Hi, welcome everyone to H.C. Wainwright's Fifth Annual Ophthalmology Conference. My name is Matthew Caulfield, I'm a Senior Biotech Analyst here at H.C. Wainwright. We're pleased to welcome 4D Molecular Therapeutics and Chris Simms, the Chief Commercial Officer of 4D. Thank you very much for joining us, Chris. It's great to connect with you guys again.
Yeah, it's good to see you again, Matthew. It's good to be here.
Great, thank you. Maybe to start things off, for those that may be newer to the 4DMT story, could you share an overview of your gene therapy platform, the great progress the team has made, kind of at a high level?
Yeah, happy to. 4D has been in existence for, I think, just a little over 10 years or so now. A genetic medicines company leveraging tech that came out of Berkeley. We think we have an approach that's new generation in terms of genetic medicines and gene therapy, utilizing our directed evolution platform, which we think helps us to develop vectors that are more targeted to the part of the body or the tissue where they're intended to do the expression work. Our current program, our most advanced program, is a program called 4D-150. It's currently in phase III for wet age-related macular degeneration. We shared data already on that program through our phase I/II program across a broad swath of patients, where 4D-150 has been studied for AMD, and most recently we shared some phase II data for the DME indication as well.
We're pretty excited about where we are, the progress we're making with our phase III program. We also have a program for cystic fibrosis that's in development. Right now, I think the majority of our effort and focus is on our retina program with 4D-150.
Sure, understandably so. With the focus on 4D-150, which as you mentioned is now in pivotal development in wet AMD, I wanted to note that gene therapy utilizes the R100 intravitreal vector designed for prospective single injection durability. Can you tell us a bit more about 4D-150's differentiation and its profile?
Yeah, happy to. As you mentioned, the vector is R100, it's a proprietary vector, and I think it leverages our science, which allows it to get to the retinal tissue to express, in our case, it expresses aflibercept, more commonly known as Eylea. What we've seen so far in our data is a pretty strong efficacy. We've studied 4D-150, at least with the wet AMD population, across a broad range of patients. We've shared data on patients that are more severe, patients that were on treatment receiving 10+ injections in the prior year to having 4D-150. We've also studied 4D-150 in patients that were more recently diagnosed, a broader patient population. What we've seen is a pretty substantial reduction in treatment burden across those patient populations and a pretty significant rate of treatment or injection-free rates as well across those different patient populations.
We're pretty excited and enthusiastic about certainly the efficacy and the potential to basically, we think, set a new paradigm in terms of treatment burden reduction. As importantly, if not more, as many of your audience, I'm sure, will be aware that have followed the retina space, efficacy doesn't matter if you don't have a safety profile that at least is commensurate with what you see today with standard of care. The anti-VEGF space is pretty well developed. It's a large market with agents that are highly efficacious and quite safe, and that's been proven over probably 16, 17 years now when Lucentis was first introduced into the market. Without safety, nothing really matters. What we think really differentiates 4D-150 is the fact that our safety profile remains quite strong, again, across a wide range of different patients from those that have been more treatment experienced.
Most recently, we shared our SPECTRA data, which is in a DME patient population, where historically there's been some challenges with gene therapy modality around some pretty severe safety events in another competitive program. Our DME safety data, at least from what we've shown in our phase II SPECTRA data, was incredibly strong. In fact, no major signs of intraocular inflammation or any of the other severe things like vasculitis or hypotony that physicians certainly get worried about. We think we certainly stand apart on safety, and our efficacy stands up quite strong as well.
That's great to hear. We'll definitely get into some of the important data points for 4D-150. I wanted to ask about the use of intravitreal delivery and how that could compare to other delivery methods such as subretinal or suprachoroidal from the standpoint of possible use within the clinic, you know, thinking about things commercially.
