4D Molecular Therapeutics, Inc. ($FDMT)

All right. Good afternoon, everyone. Thank you to those of you in the room and those dialed in on the webcast. My name is Faisal Khurshid. I'm one of the Senior Biotech Analysts here at Jefferies. Really pleased to have with us the management team of 4D Molecular Therapeutics. 4D is a super interesting company working on gene therapies for the masses with a lead-program and approach in wet AMD. So we have with us today David Kirn, CEO; Kristian Humer, CFO; and Chris Simms, Chief Commercial and Chief Business Officer. So with that, David, could I ask you to please start by introducing the company?

Yes. Thanks for having us. It's a pleasure to be here. I think we're going without slides today. Is that correct?

Yes.

Great. So, we're a next-generation AAV gene therapy company with a lead product, 4D-150 for wet AMD and diabetic eye disease. Our underlying technology is directed evolution, which is a Nobel Prize-winning technology that allows us to invent best-in-class vectors that have the features that we want for large-market products like 4D-150. So, it's been a powerful platform for us. It's allowed us to invent and develop 4D-150, which expresses the industry-leading anti-VEGF aflibercept, but does it in a continuous fashion, 24 hours a day, 7 days a week. It right in the back of the retina, right on site where it's needed. So we think this is fundamentally a backbone therapy for neovascular diseases of the retina, which can continuously suppress the disease activity and lead to better patient quality of life, treatment burden reduction and vision improvements over standard bolus therapies. We have 2 Phase IIIs, 4FRONT-1, 4FRONT-2 in wet AMD and 4FRONT-1 is completed enrollment at a very high rate, which is thrilling to see. It's been completed now in Q1 and will read out in the first half of next year. We think that high enrollment rate was driven by the unmet need that patients have and by the physicians' excitement about gene therapy and the results we're showing. We have a second product -- second Phase III, 4FRONT-1, which is a global study and that we expect to complete enrollment in the second half of this year with readout in the second half of next year. And we'll be starting a diabetic macular edema Phase III in the second half of this year.

Got it. Excellent. So maybe starting with that, you mentioned the unmet need and the rapidity of the enrollment that you saw in the pivotal studies. Can we start just high level conceptually, what is the point of 4D-150, why do we need this when there are a few drugs that are approved for this disease?

Yes, I'll kick it off and then turn it over to Chris, who's been in retina for nearly 14 years of commercializing products. So people think of wet AMD and DME is having effective therapies, and that is true. There are bolus anti-VEGF therapies that can transiently inhibit the VEGF signaling, which then calms down the blood vessels, reduces edema and allows vision to improve. However, that's transient. And so what the result is, is patients -- most patients are going to need injections roughly every 8 weeks. It could be anywhere from every 4 to every 12 weeks on average. But that's just -- most patients can't sustain that. So what happens is they get undertreated and they end up losing vision. And it's a huge impact on their quality of life, having to go to the clinic and getting a needle in the eye, which they absolutely hate. You can imagine the needle in the eye. So there's a real unmet need for a product that can actually sustain the anti-VEGF effects consistently and constantly without going up and down, up and down, up and down, and where patient compliance is not necessary for therapeutic benefit and therefore, preserve vision. So that's why there's a huge unmet need. We think that's why patients are flocking to it. And Chris has done a lot of thinking about this and analysis of various surveys on this that he can share with you to say that physicians believe the same thing.

