Good morning, everyone. My name is Gena Wang. I'm a clinical biotech analyst at Barclays. Welcome to Barclays' 27th Global Healthcare Conference. It is my great pleasure to introduce our next presenting company, 4D Molecular Therapeutics. With me on stage, we have Dave Kirn, Co-founder and the Chief Executive Officer, Chris Simms, Chief Commercial Officer, and Uneek Mehra, Chief Financial and Business Officer. Dave, I will hand over to you.
All right, thank you, Gena. It's great to be here. Thanks for having us. I'm Dave Kirn, co-founder and CEO of 4D Molecular Therapeutics. Just not working. Oh, okay. Next slide, please. Oh, there's no presentation. Okay. Okay. I will make some introductory comments then. We at 4D are a next-generation AAV gene therapy company. Our lead product is 4D-150 for wet AMD and DME. This is now a Phase 3 asset. We're excited to be in Phase 3 now, just having entered 4FRONT-1 . We expect to start our second Phase 3 study in Q3. That's 4FRONT-2 . These are wet AMD studies that are designed for BCVA non-inferiority and are powered at 90% for the U.S. FDA non-inferiority margin. These are all patients who have been diagnosed within the last six months or less and have demonstrated on-study responsiveness to aflibercept.
We're very excited about our portfolio and our opportunity with 4D-150. We think it's going to be, first of all, it's addressing a very, very large market, $17 billion annually and growing. Massive market opportunity for us. We believe we have a highly differentiated product that's going to act as a backbone or foundational therapy to knock down the VEGF levels across the board in patients. Some will be functionally cured and never have another injection. Others may need an occasional top-up as their disease flares up. Overall, we expect to see a very significant treatment burden reduction of 80%-90% + in these patients, and that would translate into a massive improvement in quality of life for patients. Treatment burden reduction is really the number one need that patients have and physicians have in these diseases. To date, our efficacy has been very strong.
We've hit anywhere from 84%-94% injection burden reduction depending on the population we look at. Seen excellent safety comparable to the aflibercept protein that our product makes in the eye. We believe that the product, given that it's a simple intravitreal injection, should fit seamlessly into clinical practice with no special handling or storage or distribution issues. Very routine. It should also work very well with the physicians' economic models in these clinics where they do a buy and bill reimbursement model, and this should actually improve their cash flow. As I said, we're in Phase 3, and we expect to have Phase 3 readouts in the second half of 2027. Our cash currently is at about $500 million, and that will last us into 2028, so well beyond the 52-week primary readout for these Phase 3s.
We also have a cystic fibrosis program where we expect to give data and regulatory updates in the second half of this year and hope to be discussing pivotal trial designs for that program with the FDA. That's an inhaled product that delivers CFTR to the lungs of cystic fibrosis patients. We've seen outstanding safety and gene expression throughout the lungs and early evidence of biological activity that we expect to update. Stay tuned on that. Another exciting opportunity for a Phase 3 trial of 4D. With that, maybe we'll just take your questions, Gena.
Sounds good. Sorry about technical.
No worries. Keep me on my toes.
Issues. Okay, I think usually we're asked about the wet AMD program, but this time I will change because you will have CF data coming in the near term, and that will be a pretty important update for the companies. Maybe share with us what we saw in the past that we know that you did have a high protein expression, but FEV1, we did not see too much improvement. Now you will have less severe patients. Maybe walk us through why we think in this next update, should we expect to see the functional FEV1 or the other lung clearance index? Should we see the improvement in there and why we should see that?
Yeah, great. 4D-710 is our product for cystic fibrosis lung disease. This is an inhaled next-generation. Invented a vector for highly efficient delivery and transduction through the mucus barriers for high-level expression. And we express the CFTR transgene, which is the gene that's mutant in the disease. We're targeting the disease right at its source. These patients have modulator therapies from Vertex that have been really transformative for a number of patient genetic mutation subtypes. For many patients, they're either not amenable to those modulators or they're intolerant of those modulators, or they have suboptimal responses. That could be anywhere from 20%-30% of the population. That's where we are starting where that unmet medical need is highest. We're starting that population. Over time, we expect to treat all patients, including in combination with the modulator therapies.
What we've shown to date is in the first, we've reported out that we've treated 13 patients at four different dose levels. We've seen outstanding gene expression, as you say, over 95% of cells staining positively by either RNA or protein, very high-level protein expression. That's really a landmark for the field. No one's achieved that before. What we've seen is excellent safety. This is all with a very routine nebulized device that, using a nebulization device, essentially inhales this mist into the lungs and results in transduction. Very routine, very safe, high-level expression. What we're now starting to see is evidence of biological activity.