Yeah, it's a great question. As the commercial guy, it's a question that comes close to me as I think about hopefully a commercialization window in the future. Retina clinics today are quite busy. They've often built themselves around administering bolus therapies that are all intravitreal delivery. Choose your bolus therapy of choice, be it VABYSMO or Eylea, or the list goes on. All of those are IVT or intravitreal delivery in the office. These clinics are quite busy. Often, you talk to most, a lot of retina doctors are seeing 50, 60, sometimes 70 or so patients per day. That's a high level of volume. We think it's critical for integration and adoption within a large and busy clinic that you complement and ideally tuck into the current process that they use to administer care to their patients.
If you can improve that, even better, but to be disruptive to that, I think is problematic in terms of delivering care. The fact that our approach is intravitreal, it's no different than injecting a bolus anti-VEGF today. Even the process by which we think we would distribute it, the process that you would store the product in your local refrigerators and so on, we think we fit seamlessly into that retina clinic process that exists today, which again is, I think, pretty important to a retina clinic so that it doesn't disrupt their process flow. IVT delivery, we think, is critically important for delivering patient care and facilitating adoption.
Maybe taking a step back for a moment, you know, there are obviously several approved intravitreal anti-VEGF-based therapies for treating indications like wet AMD or DME. What is your sense of where these standard of care therapies currently fall short, kind of where the need is to build upon?
Yeah, I think first I would say that these current therapies have been incredibly effective and life-changing for patients. I think there's data that would suggest that they change even the course of blindness, going back to the introduction of Lucentis, which I had the privilege of working on many years ago at Genentech. These therapies work so well. It's been shown time and time again. The challenge, of course, is that it is a bolus therapy. That means that patients need to get an injection in the eye at some level of frequency. Because these diseases are fairly heterogeneous, the frequency of injection can vary greatly from one patient to the next based upon their level of disease activity and what their need is.
What we've seen in a lot of real-world data is while these therapies deliver an increase in disease control, a positive change in vision upon administration, there's a lot of evidence to show that over time, a lot of those patients have lost that initial vision gain, and many actually have fallen below where they were at baseline. One of the key reasons for that is adherence and persistence to therapy. Even though these medicines are efficacious, the treatment burden can ultimately result in an under-treatment issue. That under-treatment challenge over time results in vision loss. I think that's a big problem to solve for. The other thing we see is the key biomarker for treatment in this space is the presence of retinal fluid.
With bolus therapies, which makes kind of sense, you see fluid, you treat, you see a drop in that fluid, disease reactivates, and then you get treated again. You see an oscillation quite often in the level of retinal thickness because of the drying and the reoccurrence of retinal fluid because of this bolus approach. An approach like 4D-150, where you are basically, it's a continuous sustained delivery approach, right? Where you're expressing aflibercept, a highly effective agent on a continuous basis. One, you solve for that adherence by design, right? Challenge, where you always have the agent on board so that persistence of therapy is solved for. We believe you also control this OCT or the retinal fluid oscillation, which you see so often with current bolus therapies. That over time, we believe, helps with longer-term outcomes.
We think that's incredibly important and a step change from the current bolus standard of care approach.
Very helpful. Do you see the oscillations kind of tied then to atrophy, or what kind of damage could the standard of care do then with that kind of waxing and waning of the therapy effect?
Yeah, very much so. I think the potential for fibrosis or atrophy over time because of that, again, expansion and shrinkage of the retinal tissue is very real. That's one of the theories as to why some patients over a longer period of time that are on bolus therapy also start to lose vision. The belief is continuous expression and control of that disease over a longer period should solve for, we think, those issues.
We think ultimately, we start to see some evidence of this right now where, look, I think SUSVIMO from Genentech recently shared some long-term data at ASRS where a continuous delivery of anti-VEGF approach, albeit in their case through a device, the PDS device, did show that, hey, that initial vision gain that a patient experienced, you were able to maintain that over a pretty significant window of time, I think up to five years. Our approach is, in terms of the continuous expression and treatment, is similar. We're just doing it through a genetic medicine, a gene therapy modality. We think that's promising. We think the value of that, the obvious value for a patient is clear for a physician. Matthew, I think that's also a pretty strong story for a payer as well, right?