Yes, I can add a little bit of color. Thanks, David. So as David mentioned, the current standard of care is bolus anti-VEGF treatment. And that modality has existed for about 20 years now, actually. I think the initial anti-VEGF therapy was launched in 2006 and highly efficacious initially LUCENTIS and then follow-on medicines like EYLEA and more recently, VABYSMO and EYLEA HD. What's important to recognize is that all the innovation that's come from follow-on, more next-gen bolus therapies have largely extended the durability interval a little bit. So every new entrant has kind of stretched the durability by a week or 2. And when you talk to physicians, that's super important for the obvious reasons that David just mentioned, right, needles in the eye, the frequency of that is burdensome for the patient and for the clinic. But despite that incremental advancement in innovation, we've seen large commercial success. You've got a medicine like VABYSMO, I think, which, again, added an extra benefit of a couple of weeks of durability. And I think it's on pace to be nearly a $4 billion to $5 billion in sales medicine for Roche/Genentech. So we know that incremental advances in durability are highly important and they translate to commercial value. We've seen that historically. And our simple proposition is we're not trying to advance the incrementality by a week or 2. We think we can make a paradigm shift in an incrementality measured in months, if not years and not for the rest of the life for many patients, and that's a completely different treatment paradigm, and we think the commercial opportunities would be consistent with that shift in treatment paradigm as well.

Got it. And then from a clinical and commercial value proposition perspective, can you explain like your view on how -- like should investors think that this has to be curative to have a real value proposition? Or what does kind of extending durability look like? And what's kind of the benchmark that would really reframe expectations in the disease?

Yes. it's a good question. It comes up a lot, especially when people hear gene therapy. I think sometimes the natural reaction, gene therapy must be one, highly expensive and it must be curative. And I think that's true for other gene therapy approaches. It's not true for what we're doing. So we're looking at a mass-market approach -- we don't believe it needs to be curative. We think it is functionally curative for some patients, and we think we've shown that in some of the data that we've generated thus far through our Phase I/II program. But doctors will tell you, it's like if you reduce the treatment burden and even better if you do that while also giving patients the possibility of holding on to their vision gains, which both therapies don't seem to be able to do, then that's an absolute game-changer. And of course, for some patients, if that means that 4D-150 is the last needle in the eye that they'll ever need, and we think that will be true for some, then that's incredible. But it doesn't have to be curative. And the good news is that we work in a space where there's great bolus anti-VEGF options available today. There's more in development. And for patients that need occasional supplementation with a 4D-150 backbone therapy in place, physicians and patients have and will have great options to choose from.

Got it. So what proportion of patients still needing supplementation with EYLEA or another injectable VEGF? What proportion would be acceptable? And in terms of like from the physician and patient perspective, what does that look like from a treatment burden perspective? Like do they mind that they would still have to go into the office at some frequency? Or is that part of normal standard of care anyways?

Yes. I think it's -- I'll start with the end. I think it's part of normal standard of care and the frequency of visitation back to the office will depend upon how recently you were treated with 4D-150. So upon initiation, you're likely to be -- have to come back a little bit more frequently to assess how you're doing. And assuming that you do well, that interval for revisiting would get extended out over time. And to your other question, I don't think there's a magical number that says if you're at this binary point, then physicians think you're successful or not. But what I would tell you is when we share the data that we generated from our Phase II PRISM study, which broadly showed like a 50% treatment-free rate at 52 weeks and about 80% to 90% treatment burden reduction across a broad range of different patient types, that profile from a physician and a patient standpoint was received very favorably. So we believe if we show something like that and maybe even better in Phase III, then we have, I think, a massive opportunity on our hands.

Got it. And then let's talk more about PRISM because that's your Phase II study that kind of helps support going into 4FRONT-1 and 4FRONT-1. Can you remind us what have you seen so far in PRISM? And I believe you're going to give an update on the 2-year data from that study coming up in a few months now. Can you help set expectations for what does good look like for that as well?

