All right. Well, thanks everybody for joining us. Here today with 4D and welcome to sunny Miami! Thank you. Thanks for having us. Great place, yeah. Thanks for joining us. All right, before I start torturing you on the nitty-gritty of the programs, why don't you take a minute and just give us the lay of the land heading into 2024. What are you excited about? What should we be excited about? Yeah, well, first of all, thanks for having us. Beautiful location. I can kick it off, and then Uneek can weigh in. I'm David Kirn, co-founder and CEO. And, you know, we're a next generation genetic medicines company with targeted and customized AAV vectors for essentially any tissue we want to address in the body. We've got four clinical stage products. The lead assets that we have are 4D-150 for wet AMD, DME, and DR, so multiple multi-billion-dollar opportunities there. We've got a GA asset that's coming behind that with a complement factor H construct, which is really promising. And then, that's an IND candidate. And then, we also have a cystic fibrosis program, both as a monotherapy and in combination with modulators using a aerosolized delivery method there. All these products use vectors that we've invented internally, and so we're thrilled with the fact that the clinical data is validating the platform across multiple vectors, three different vectors, three different routes of administration. I think in terms of catalysts for next year, it's gonna be a huge year for us. In large market ophthalmology, we have five different catalysts. We've got the randomized 4D-150 wet AMD study in high-need patients. We've also got an ongoing study that should read out and be shared publicly early in Q1. And then the second half of the year, we should have data on our kind of more traditional standard need wet AMD patients with 4D-150, and then we're also enrolling a DME study as well. So we've got those three, plus regulatory guidance on the Phase III pivotal trial design we expect to share in Q1. And then, we expect to file the IND for the GA asset in the first half of the year. Mm-hmm. So that's just on large market ophthalmology there. And then, in terms of the cystic fibrosis program, we expect to release additional data on that program sort of mid-year, and then, also give regulatory feedback, and guidance on the pivotal trial design for that program as well. So it's a really busy year for us. Oh, my goodness! Yanik, anything you want to add? Yeah, no, just to emphasize on that and to contextualize. So, as David mentioned, so wet AMD data update, DME, we have the program update on GA. We potentially are also thinking once wet AMD and DME sort of starts to move forward about DR, and then, cystic fibrosis. So we're talking of four or five potential indications, which are north of... whichever way you cut and slice and dice the market, north of $1 billion each. Mm. So that's a pretty impressive runway to get into in 2024, and that sets up 4DMT, I think, truly for a breakout 2024. Yeah. All right, well, we're excited to see all of that data. Let's dive into some of the nitty-gritty of the data that we have on the table as we get prepped for those catalysts. For 150, for the wet AMD program, let's start here. As you move into a larger patient population, you've talked about several subpopulations there, but as you move into a more general wet AMD space, how do you frame expectations for clinical outcomes that we've seen from the more traditional VEGFs, like BCVA, excuse me, BCVA and CST? You know, what should we be expecting from gene therapy on outcomes rather than just sparing of injection? Yeah. I think it's a really important point. You know, 4D-150, it's not just about convenience, right? Yes, it's important that it's intravitreal, and yes, it's important that it's a single injection, and that's a huge advantage for patients and physicians, and we've seen great enrollment on our studies on that basis. But it's also important to remember that we're expressing not only aflibercept, but we're also expressing an anti-VEGF-C, which has been shown in randomized studies to improve BCVA on top of a VEGF-A inhibitor. So, you know, we're targeting all four molecules in a single product. You know, that's never been done before. Mm. And then, you know, we think there's a real opportunity for superiority, based on the fact that the expression is in the deepest parts of the retina, so it's right on top of the blood vessels. You're not requiring diffusion from the vitreous all the way through multiple layers into the, into the vessel. You know, we're expressing it right where it needs to be, and it's constitutive expression. It's expressed 24 hours a day, 7 days a week, 365 days a year. So we know that under treatment in the community results in worse visual acuity outcomes over time. Mm. There's every reason to believe that constitutive expression should result in better outcomes. Mm-hmm. Certainly, better compliance, because- Yeah ... patients don't need to participate. You only need to be compliant once. Uh, yeah. To what extent do you