When we focus in on the patients who start with an FEV1 of lung function of 80% or less, for example, we've already shown two of three patients in that subgroup showing very meaningful improvements in FEV1 of 5% and 6%, which if we saw that in a Phase 3, that would absolutely be approvable. We've also started to explore other more sensitive assays such as lung clearance index. We expect to report that out. We also explore some very high-quality quality of life instruments that are specific for CF lung disease. We've shown anecdotal improvements in those. It is a robust data package. We expect to, in the second half of the year, have anywhere from six to two years follow-up on patients.
We would also expect to have regulatory guidance on a potential accelerated approval pivotal trial design similar to what's been seen in other rare diseases with AAV.
How many patients should we expect to see? And then in terms of the baseline FEV1, I don't know if you can share that yet.
Sure. Yeah. We reported out, as of our last update, had treated 13 patients. We expect to treat up to three more. At the time of data release, we'll be approximately 16 patients, including a number at a lower dose that we think would be our Phase 3 dose now. FDA does like us to use the lowest effective dose. We're seeing that the lower doses, we believe, are highly active. That will be the update. We're excited to proceed with discussions with FDA.
Okay. The FEV1, you did mention you saw anecdotally 5%-6% improvement. Would that be the bar we should be looking for when you have the data update?
Yeah, I think historically FDA said that if you hit 5% or more, that definitely would be perceived as meaningful and approvable. In this population, the bar may be even lower. In these patients who have no available therapies, we've had cystic fibrosis experts tell us if you could just stabilize their FEV1 and prevent that decrease every year, that would be meaningful. That is something we'll look at is patients' trajectory of the FEV1 decline before and then after treatment and hope to show stopping, hope to show a reduction and decrease and actually show an improvement. That change in slope would be very important endpoint, I think. That is the bar. Again, there's approvals for Orkambi and other modulators in mutation subtypes where 2%-3% could be approvable.
It is somewhere in that range between stabilization up to 5% + would be sufficient, we believe.
What about a Lung Clearance Index? What could be the benchmark there?
Yeah, this is an exciting new technique that's used. It started in children who were unable to reproducibly do the FEV1 test. It is a very sensitive, reproducible test that is not effort dependent the way FEV1 is. Generally speaking, 1%-1.5% improvement there would be felt to be meaningful. We would be looking to hit at least that bar or better over time.
Okay. I think for the nonsense mutation, I think Vertex and Moderna are also doing the RNA therapy. They likely will also share data later this year. What do you think? Of course, it's all moving targets, right? How do you think from the gene therapy perspective, the efficacy bar, do you think it will still be similar? You need to be competitive with the RNA therapy.
Yeah, I think the big difference between a gene therapy with DNA versus an RNA-based therapy is gene therapy is very durable. We'd expect multi-year durability here in the lung. We do expect eventually to redose, which is great from a patient standpoint and commercial standpoint, but it'd be on the order of anywhere from a year and a half to three years out. RNA therapy is RNA, as you know, is a very short-lived molecule. We're talking about weekly or even daily administration, which is a very much higher burden on the patient. We wish them the best. We hope it works. DNA would have a clear advantage there.
Okay. How would you share the data? It would be press release and the conference call, and we'll walk through the data, or would it be a medical conference?
I think all of the above. We haven't committed yet to whether we give some sort of corporate summary of the data first, followed by a medical meeting, or do it simultaneously. We'll look at both.
Okay, good. Now switching gear to your 150. And you do have two different indications, wet AMD and DME, share the data on both indications. Maybe some pushback from the investors, I would say like data overall looks pretty good, but you do have investor pushback, the durability. I think that was the key question that may be hurting the stock when certain data update, the stock react differently when maybe when we look at it. Maybe help us understand, say, from the durability question and also what endpoint would be the most important based on your interaction with the doctors.
Sure. I'll kick it off, and then we'll turn it over to Chris, who's had several hundred interactions with retinal specialists just at 4D and has been in the field for well over 10 years and has gotten approval of, helped with the launch and/or approval of a number of agents, including Lucentis and Beovu and Eylea. Look, when we look at this massive market of $17 billion annually, what patients most want is treatment burden reduction. They don't want to be getting poked in the eye. Every time they do it, it could be half a day to a day out of their life, their caregiver's life. They've got to go in, they've got to wait, they've got this anxiety around getting the needle in their eye, et cetera. That's the number one unmet need, full stop. That's clear.