Sure. So PRISM is really several -- a couple of studies as a program, a Phase I/II program. And we, as good drug developers, studied a broad range of patients with wet AMD. It's quite a heterogeneous disease. It waxes and wanes over time. So we felt that was important. And so first-in-human studies, we started in the most severe patient population. So these are patients who had 10 injections on average in the prior year, 10 needles in the eye, if you can believe that. And then still had very swollen, thickened retinas despite that. Many have had disease for anywhere from 4 to more than 10 years -- so in that population, we still saw what we thought was very compelling efficacy and biological activity with treatment burden reductions on the order of 70% to 80%. A significant proportion of patients either went to 0 or only 1 injection a year. That -- what was important about that was that is likely where the product will first be used in the market. And so showing that kind of efficacy where others have failed is really very, very valuable. Safety was phenomenal there. No significant adverse events at all. And I'll get to kind of a summary safety statement in a minute. We also looked then at a broad population, a Phase IIb population where we took 30 patients who look more like a routine clinic, some severe, some less severe and a broad range. There, we saw, again, about an 80% treatment burden reduction, about 50% of patients injection-free at 1 year, 1.5 years follow-up. And again, there, just like in the severe population, we saw constant treatment burden reduction across each increment of time. So there was no evidence that it was waning over time. It was stable as expected with the gene therapy, which we expect would be lifelong expression. So that's what we've shown there when we looked at the most recently diagnosed population. So patients we got to earlier when the retina was healthier. There, we saw a 90% treatment burden reduction and about nearly 3/4 of patients were injection-free at the middle of the second year at 18 months. So very compelling efficacy, far above a bar that would make this a highly successful product. The injection is routine as an outpatient simple intravitreal just like EYLEA. So nothing there. And so the last box to check was safety, and that's critical with a market like this. And there, what we've seen is a very good safety profile with no serious or significant clinical adverse events. And at the Phase III dose with the Phase III steroid regimen, out of just over 70 patients that we've put into the public domain so far, we only had 2 who had very mild inflammatory cells detected at a single time point, so not clinically significant. So we're pretty thrilled with the safety profile. In terms of what we expect at the 2-year mark, more of the same. Just boring is good for us, continued safety, continued treatment-burden reduction at roughly the same level, and that's fully what we expect to see.

Got it. And then based on just what's known about the mechanism of expressing VEGF intraocularly, is there any risk known like scientifically about like late-onset inflammation? Yes, let's start with that.

So short answer is no. In terms of -- when we think about inflammation with a product like this, there's kind of the capsid itself, the delivery vehicle that's only there for several weeks and then it's gone. So you kind of cover with steroid eye drops while that's clearing. But then you think about what's the protein that I'm producing with my therapy. And in this case, it's aflibercept. Good news is we know aflibercept has been in over 60 million eyes safely. So it's very, very de-risked in terms of knowing it's non-inflammatory, knowing that it's well tolerated and not immunogenic.

Got it. And based on what you know about the expression profile of your vector, what would you expect to see on duration of benefit?

On the duration?

On duration, like durability of expression?

Well, we would expect -- based -- so AAV, what happens is it goes to the nucleus of the cell, the target cell. And then the protein dissolves the carrier. And then you're just left with a circular piece of DNA, which is inert. So that should be there the rest of the patient's life. And unless the tissue is turning over, it should be lifelong expression. And in fact, the retina does not turn over. And so it should be lifelong expression. There is data -- the longest follow-up data with AAV in the retina is with Luxturna for LCA2, a rare disease, and that's shown really nice stable efficacy out through 10-plus years. So we think it's going to be lifelong and not wane, and I think patients are going to love that.

Yes. I think it's an important point because I think for a lot of investors, at least like hemophilia and like liver-vector gene therapy is, I think, the greatest kind of piece of like AAV gene therapy exposure for investors. That's an interesting point.

Well, I think that's a really -- that's an important point is -- people hear gene therapy, many think of very, very high doses IV. They think of $1 million to $2 million price tag. They think about the risk of serious IV toxicities. That's not the game we're playing. Our dose is -- I think, 1 billion of their dose probably. And it's just localized in the eyes, you're not getting that systemic exposure. Our cost of goods because of that, because of the low dose is less than $1,000. So, it gives us big pricing flexibility.

Yes. Can we talk more about that? Like how do you -- because the things like in like retina therapy, there's a huge part of it is fitting in with the current practice dynamics in a buy-and-bill setting and working with these practices and the financial aspect of the practices as well. How do you think about kind of fitting into that ecosystem with respect to the gene therapy and understanding that you have some nice COGS leverage here?

