing, but you gotta be able to see. I was gonna get any treatment that I thought would work for me, and I was going to go anywhere to get that treatment. What I've learned from this experience is it's so important to seek out the best medical care that you can get, and then research that medical care, and be an advocate and be adamant about getting the best treatment possible. I'm just blessed to have a great life, blessed to the vision I got. If I could get a treatment that would protect my vision, I would definitely do it. I think Judy's story really highlights the emotional impact of the disease and the motivation that patients feel to get treatment. And they know what's at stake. They know what's 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 Arshada 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 profile to patients. And you won't be surprised to know that they were barely 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 gonna take away the anxiety of having to fear getting to treatment, it was gonna 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 4150. 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 4D150. And to share more about the patient perspective, I'd like to invite Dr. Sarah Haug onto stage to tell us more about patients that she sees. Thanks, Sarah. 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. So maybe we can start and talk a little bit about the patients you see and your practice. So I am a retinasurgeon 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 nine doctors, but three of those are optometrists, not but, and, three of these are optomotrists. So we had 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. So when you talk about that wide geography, how far are patients coming? Yeah, so we have patients coming four to six hours, one direction, just driving. That doesn't even include the visit or the time that it takes just to like, it's a whole day. 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. 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, you know, didn't go blind from wet macular degeneration. But 20 years on, we're weary. 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'll be upward of 100. Yeah. 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, you know, 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 a hundred 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 tears. 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? Dr. 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 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 until truly the patients fail treatment, then I say, oh, 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 to 60% of my patients are on every four to six-week treatment. And you have patients coming four to six hours every four to five 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. 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 in every 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 go home to Oregon I mean these are it's 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 your pain 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, drops off a little bit in the winter, although not so much anymore. And so I don't, you know, 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 to see. Well, that's the thing. I mean, you know, what am I going to do? And it's interesting when we talk about patients that, you Know, 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 is really hard to get them in. So what question are your patients most asking you? So I actually asked Kat to ask me this because I hear it every single day. How many more injections do I need? And the answer is forever. They, you know, 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 the way we think about what macular degeneration and how we treat it is going to be very different in three to five years I hope and you also been an investigator in our forefront program so what has been the reception to gene therapy you know it's interesting I wondered so Durango has a very you know of course it runs the complete gamut from very educated you know we have a 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 injections they're like, I've been getting this for five years. Why can't I sign up? And they ask me every single time, when is it coming? When is it going? And it's never soon enough. So the reception has been very, very positive. I've had very few people express concern about this gene therapy. How do you explain, if you get a question about gene therapy, how do you, how to explain it? It sort of depends on the patient, but, you know, 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's all you need to say. And then they're just like, sign me up. I'm in. Yeah. Yeah, so if you think forward, you imagine a world where 4158 becomes approved. How do you see it changing your patients' lives, your clinic? Yes, so, you know, there is this worry that retina specialists have become so used to just being the, I'm going to go and I'm to do a hundred patients today. We do, you know, 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 don't see that there's a wet macular degeneration patient that wouldn't benefit from this technology. But to, you now, 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, you know, 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 four to six 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 macula degeneration patients. That's great, Sarah. Well, thank you so much for sharing your thank you it's a pleasure yes and with that I'd like to ask Chris to come back to talk to us more about the retina specialist perspective thank you Kat you Kat and Sarah 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 like for the clinics we talked about payers and reimbursement so the retinas 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 twelve hundred and fifty of them so roughly less than half had about three thousand represent about ninety percent of all the patient volume and of course that's relatively small community as we've seen already can drive pretty significant commercial success with the bismo largely those numbers i shared earlier was driven by this 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 for 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 seek 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 startup biotech company, can absolutely do this and it's in the community of this size because of this dynamic personally myself Dovile 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 setting of a large pharma company and the other was in the setting up a smaller biotech company not that dissimilar from 40 MT 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 4D150 can mean for a clinic is addressing this capacity issue. And you just heard Sarah 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 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 4D150 can affect that. So 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 4150 with 75 percent 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 