We also see that these retinal specialists, if you ask them, "What technology are you most excited about?" it's gene therapy. Why is that? It's because gene therapy is the only modality that has the potential for multi-year significant treatment burden reduction. What's the evidence that treatment burden reduction could lead to a blockbuster product? If we look at Vabysmo, they reduce treatment burden by about 30% versus aflibercept, the standard of care. That 30% has translated into blockbuster status in record time. It's growing rapidly, and Chris can speak to that. That is 30% reduction. What we've shown in our studies is anywhere from 84%-94% treatment burden reduction with the same simple routine intravitreal injection. How could that not be a blockbuster? We also know that AAV is extremely durable.
We know from Luxturna that AAV gene therapy in the retina was effective out to 10 years. We know from Regenxbio subretinal, four and a half years and counting, high degree of efficacy and expression. Same with Adverum with their intravitreal injection out four and a half years. We know that AAV is highly durable in the retina. The retina is a post-mitotic tissue. It does not turn over. That is going to happen. We have shown durability. We have patients out to three years who have gotten no injections, whereas previously they were receiving 10 injections in the prior year. People always want to see that durability, but we have now got the data to show that. We will continue to update that. More importantly, we know from many other programs, AAV as a therapeutic class is extremely durable in the retina.
I'll turn it over to Chris to speak to what doctors are looking for and what he's hearing.
Yeah, happy to. I don't think there's any debate in the space around the unmet need that continues around treatment burden reduction. I think we've seen that with new launches and how they've been successful in record time with incremental improvements. That's still real. I'll tell you that the treatment burden reduction is important in two aspects. One is from a patient perspective. Obviously, fewer needles in your eye without sacrificing safety or efficacy is critical. Also from a retina clinic point of view, regardless of where the retina clinic is, be it in the U.S. or ex-U.S. and international markets, the vast majority of retina clinics have a challenge with capacity. They have more demand for their services, and they have time and doctors to fulfill those services. That gap is projected to increase over the coming years.
A backbone therapy like 4D-150 not only can relieve treatment burden from a patient and caregiver point of view, but also could relieve some of the capacity constraints that many retina clinics find are pretty problematic in their real world today. Physician feedback, as we've taken our Phase 2 data out and shared it with them, has been overwhelmingly positive. Again, reaffirmed the unmet need. Gena, I think one of the things that first doctors go to is the safety profile. I think there's evidence in the past that a lot of new agents, the physicians understandably so, want to see real-world safety before they kind of move to more of a mass adoption. Familiar with that, I launched Beovu at Novartis and then recently launched Eysuvis with Eyevance. That real-world safety demonstration is critically important for any new agent being introduced.
We think we have an advantage there with what we've demonstrated in terms of our safety profile thus far through our Phase 1 and Phase 2 data. The safety is very compelling. I think over the next couple of months, we'll get evidence as to what could be commercial enthusiasm for 4D-150 because, as David mentioned, we just started our Phase 3 program. Hopefully, as we start to see enrollment in the next couple of months, we'll get evidence of, one, the unmet need and the enthusiasm for our profile.
Good. I know from the investor community, they were focusing on injection-free rate in addition to the burden reduction, right? Maybe based on your doctor feedback, which one they care, or the patient perspective, which one they care more. Also, there is a caveat. In the practice versus clinical trial setting, the criteria of a retreatment is very different, right? Usually in the clinical trial setting, it's much loose. In the reality, real world, maybe every doctor has their own threshold when they wanted to do the injection. You have a large variability there. How do you, more thinking fast forward and given the Phase 3 trial design, I think you have a very good chance to show positive study. Fast forward, when you go to the doctors and the patient, how do you send in the message?
What do they care most when you're presenting the data profile?
Injection-free versus treatment burden reduction is highly interrelated, of course. They're not separate from each other. They care primarily around treatment burden reduction, first and foremost. If a patient can be injection-free over months or years, then obviously that's great for them and for the patient as well. The appeal of the profile, again, foundationally, you have to have safety. And then strong demonstration of meaningful treatment burden reduction over a long period of time is ultimately, I think, what drives their enthusiasm. You're right. In the real world, every physician may have a different tolerance for fluid. When they choose to reinject, we think our retreatment criteria, one is, I think, fairly consistent with what many other pivotal trials have done recently. We've also pressure tested our criteria through a number of advisory boards and physician feedback.