Yes, I can take that one. So I think, first of all, we think we fit pretty seamlessly into the current logistics of a retina practice. Starting -- I'll come to the reimbursement part of that in a second, but it's important to highlight that because we are intravitreal delivery, we think the storage, the distribution channel, all of those things that a physician is really used to today would be the same as what they would experience if they're injecting bolus anti-VEGF.

Yes. Is there anything different from like a handling perspective, like site certification or like a temperature fridge or anything like that?

It's a good question because often that is the case for other gene therapies or unique modalities. For us, it's not. So again, pretty seamless logistics operations, pretty seamless integration into the operational flow of a retina clinic. The difference would be, as you alluded to, we do think it would be a buy-and-bill product. So all of the things that come with buy-and-bill that exist today, the opportunity to earn margin on these products and all of those things, we think, would be true for us as well. And while it's way too early to speculate on what pricing would be, certainly, it would be higher than a single bolus injection of a branded anti-VEGF. And so when you think about practice economics, practice economics are driven by, first of all, it is the price of the medicine. Reimbursement is a function of that. So we think the value of reimbursement on what is likely to be a higher price point, in combination with the fact that you get that reimbursement upfront. And then there's other follow-on implications for capturing patients that otherwise would have been lost to follow-up, and we think an implication for helping with practice capacity where you put all those things together, we actually think our practice economics proposition would be better than what they experience today with current bolus therapeutics. We just got to do some education as to what comprises that because the formula is a little different than what the current paradigm is. But I've had the opportunity to talk to many physicians about that concept and how it differs. They get it pretty quickly.

Understood. And then with respect to the competitive landscape, there's 2 other programs that are in Phase III gene therapy programs for wet AMD. Can you talk about the differences between those programs and your approach?

Sure. I can start and then Chris can weigh in. So again, the issue with AAV is the standard wild-type AAVs that other groups have used cannot be used intravitreally to get to the retina. There are barriers. So we did directed evolution to get over -- through those barriers and come out of the vector that could pass through and then transduce back of the eye very efficiently. There are other -- 2 other gene therapies we're aware of in Phase III. One is overcoming the problem with the vector by doing a subretinal surgery. So implanting high-pressure fluid containing their vector by detaching the retina surgically and infusing at high-pressure that material into the retina with the hope that they can sort of force the vector into cells and get enough expression to have efficacy. So -- that is REGENXBIO partnered with AbbVie. That subretinal approach has been very, very slow to enroll, as you might imagine, because most patients don't like the idea of that surgery and the physicians in a busy practice. It's just kind of a nonstarter for many of them. So that is going to be reading out, I believe, in the second half of this year. But again, it's been very slow to progress, and we think commercially, we will have distinct advantages. But we would expect and hope that, that would be effective because it will be expressing continuous anti-VEGF, which should work. The other competitor is Adverum. This is a group that has a vector that was evolved in mice for intravitreal. When it went into primates in humans, it's had issues with being inflammatory, which if you have severe long-standing inflammation, it can last -- result in serious adverse events such as vision loss, which they've seen in the diabetic population, but they're still -- so they've shut down diabetic eye disease, but they are still developing it in Phase III for wet AMD. So we keep an eye on them. But again, we started about 5 years behind them, and we've sprinted right past them because of our lack of safety issues. So we think, again, we have a big competitive advantage there.

Got it. And do you believe that the safety issues seen with the Adverum program are more driven by vector or by dose or by capsid? And how is your approach different on those kind of major characteristics?

Yes. So it's driven by the capsid. And so the capsid dose, the vector dose is critical. They started with much higher doses than we needed because, again, the vector is not apparently not as efficient. That forced because of the toxicity, which is related to the total dose and we believe the immunogenicity of that vector, they had to drop the dose, which made a lot of sense. And when they did that, the tolerability was improved. And then they spent a number of years trying to optimize the steroid regimens, including oral steroid regimens and the like to try to combat the front-of-the-eye inflammation that they were seeing that they felt resulted in the severe toxicities in DME -- so they're in Phase III, and that should be effective. I think the big question there is just the safety and can that be maintained. Physicians really don't want to be managing complex steroid regimens and putting patients back on steroids after they go off. And that's something that their early programs were grappling with.