41 50 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. patients that have a higher healthcare 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 4D150 be adopted in the commercial setting? So 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 defined 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 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-build model so in confidence and 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 did additional work that said well what portion of patients would you consider and and we see results that we think are encouraging we see patients share numbers in the 30 to 40 percent 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 percent of newly diagnosed patients that may be considered for a therapy like 40 150 of course we recognize that this is early this has all the limitations that come with market research and 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 4150 could have and as Kat mentioned earlier we know that patients are motivated to act ninety percent said they would ask their physician about a product like 4150 and in addition to that when we did 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 and we see a very similar response where 90% of doctors said they will 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 a 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 it says hey this is a retina buy and build model right physicians and clinics make margin in that retina by and build 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 build 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 So I just explained that in four easy steps It sounds pretty simple and for the most part it kind of is is. However, what's lost in this is a couple of things. One, 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, 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' need to understand how a new surgery needs to be coded because it doesn't require a surgery. You also don't need to understanding how reimbursement logistics and cash flow would flow in a surgery side of care. So while the buy and build model certainly creates economic value we want to actually 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 economics is built upon injection frequency to make a couple of obvious statements but it bears repeating if there's no injection there's 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 could potentially amplify that value through one treatment so you capture that value upfront of course 4150 has adherence by design right it's a lifelong therapy and if 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 understand that economic value that's generated for a clinic that we actually created a 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 five years result in in terms of reimbursement potential so ten patients on therapy for 5 years if those patients are considered relatively adherent they will get an average of six injections per year so per patient that's 30 injections over that five year period and of course we have 10 patients so the total reimbursable injections would we would result in 300 events over a five year period five year period again for ten patients getting six injections a year then we said well what would need to be true to make that potential real and this is what would lead to be in today's treatment paradigm so 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 wouldn't need 300 potentially benefits investigations and other amounts of back-office work and you would need 300 incidents of getting full and accurate and ideally timely reimbursement if all of those things were true for five for ten 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 that treatment paradigm today 160 means that what should have been a hundred percent 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 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 a hundred percent of that reimbursement value and of course while this figure is illustrative it's not suggestion of a proposed proposed price or read reimbursement commitment and to put it altogether the potential value proposition we believe is not just simply fewer injections it's not just upfront reimbursement in 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 payors by looking at who the primary payer is so in this wet AMD market because it's an older patient population and the primary payer is Medicare. In fact, today, about 90% of patients are reimbursed with a Medicare plan. 37% of those are re-imbursed through CMS. It's our drawn 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 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 build 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 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 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. And 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. And of course, it's 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. right? We still need to know more about our product profile. We still need to see what phase 3 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 four key stakeholders patients retina specialists retina practices and payers hopefully if you've seen how 4150 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 4150 can operationally be incorporated into a busy retina clinic and to help us with that understanding I'd like to invite dr. David Ischenbaum to join me Thanks Chris. Happy to be here. Great to have you. Have a seat. Hi there. I'm David Eichenbaum. I am director of research at a doctor retina practice in Florida. We were one of the highest volume forefront investigative sites globally. I've been NPI in over 130 clinical trials and we see lots of patients with what AMD you do so David and I know each other for a while we go back probably when I joined the Genentech years ago when centers years on the centers um Sarah mentioned earlier about the volume of patients in her clinic can you just share a few data points or just your your your clinic experience just in terms of number of patients you guys see and what that what that could look like as well our volumes are a little lower than than Sarah'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 so that requires as we just alluded to I think a quite a significant amount of operational support advantage of the logistics around that when you think about a therapy like 4150 how do you think about it in terms of how it fits into the operational flow of your clinic yeah so we do intra vitriol injections in the clinic a lot of branded agents the majority of our injections are branded we've always been a heavily branded clinic and we're very comfortable with biome bill we have a very well supported biome Bill model we do all of our billing internally with our own in-house billers and you know we're access sensitive and we're 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 so I mentioned earlier because this is a buy and build model that there's a there's an need to ensure that you have the confidence that that