expect to be able to see those sorts of effects in a clinical trial setting? Well, I think it depends on the trial design. You know, certainly, the traditional way of getting drugs approved in this area is a non-inferiority study based on equivalence in BCVA, and- Right ... we anticipate that could be a design that would be well suited for us. But we think over time, you could think about designing studies, even after initial approval, that show that superiority opportunity. Longer-term follow-up. Exactly. Patients who, for example, are non-compliant or underdosaged, where you're getting kind of this sawtooth effect, where the retina is getting edematous and then coming back together, back and forth, that's just not a good outcome for a patient. Not good. That's not necessarily for approval. Sure. but over time, we could differentiate and, and get a greater market share. Well, I'd love to talk about that trial, but I think we have a limited amount of time. So let's stay on track. One thing that we noticed going through the data that you've shown already is that there is some variability from patient to patient in terms of folks who are stable versus folks who are improving. Mm-hmm. BCVA looks stable, which is sensible, coming off of a treated patient population already on VEGF. But CST does seem to show some variability between patients, some of whom appear to be improving dramatically and others who are stable. Is there anything you can pull out of the data set that you have that guides to what to expect there and which patients are which? Yeah, I think it's probably too early to know. It, a lot of it probably has to do with how adequately treated patients were treated coming into the study. So if they've been really heavily pre-treated and they're essentially dry- Mm. Then you don't expect to see improvement. It's not possible. You just hope to retain that. But if you have a patient who's perhaps been underdosed and has a particularly edematous retina, then we could see an improvement, and we have seen that. So I think it's probably most dependent on kind of where they are at the starting point and how much room there is to actually show an improvement. Just on that point, so for wet AMD, you are like enrolling patients based on VEGF requirement in the year before. Would BCVA and CST also be like a parameter observed at baseline to see which patients are better responders or Yeah, absolutely. I think both the OCT, CST, and the BCVA might predict. Again, I think it probably most of it, though, has to do with how well treated you are coming into the study, you know, because some patients may have already lost a certain amount of vision, they're never gonna regain that. But certainly, if they're undertreated, then we could see an improvement. I think what's important to remember is this first population that we've gone into, because it's a first in human program, we have started in the most difficult to treat patients. And when we think about most of these drugs get approved sort of in a frontline setting, patients who really haven't seen anything before. So the difference between starting from zero and being treated- Yeah, exactly. You see this dramatic improvement- Mm Where what we're taking is patients who've been heavily treated and trying to retain that outcome with far fewer injections. So that's the difference. So I think 4D-150 is, you know, designed to be active in all of those patient populations. One of the things that came out in the phase I data, that obviously people were very focused on was a reduction in injection burden. Mm-hmm. But something that struck me, looking at the patient-level data, is that most patients have no injections at all, and there's really a few folks that are driving residual injection burden. Is there something in those patients that we should be looking at? Is there something in the way that the trial was run or the conduct around those patients that can inform the—I guess a better truth of the average reduction in injection burden? Is the average reduction down to zero, and you have a couple of patients that are, for whatever reason, driving an issue, or is the average reduction more truly- Mm-hmm ... you know, what was reflected in the aggregate data? Yeah, I would say that it's a good point. The phase I, you know, you got sort of five patients per dose level, so there's different dose levels, different starting points, so it's hard to make a lot out of it. I think we'll get a much better sense with the randomized phase II data that we anticipate releasing in early next year. But you can- But nevertheless, my expectation would have been that if there was a dose response, you'd see some level of residual injection burden at the low dose, and then lesser, and then lesser across all patients. But rather, it was a small number of the total patients who were driving all of the residual burden. Yeah, I would say there was a clear dose response, but I think, I think your point is, is there appear to be certain patients who just don't respond very well at all, and they may