As you think about the commercialization window, the potential to show a payer that, hey, you treat these patients, right now you're often the benefit is lost for a lot of patients as soon as a year and a half or two years. What if you could hold on to that vision for some patients for the rest of their life, particularly an AMD patient? We think that's a compelling part of the value proposition.
No, I'd agree with that, certainly. Similarly, we've seen durability extension with approved therapies like Vabysmo, Eylea HD, and current development of tyrosine kinase inhibitors. What's your sense of where gene therapy for an indication like wet AMD could come in? Is there a certain patient profile that could define the best candidate for that type of therapy?
Yeah, I think first thing I would say is the fact that retina is a very dynamic space, as you know well. There's lots of new agents, particularly in the anti-VEGF or the treatment of AMD or DME that's under development. All of them, for the most part, are pursuing increased advances in durability. It just points to the continued unmet need of agents that reduce the treatment burden through more durable approaches. We've seen this, of course, with the most recent introductions, Vabysmo, great medicines, really strong commercial success upon launch. We think the benefit of Vabysmo versus what was, I think, Eylea as a standard of care upon launch is maybe a couple of weeks of benefit. Eylea versus Lucentis back in the day maybe had a week or two of additional benefit. The durability advances have been measured in weeks from all of these assets.
They've proved significant commercial success with what I would suggest is largely an incremental benefit in durability. We think 4D-150 is not going after a benefit measured in weeks. We're going after a benefit measured in, we think, years for many patients and months for others. That's a game changer. We think that sets a new paradigm. Our view and our goal for 4D-150 should be to get it to a commercialization stage is that we think it can become a backbone therapy for this space. It's the therapy that you should consider for continuous treatment of disease. The good news is that for patients that may need occasional supplementation, you have a wide swath of really effective bolus therapies that you can use if and when you need supplementation, including, you know, assets like a TKI that's under development should they, you know, ultimately get commercialized as well.
That's where we see 4D-150 fitting in the future is that backbone therapy, continuous expression, long-term control of disease, offering massive treatment burden reduction for a majority of patients. For some patients, we think that's an injection-free status. Where needed, you have fantastic bolus therapies to supplement.
We've seen the positive phase II-B PRISM trial, looking at the 52-week top line in wet AMD patients. The 4D-150 profile has remained robust with a single injection, which is important to appreciate, and predictable long-term safety. How would you best characterize the clinically meaningful and durable injection reduction shown so far by 150?
Yeah, it's a great question. Again, our durability advances are measured in months. You'll see in that data, I think the thing that I would point people to when they look at our PRISM data is it's really important to recognize that we've shown significant treatment burden reduction and injection-free rates across a wide swath of different patient types, right? The first patients that we reported on were patients that had a really high treatment burden, getting over 10 injections in the prior year. We showed the effect on treatment burden and injection-free across a more recently diagnosed or a broader patient population. You see this trend around increases in that burden reduction and certainly the injection-free rate as patients become more recently diagnosed in terms of their treatment journey. We think that's compelling.
The fact that we've shown significant benefit across a broad range of patient populations, that's certainly important as you think about the opportunity from a commercial perspective. I think it's really important in equal weighting to point out that our safety profile through all of those patient profiles remains quite strong. Again, repeat what I started with is one of the key differentiating factors we think of 4D-150 is our safety profile, which we think largely reflects what physicians would see with current standard of care.
You mentioned kind of going back to the 52-week phase II-B data, looking at the pivotal 3E10 dosing, the broad population had about 60% injection freedom at one year. As you kind of alluded to, the more recently diagnosed subgroup reflected 80% injection freedom. What could this suggest in terms of potential commercial positioning of 4D-150 if ultimately approved? Do you feel that it's realistic for those kind of newly diagnosed patients to be able to access something like a gene therapy? Do you feel that there's going to be a lot of insurance pushback, some step-through work, but prospectively? How could you see that playing out in the commercial landscape?