if you're going to inject a medicine that's expensive, that you feel confident that you will get reimbursed for that. Is that an accurate statement? And clearly in a 40-150 world, how would that show up with your decision to use the therapy? Yeah, it's a key, 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 practise. And if you don't have revenue to support your cost, all the rest of your revenue isn't gonna make that up. So it's very important that we have processes which we've established over 20 years since the approval of Lucentis. And 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. So the importance of a medicine like 4152, 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, it would be an important feature. Absolutely, it has to be able to not require special equipment, not require special handling. It has to something that looks and feels like an ilea injection, more or less. Right, yeah, that's really helpful. We sometimes hear the question, because as Davo covered earlier, there is a prophylactic steroid regimen that patients would go on upon receiving 4150. And there's this question that comes around, well, how will patients react to that? And how would you as a physician, if you had a patient on 4150 in the real world, how would your monitor them? Can you just speak more to what that would look like? Yeah, sure, from a clinical perspective, I really like what Carl said about that. Carl said, if I have a patient with a retinal detachment, and all four of your doctors here today are surgical retinal specialists. If I have patient with retinal detachments, I'm not withholding their retinal detached repair because they're gonna have inflammation for four to eight weeks afterwards. I'm gonna manage the inflammation with drops, almost all the time with drops and they're going to get better. And I think that's a similar approach to what we would take with intravitreal gene therapy with 4D150. It is a 20-week corticosteroid taper, so that's 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's helpful. And I shared a few slides to talk about the potential economic value that 4150 could have for a practice. I think we recognize that how we derive that is different than maybe the current treatment paradigm. How did that resonate with you? That makes sense in 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 Sarah said, we are not good at following the attrition from clinic, but we know there's 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 4D150, I think, is what's gonna compel doctors the most, but there is this tremendous economic value. There's 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 don't come in. The patient's not going to do and we're not gonna 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's a win-win for the clinics as well as the patients. And currently, you know, in 2026, 2027, we expect to buy and build model to exist now and in the at least near to midterm future, exactly like it exists today and 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. We asked you this question yesterday, I thought your answer was really interesting, which is, you know, let's assume 4150 is commercially available in your clinic, and 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 feel about making those decisions? Sure, certainly. So, they'd have to be patients who have good access, who early on, they would be original Medicare with supplement patients aside from that clinically I started 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 it's 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 trial, just to see if they work. And I think there are a lot of doctors who, when they see the data and they see that 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. But we hear more and more from physicians with the caveat that you just made, of course, reimbursement. 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, so based upon everything that you knew about 4150, what we believe the potential could be for your clinic and for your patients, what gives you the greatest confidence that a product like 4150 can become a key part of the future treatment paradigm? The greatest confidence I have is the existing data set. The existing data said, combined with what we know about port delivery system and Arshad and Carl and I were all deeply involved starting in phase two 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. So I think it's the data combined with the alignment gives me a lot of excitement about 4D150. 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 meet all of them but you through that time period been been full of insight 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 and with that I'm going to move to the next section pleasure thank you thanks for having me nice to see you so to bring us home I'd like to invite our CEO David back to the stage David thank you Chris all right and thanks David for those incredible insights and Sarah for your insights as well so as Chris said I'm gonna bring us home we'll try to make this pretty efficient and get on to our Q&A session so I want to start by reminding you that we have assembled a phenomenal team at I'm very very proud to be working with these people all deep experts in their own fields and importantly for today they have deep expertise in retina therapeutics development and retina therapeutics commercialization and in manufacturing regulatory affairs so we are set up for great success second I want to acknowledge we have a number of board members here thank you for attending but we have a phenomenal board of directors and in particular they're particularly well suited for the company is today and where we're going they have deep experience in commercialization scaling of companies and I think they're going to be very very instrumental in helping to guide the next evolution of 4d and do a commercial stage company so thank you this is our catalyst calendar we've had a very busy and robust and successful 2026 we're set up for success in 2027 with two very important readouts forefront one our first phase three trial will read out in q1 a q2 sees me of 2027 and forefront two will read out in the second half of 2027 so it's 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 twenty twenty eight so again come back to the four key takeaways at 4d you'll notice there's a theme of four of everything but at any rate number one 4150 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 what AMD vision preservation and treatment burden reduction with the potential for long-term freedom from injections number Number three, our clinical data, our design of phase three and execution on phase three positions us for great success in 2027 and beyond. And 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'd like to end by thanking our amazing KOLs for your attendance today and your insights. Thanks to the 40MT 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. And with that, I'd to invite our speakers back up to the stage, and now we'll take on some of your questions. Thank