They think it's reasonable and fair relative to how they treat in the real world. There will always be exceptions to that, sometimes more stringent, sometimes less. We think it'll be reflective of, again, how real-world treatment would be conducted.
You also mentioned that you already start in your Phase 3 trial. What is your, I know it's a little bit difficult question, Michael, but what is, say, your assumption building for the enrollment completion, the time that will take?
Yeah, I think we've said publicly the target would be approximately 15 months. That's why we get readouts for both 4FRONT-1 and 4FRONT-2 in the second half of 2027. Now, we have a very, very experienced team, a very energetic team, a team with great relationships with the retina physicians. We hope to beat that. We do think that if we can hit that enrollment rate or even better, that would be clear evidence that this target product profile is exactly what physicians want. It's exactly what patients want if they're voting with their feet and essentially enrolling in the study. We think it's important for advancing the product, but also demonstrating the commercial potential of this potential blockbuster therapy.
Regarding, say, the physician or patients, the threshold, the treatment burden reduction, what is the number there? I talked to also lots of doctors, some like your investigators. There are wide range of numbers. Let's say for the treatment, the injection-free rate, usually the threshold is about 50%. The burden reduction would be a little bit higher. I'd love to hear your thoughts based on your interaction.
Yeah, I'll give you my background comments, and then Chris is the expert here. I think let's just put this in context. Vabysmo, blockbuster, fastest launch ever, decreases burden reduction by 30%. The number of patients who are injection-free is zero. Zero. And it's a blockbuster. Why are we being held to a different standard? It's because of the history of gene therapy. First-generation gene therapies cause toxicity. Some required subretinal injection. If you look at rare diseases like hemophilia, they were priced at millions of dollars. That's not what we're talking about here. This is next-generation large market gene therapy where our cost of goods is less than $1,000. We have huge pricing flexibility. We've seen a clean safety profile that looks like aflibercept, roughly. We have a routine simple intravitreal injection that fits seamlessly in clinical practice.
This is just a very, very different form of gene therapy where the first ones to do this. I think it's a matter of educating people over time that this is a very different value proposition. Chris, over to you.
I don't sure I have much more to add. I think the answer to what's a meaningful level of treatment reduction is somewhat arbitrary. It's multifactorial in the real world. We've seen, to David's point, a benefit of a couple of weeks result in massive success for the most recent launch. I think when the real world hits, certainly there's no patient that I think would desire more needles in their eye, right? Everyone would desire some relief from a treatment burden standpoint. The doctors are looking for that as well. It's hard to give a percentage per se because ultimately it's going to be multifactorial. It's not just based upon the clinical benefit. It's based upon factors like reimbursement and pricing, all of which still need to be determined. The reality is we've seen lots of evidence where an incremental benefit can be incredibly meaningful.
Incremental benefit. Our ultimate benefit is measured in months, if not years. It truly is a paradigm shift. I do not know the actual percentage. I think wherever it lands in our Phase 3 data, assuming that it replicates or even is better than Phase 2, it has the potential to, one, establish a backbone therapy approach and be paradigm shifting.
I'll just make one final comment. I know we're short on time. We hit 94% treatment burden reduction in the Phase 3 population in Phase 2b. 94% reduction versus 30% for Vabysmo. That was in a patient population that's not as enriched as what we're going to do in Phase 3. In Phase 3, we're going to enrich even more for success. We're not promising 90% +. That's what we've hit to date. I think anything over 70% would be huge for patients.
Okay. We are out of time, but do want to quickly ask one question each for you two. For Chris, our conversation with the payer is for gene therapy, actually very simple formula, standard of care times five or times three to five. That is the price they are willing to pay for gene therapy. Is that aligned with your thinking? And quickly for Uneek, cash and the runway assumption.
Yeah, Chris, you want to go first?
I think that's where you start, for sure. I think the added piece to that needs to be considered. We have the potential to hold on to vision gains for a longer period of time. Many bolus therapies, a lot of that vision is lost. I think that's important. We know that's important to payers. I think that's a good place to start. I think it'll evolve from there. The last thing I'll say is regardless of where we ultimately land, we have flexibility based upon a very low cost of goods. We can be adaptable based upon what the market looks like at that point.
Okay, good.
Gena, have you have a strong balance sheet, $500 million of cash projecting runway into cash runway into 2028 beyond the top line readouts of 4FRONT-1 and 4FRONT-2 ?
Okay, great. Thank you very much. We look forward to first the CF update and then the other popular update as well.
Yeah, thanks for that.