Yeah, I love that question. A couple of things. I'll answer that from probably more of a practical standpoint, right? It's the reality in this space where you have really good therapeutics that are highly efficacious and proven to be safe. When retina docs look to incorporate a new therapy into their practice, and I've seen this as I've launched a couple of medicines in this space previously, they first look to patients that have the highest unmet needs. You're likely going to get tested in the majority of times when you commercialize with patients that have a relatively high treatment burden that have been on existing bolus therapies for a while. Regardless of, by the way, what you study in your phase III program. I think that'll be true for us. I think it'll be true for any new agent that's introduced into the market in the coming years.
What we see, though, is that with time that evolves and that changes, and once physicians get comfortable with the product, once they have seen evidence of real-world safety, super important in a space where there's been some safety concerns with launches in the past. Once you get that comfort level and you see how the product performs in the real world, you start to graduate to an expanded patient population that you consider for treatment. We think with time, 4D-150 will certainly be considered as a backbone therapeutic approach, regardless of the patient type, type defined as how recently you've been diagnosed. We think naive patients will be considered for treatment like this, the proportion of which will probably be lower out of the gate, but we think over time that'll have a significant source of patient volume.
The last thing I would say on that, Matthew, is, as I mentioned earlier, we've started our 4FRONT- 1 and 4FRONT-2 programs. 4FRONT-1 was started in the end of March or so, so we're a few months into that. One of the questions that I certainly had going out of the gate is, hey, what's going to be the appetite to treat a naive patient with a new modality like a gene therapy? We couldn't be more, I think, excited and enthusiastic about that progress on our 4FRONT-1 program. We're well above where we were initially projecting enrollment. We've said publicly that what was initially our potential readout time of back half of 2027, we've now been able to pull that into the first half of 2027. The enthusiasm has been strong. I think that points to the potential of a therapy.
As the Commercial Guy is setting it out a couple of years away from potential commercialization, you always look for points of evidence that say, hey, the commercial opportunity is as significant as what we think it is based upon our research. One of the good proxies for that is when you see enrollment in your phase III program. At this point, that enrollment has been incredibly encouraging. Again, it points to, I guess, your question of, hey, is there motivation and desire to consider a treatment-naive patient for a therapy like this? We think the answer is absolutely yes.
I think that also speaks to the unmet need, you know, that demand.
Absolutely. Yeah.
Definitely. Some KOLs have proposed that if at least 50% of patients remain injection-free, gene therapy could be considered a paradigm shift in wet AMD treatment. Is there a particular threshold or percentage of patients that you'd want to remain injection-free following single injection with 4D-150, or is it kind of a broader, more holistic assessment?
I think it's easy to get caught up in like a binary cutoff. It can be somewhat confusing sometimes. It's like if you anchor to a 50% and it comes out to 49% or 51%, it's largely the same thing, but it can change the narrative. I think somewhere in that range is a fair place to start. I think more importantly is to think about the overall treatment burden reduction that you think you can affect, which is why we continue to anchor the conversation around that. Listen, these diseases are dynamic. For some patients, they're stable. For other patients, they oscillate in terms of treatment burden and disease activity. Something in that range is probably fair. We think that's even greater for patients that are more new in their treatment journey.
We saw that with our PRISM data, right, which you alluded to, a more recently diagnosed patient population saw upwards, I think, of like an 80% treatment injection-free rate out to 52 weeks. We think it's variable based upon patient type. We think more importantly, and we hear this, by the way, from physicians as well, we in the industry and sometimes on the investor side can get really myopic on an injection-free number. When you talk to most physicians and patients, yeah, that's certainly important. They would love for most, if not all, of their patients to fall into that category. What's more important is that there's a significant and game-changing change in treatment burden reduction.