you. Thank you. All right, thank you. you guys do an incredible job like stage management here it's impressive okay I think the there we go all right we got a lot of questions in the queue so we'll try to get to as many as possible but if there are further questions please find us after the reception so the first question comes from Josh shimmer at Cantor what kind of BC VA change do you expect from the day one to 52 week BC VA non-inferiority analysis, what do you expect in the Flibercept arm, and 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'm going to turn that over to Double, and then you can also share it with some of our key opinion leaders. Yeah, so I'll take it in first part of that question first. So you heard me reference, you know, kind of this treatment-naive patient population and what we would expect to see out of that. If you go back to every single phase three study that's been done, you see that visual acuity show up somewhere around six to eight letters. Where it exactly is is dependent upon what the starting visual acuity is, but we picked this population because that's where we expect this outcome to kind of wind up, in that six to eight letter frame really depend upon where the baseline visual acuity is. And then on the second question as it relates to the weak minus five analysis, I'm not going to comment specifically on what is or isn't in the SAP. But 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 three study that's been done. Those studies measure visual acuity from the first loading injection. So in order to make that same comparison, we will have an analysis showing from the very first injection. Male Speaker 3 Yep. And there was a follow-up question on this in terms of most Forefront 1 patients are now past the 20-week taper period. On a pooled mass basis, has any patient restarted steroids? I just want to, you know, Dave, do you want to actually say that? Male Speaker 4 Sure. I think, you now, we've reported that data, and we're very thrilled with what we're seeing in terms of overall safety and also just completion of steroid drops on time, and, you know, I think it sets us up for commercial success. Male Speaker 3 Yep. And I just want to comment that we are in a blinded study, so in order to study integrity, we are not commenting on blinded safety events in the phase three trial. So second question comes from my team at B. Reilly. So we talked about the Fliberstep response criteria as a way to reduce variability in forefront. Could you speak to how that's played out operationally in screening, whether you can characterize what share of screened patients didn't make it and what their prior injection frequency like? It is a treatment-naive study, so there shouldn't be a prior treatment injection frequency, but yeah. Male Speaker 1 Yeah, perfect. Why don't we start with Double, and then maybe hear from Arshad as well. Male Speaker 2 Yeah, I think the question is asking how many patients were screened out due to the Aflibir step. So again, not commenting on, you know, kind of exact results on an ongoing mass 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 a Flibercept was a 15 percent response, so 15 percent of 350 is significantly smaller than 100 so when I made the comment that the criteria were put in place and specifically the response criteria were put in as to maximize the visual acuity outcomes but not fundamentally alter the week 52 expectations that's what we're talking about so 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. So 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 quote unquote no response that will show response in one week, and then they'll have recurrent fluid. So, we are inclusive. We have not really, you know, 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 Denia and Lucerne. Great. So the next question is from Daniel Giraldo at Bank of America. How are you thinking about the potential for redosing or bilateral dosing? What data are we collecting for that? Yeah, that's a great question. Maybe I'll start with Double from the technical side, and then Chris and some of the KOLs can weigh in on the commercial opportunity there. So the question is just redosing in same eye or fellow eye? Bilateral, yeah. Bilateral. Yeah, so 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-wide program. And we've put on clinicaltrials.gov that that program is currently underway, and so we fully expect at the time of launch to be able to administer 4D150 to patients biliterally. Yeah, I mean, the only comment I would add is that commercially, as I showed earlier, 30 to 40 percent of wet AMD patients will develop disease in their fellow eyes, so we think that's a significant opportunity just from a commercial perspective. When their fellow eye is treated, I think, will be up to physician, doctor discretion. Maybe one of the KOLs can speak to when they would be comfortable treating the fellow eye, but certainly the amount of opportunity there, considering the bilateral rate, is quite significant. David, do you want to start? Sure. Yeah, so I am involved in the bilateral study from the phase two 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, and if they're a bilateral patient, they want that treatment in the other eye. With surgery, you know, 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 one to two months and I think that principle would translate to 4d 150 I think bilateral treatment is common in retinal disease because people tend to be somewhat metric more or less you know my feet are almost the same size left to right and 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 time are you had a comment to it 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 the what will be nice about gene therapy though with an individual 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. It wouldn't be a constraint with an antiretroviral 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 I study and not everybody can get in but every single patient is asking that I want this in my other eye because you know if you think about it you are getting every four to eight weeks on average injections every four to eight in both eyes you do one eye but the other eye still has that treatment burden visit burden right so just like as David said after you treat one eye you're off the steroids everything looks great you you treat so within three to six months after the initial injection would be my timing awesome thank you so I think the next question is around really kind of the phase three design in terms of supplemental criteria and how supplemental criteria should be thought of so we double you talked about the kind of retreat minerals you know how do these compare across different trials and how to touch we think about that yeah and why did you kick it off double and then we can hear from some of the investigators on the study yes 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 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 forefront program with a secondary emphasis on treatment burden reduction