continue to get multiple injections- Mm-hmm. and then there are other patients who are injection free for long periods of time. Yes. I think that's right, and we'll see if that holds up in the phase II data. And then, you know, over time, I'm sure we can get better at predicting, based on any number of clinical or biomarker analyses, which patients are most likely to have these outstanding results and really essentially be injection free. Also, one of the patients was determined to not be eligible for phase 2- Mm-hmm. -uh, right? Yeah. So that is like an example of selecting patients in this? Yeah, I think, phase I, you know, we allowed patients to have pretty advanced disease and relatively poor BCVA, very thickened retina. So I think as you move forward in development, we'll tighten that up and sort of exclude patients who are, you know, unlikely to respond to any therapy or patients who have pre-existing cataracts, those sorts of things we can weed out. Maybe let's move on to CF. Obviously, you presented data here recently, which, which characterized as being very supportive. Certainly, you saw really excellent gene delivery, although obviously small patient numbers. How should we be viewing the, beyond just gene delivery and PD, how should we be viewing functional data in that data set, you know, relative to established therapies? ... Yeah, so, so first of all, very exciting product, single aerosol delivery. We use a nebulizer device that gives beautiful distribution throughout the large and small airways, all the way out to the alveoli. So the vector doesn't really need to do that much work other than get through the mucus and transduce and express. So it's a great system for treating any number of lung diseases. So in terms of CF, we're starting in the 15% of patients who have no available modulator treatments. So that could be based on the mutation, or in a small percentage, it could be due to intolerance. Correct. So those patients have nothing. Coming into this study, we hope to see good safety, which we have seen outstanding safety and tolerability. And then, we hope to get up to about a 30% level of expression, based on other studies that suggested that would be highly therapeutic. We said, "Boy, if we could get to that, that'd be a home run." Well, we're at 450%, so we've clearly overshot, given the efficiency of our vector, which is because we use directed evolution to make them highly efficient. So now we're gonna explore lower doses and work that back and see if we can get more down in the 100% range, and then we can do a comparison between that 100% range and then that, the higher dose, which gives us, you know, beyond 400% expression. In terms of clinical activity, these are obviously small studies, variable patients. They start at different points in their disease, so it's difficult to make too many conclusions. We're excited about the signals that we've seen based on the totality of the data. One is we've seen all three patients had improvement in quality of life with a well-validated respiratory quality of life instrument for CF. We've seen a very promising lack of pulmonary exacerbations in patients after the ramp-up phase of gene therapy, and that's all the way out to 15-17 months, we haven't seen those exacerbations. These patients are usually getting a couple a year. Mm-hmm. And then FEV1, two patients started up in the normal range, so they remained stable. I can't say much there, but we did have one patient who started at a mildly depressed level of 69% of predicted, and that's the—you know, that's within that 40%-80% range that Vertex uses for- Mm-hmm. FEV1 studies, and there we did see a really nice response of 5-7 points, which is felt to be clinically meaningful. So early data, but I think all the clinical activity data points us in the same direction, that it's validating the high level of expression we're seeing. Now, at the time that that data came out, I recall pushing you pretty hard on the reliability of small patient numbers and the variability of some of these metrics, and one thing that you kept coming back to is that some of these metrics are very well validated in the community for- Mm these size of differences, and especially the PRO endpoints. Yeah. So maybe you could touch on that a little bit. How do you think the critical endpoints have evolved since the initial Vertex approvals, and what are the results that the community is gonna be most excited to see? Yeah. So first of all, you're appropriate to, to push us hard on small patient numbers. They are. You know, we're starting getting more data. I think when you ask the physicians... You need some more water? Yeah. I think John- Yikes! More or less water? Sure. I- Robitussin, that's what I need. At any rate, you know, when you ask physicians and patients what they care about, they could care less about FEV1. It's a biomarker. Yeah. But what they really care about is quality of life. Mm-hmm. They care about not having exacerbations that take them out of work, take them out of their home, put them in the hospital