If you can affect that by months or, and we think, years for a lot of patients as opposed to weeks, we think the potential to become a backbone therapy and to affect a paradigm shift in treatment is possible. That's what we're pursuing.
That makes sense. In terms of the wet AMD pivotal development, the 4FRONT-1 trials focused on treatment-naive, while 4FRONT-2 has the 60/40 split between treatment-naive and previously treated patients diagnosed within six months. Do you anticipate a difference between these populations for the primary endpoint BCVA non-inferiority?
You may see a difference in terms of just the number of letters gained because, as you alluded to, in 4FRONT- 2, you have a portion of patients that are previously treated. We feel good about how these trials are designed. The end size in these trials is quite robust. It's 200 patients per arm per trial. We believe that the arms will be balanced. In both trials, the primary endpoint at 52 weeks is non-inferiority in vision. We feel confident that while that number may have a slight delta between 4FRONT-1 and 4FRONT- 2, we think the chances of success in hitting our primary endpoint are high in both trials, largely by the fact that I think the design is strong, the enrollment criteria is really strong, and both arms should be pretty balanced between the two.
Very exciting. I mean, it's been great to see the progress. As we approach our time here, I wanted to make sure to ask what are the most important near-term catalysts for investors to keep in mind? Are there any aspects of the 4DMT story that you believe are currently underappreciated by the market or by investors?
Yeah, I could take that second part of the question for the next hour, I think. First, on the catalysts, we're scheduled, planning to release some longer-term durability data, I think, in Q4 of this year from the PRISM study. Stay tuned for that. I think those short terms are two years in the treatment experience population, so the severe population, and I think upwards of a year and a half in the broader population that we talked about earlier. That's coming Q4, I believe, is the timeframe for that. The other, I think, important update to keep a close eye on is we will report out on enrollment progress as it becomes material, particularly if the enrollment progress shifts in the guidance we've given on top line readout and so on.
As that enrollment continues to progress, we'll provide appropriate updates on that throughout the back of the year and certainly into 2026. On the other appreciation of the story, listen, it's been, as you know, better than anybody. It's been an interesting 12 months, 18 months in the biotech space, and gene therapy is probably even more pronounced than that. As it relates to the story and how much it's reflected in things like market cap and share price, there's a lot of factors that come into play in that conversation, as you know. What I would continue to point people to is the modality and the opportunity around durability is very clear. We've seen evidence of this. Everyone in this space would validate that increased durability that reduces treatment burden is a huge unmet need.
I'll also point to most recent, I think two weeks ago, ASRS released their PAT survey. Many of your audience is probably familiar with that. American Society of Retina Specialists does an annual survey of all their members. I think almost 1,000na of their members replied to this survey. One of the questions, it's a really well-done survey. I encourage people to look it up if you haven't. It covers a broad range of topics. One of the topics they touch upon is what new modalities or things in development are retina docs most excited about. The number one answer by far, I think around 50% of respondents said gene therapy is the thing that they are most excited about in terms of a new modality, a new approach that could make a really meaningful difference for their practices and more importantly, their patients.
The next was TKIs, which have a level of excitement, but I think it was less, you know, proportionately less than half of the respondents rated that modality as something they were as excited about as gene therapy. We think a couple of things. The unmet need is real. It's been validated. The market is significant. Our approach, being a gene therapy-based modality that can provide real meaningful treatment burden reduction over a long period of time, is what doctors and patients tell us they're most enthusiastic about. Those elements, I think, point to a significant commercial opportunity. Right now, our focus at 4DMT is to be laser focused on execution and get through our phase three program, first with AMD.
We think with time, we'll have an opportunity to show just what the potential is of our asset, certainly for the value of the company, but as importantly for patients and physicians.
Yeah, very exciting to see the progress. I'd like to thank you, Chris, for 4D Molecular Therapeutics, a really engaging story. You know, really exciting to see the pivotal progress across the platform.
Yeah, we agree. Thank you for the opportunity to share this story, and good to see you.
Absolutely.