yeah I think you know 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 so 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 and 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 so you have all seen the criteria for forefront program is it's both anatomy and vision at 50 and 5 we have anatomy by itself and then of course retinal retinal hemorrhage so I think in this program as double said the goal is to protect the vision and the primary outcome because if you don't need a prime if you meet the primary outcomes and it is irrelevant how much treatment burden reduction is there how many patients are injection-free. So, 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. Male Speaker 1 Okay. Great. So next question is really around steroids. So 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 talkable steroid taper? Also, how concerned are you about patients developing cataracts due to this level of steroid use? Sarah? In our clinic for a steroid taper, we actually have a whole checkbox sheet that we give them. You know, 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. And yeah, you know, 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 catarct. And so, you know, catarect surgery is an inevitability. It's not something that would make me worried about using steroids in this situation. Carl? No, I tell my patients for other reasons, catarects are inevitable and catareicts are replaceable. Your macula is not replaceable, and so we are always going to prioritize what's best for your macula or your retina. So it'd be nice if we didn't have that as a side effect, but it's not something that would constrain me in the least. Yeah, because we're used to using steroids for diabetic macular edema. We use steroids topically for uveitis. And we know that 20 or 30% of patients will have increase in pressure, but I haven't had to stop anybody on steroids because we can control pressure with other eye drops. But I think I want the audience to put themselves in the situation of a patient if you have three option you have either surgery to decrease your burden you have no just continue the way you are doing injections four to eight weeks for the rest of your life or take 20 week of steroids topically at home i think all of you are going to pick that third or most of the people are going gonna pick the third option now of course patients who cannot take steroids because of glaucoma or they just don't have you know compliance issues sometime elderly patients can put it so we have other options in real world you know we have options of steroids we have subtenon injection of steroid we have intravitreal steroids we can give so 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 trial and I would say the key is based on the data we have so far from phase two it's episodic this is not chronic inflammation that requires ongoing steroids as far as we can tell to date and as long as it remains essentially episodic it's something that we can deal with clinically all right I think we'll we're kind of out of running out of time so take one last question so So the last question is from Matthew Caulfield at H.C. Wainwright. For the potential adoption of 4150 in wet AMD, how could you see uptake playing out in the first one, three, and five years? And how quickly could you real-world use expand beyond those first hybrid inpatient, which we talked about kind of earlier today? Matthew Caulfield, M.D.: Well, thanks, Matthew. And Chris, you want to take that? Chris Winslow, MnD.: 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 it's not an insignificant number of patients 25% of eyes fall into that what we would deem as a higher need category the exact time as to when patients or in positions would consider a broader population I think it's going to be dependent upon a couple of things I think the first thing is demonstration of railroad safety we've seen that with other drugs that we've launched my experience that happens somewhere in the six to twelve month period the other key factor is actually not clinical at all it's actually about confidence and reimbursement and the key thing I think in a buy and build model that drives that is the get a permanent J code right once you get a permit a J code reimbursement using works a little bit smoother it comes a little faster and what we usually model in a commercial setting is about nine months from the time your medicine is approved at a time you get your permanent J Code so those factors we think cause the adoption to get broader beyond that higher need patient population and I think we have that happens I think you know from rough Matt modeling we think you know nine to twelve months is when you would start to see that that graduation occur 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 an anonymous day code I think the penetration into the market in the first year will be low I think after you have the day 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 the 20 to 25 percent 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 you know I'm 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 that what'll be different with this is that we're gonna have tremendous demand by patients. So 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. So I think that we'll actually see much more of a drive of patients coming into the office saying I've heard about you know This gene therapy, you know, why can't I get that much more so than we do with different individual injection? 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 that I don t want these injections So this is very common and it has happened with clinical trials and it happened with poor delivery system And I think it's happened with the vizmo. Yeah I think I totally agree I think from my perspective I think payers right so the the number of patients in my clinic who have straight Medicare as Chris called it is about 40% so those are the first group of patients that I'm going after of course we'll have to figure out copay assistance and other things but those are the patients that don't need auth right you can you can give them 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 I need or patients you know who need frequent treatments are gonna be the one and we'll do studies like Truckee where we share the real-world experience we have done the summit study with poor delivery systems as Rima and it's very similar to what the outcomes we saw obviously in the clinical trial so so 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 you know safety and efficacy and durability hopefully that highlights that's highlighted in the phase 3 of course we have to wait for the data so I think we have a think about a broader market this is not for a specific small number of patients part of it is the delivery part of it is data of efficacy and durability, and part of it a safety. Perfect. David, take us home. All right, well thank you all for being here. We're gonna have a reception afterwards. We look forward to networking with all of you, and again, thanks all for your time.