for several weeks or a month, where they get IV antibiotics. So that's what really matters to them. And so it's kind of interesting the way the field has evolved, where, you know, Vertex very wisely used FEV1 as a biomarker, essentially a surrogate biomarker- Mm. For clinical benefit, that eventually they showed was, you know, confirmed, a improvement on quality of life, for example. But I think when you talk to patients and physicians, what gets them really excited is quality of life and fewer exacerbations. And so, you know, I think we'll look at all those endpoints, they're all important, and at the end of the day, it's gonna be the totality of the data that determines, you know, our approval and commercial uptake. Mm-hmm. Makes sense. We've got a few minutes left. Do you have one more on CF before we- I just wanted to ask, when you're moving to the modulator-eligible population- Mm-hmm. The burden of using a gene therapy and Trikafta could be very high. How do you expect, you know, that would be received by the community? Would it be less use of Trikafta, with, along with gene therapy or? You know, we'll see. I think there's a significant population who have modulators available to them, who have a suboptimal response or no response, but may stay on it anyway, perhaps for the GI effects. And so, yeah, we think there's a real opportunity, you know, if we can get 15,000 patients, approximately modulator ineligible, we think there's another 20,000 or more that we could go in combination. There's a reasonable likelihood of synergy between the agents. And I think, there's certainly a cost issue to the system, there's no doubt about that, where people are gonna ask the question, "Okay, how much does this add on top of Trikafta?" Trikafta is not cheap. But there may be patients who use less Trikafta once they're on our product. So we'll see, but I think in terms of the mechanisms of action, the potential for clinical benefit, it's very high in that population, and we'll, in parallel with developing the drug, we'll have to sort out the pricing. ... building on that a little bit, obviously, there are extra lung symptoms of CF. There's other things that the CFTR issues drive- Yeah. which presumably an inhaled gene therapy isn't going to correct. Correct. Is there any way to address those? Do you have any plans to deliver CFTR to the pancreas or- We've certainly thought about it, and our platform allows for that. It's not something that we're focused on today. We're laser focused on 4D-150 for all these indications and on 4D-710 for CF lung disease. But there's certainly an opportunity to use our platform to develop gene delivery vehicles to deliver CFTR to pancreas and liver and gene and elsewhere. Okay. Well, then let's move on to talk about GA. Mm-hmm. So, can you describe a little bit about the differences in the vector between 175 and 150, between the wet AMD and the GA programs? Yeah. So the beauty is there's no difference in the vector, in the capsid. Mm-hmm. The capsid's exactly the same, the promoter is the same, the manufacturing is all the same. So that there's incredible economies here when you have multiple products built off the same vector system. Mm. Each time we go into the clinic with a new product using the R100 vector, FDA asks for less information. Mm. And so it's, it gets cheaper and cheaper and faster and faster to get in with these new products. So 4D-175 for GA, same exact vector, same manufacturing, same promoter. What's different is the transgene payload, and here we're using a complement factor H that has been shortened such that it could fit into AAV. And it's really exciting because one of the primary drivers of this disease in over 50% of the patients is patients have a reduced function complement factor H. So we're hitting the disease right at the central driver of it. And so we think with this, we have a real opportunity here. We're going to express the complement factor H right in the deepest layers of the retina, right on top of the Bruch's membrane and the vessels. So it, you know, again, we not only have an ability to have potentially greater convenience compared to some of the other agents, but the potential, certainly for superior efficacy. Well, it does bring us to the currently approved- To time ... agents and to the, comparisons there. I mean, obviously, we'll all be looking at the initial data out of your, program very closely when it's available, but, but we are, as you say, unfortunately, outside. But, as we eat into our passing period, any final thoughts, things that you want to leave us with as we head into 2024? Ravi, you want to add? No, I mean, I think we said it right up front. We're really excited with how the pipeline and the platform, and the beauty of it is one particular sort of therapeutic area actually leverages and improves on the other. So the overall platform continues to demonstrate safety, which is immaculate, and efficacy across different tissues. So we're really excited. Well, we're really excited to see all the data next year and to follow the story.