Makes sense. And clearly, between these 2 programs, they're both partnered or sold to larger pharma companies. How are you thinking about the strategic landscape for gene therapy approaches in wet AMD?

I'll kick it off and then hand it over to Chris and Kristian. If you think broadly about treatment in neovascular disease of the retina, which is soon to be a $20 billion market that we'll be launching into, there's going to be a wide range of bolus anti-VEGF therapies with different mechanisms of action, different price points. There will be TKIs, there's going to be VABYSMO competing with TKIs. There's going to be some new combination mechanism products. There's going to be biosimilars. So it's going to be a complex space there. But if you think about the backbone therapy, which we believe is going to be the basal that everybody should get and then they can rescue with these bolus therapies. There's only a few, and we believe we're clearly the market leader there at this point in time. And again, we got to finish our Phase III and prove that holds up. But to date -- we have best-in-class data and a best-in-class opportunity. So I would think that if you are interested in a $20 billion market and you think that these foundational backbone therapies are going to be a critical component of that, and we have the best in that class, then there's going to be very significant interest. But we hired Chris because he has experience building U.S. sales forces, and we think we can do it and really capitalize on a lot of value for our shareholders.

Yes. I think you kind of covered it. I don't think you can potentially have a very disruptive backbone therapy type of asset in a multibillion-dollar growing market without having significant strategic interest, probably stating the obvious. That said, to David's point, like the beauty about retina, both in the U.S. and ex-U.S. as well, is that you don't need a large pharma partner to commercialize. Like I've done this 2, 3 times in different settings and launch new medicines in retina in the U.S. and your total commercial footprint is probably less than 150 headcount. And there's not many multi-blockbuster therapeutic areas where that really is the commercial footprint that you need. So very scalable even for a start-up biotech like us. So we'll plan to do that. And certainly, that's part of my responsibility. And should there be strategic interest, we'll entertain those conversations when the time is right, but we're also well prepared to go it alone, and we can do that.

Got it. And how do you think about that piece of when the time is right?

You need Phase III data in hand. So we're in execution mode. We've said publicly, we're in the first half of next year, we'll have 4FRONT-1 data. And shortly after that, we'll have 4FRONT-2. So that's the key time point for us. So we've got an exciting year ahead of us.

Yes, totally. And then zooming in on 4FRONT-1 or both 4FRONT-1 and 4FRONT-2 a little bit. Can you talk to us about the -- on the Phase III, there's 2 key differences on the patient population and the rescue criteria. Can you describe those changes that you made from the Phase II to Phase III and what impact that has on probability of success for the study?

Sure. So I think overall, the minor changes we made going from PRISM Phase IIb to Phase III, we think overall will increase the likelihood of success, albeit we think it was already very high. We refined the patient population to exclude patients who did not have a robust response to a bolus aflibercept just to make sure we read out those 10% are relatively resistant, which makes sense. And I think that's one minor addition we've made. And then we've also made sure that patients -- the CST, the thickness of the retina is capped, such that if they had anatomical abnormalities like PEDs, they'll be weeded out. So those are just a couple of refinements that should, if anything, make things better. And then in terms of the supplemental injection criteria, we made some very small changes to make sure we did everything we could to protect the BCVA endpoint, which is Phase III, you got to hit your primary endpoint. Primary endpoint is BCVA non-inferiority. And we don't think it will materially change the reduction in treatment burden. Again, all these are set by the best investigators in the field that we're fortunate to work with, as do other companies. So we think if anything, this has increased the likelihood of success. I think in terms of what good looks like, I think just look at our Phase IIb data, that's -- if we hit something close to 80% to 80-plus percent, that's a huge win. And the safety profile that we've shown, if that holds up, that's a huge win. And then there will be a significant portion who are injection-free for a year, 2 years or more. And I think that will be a big win because there's no other treatment class that is going to achieve that.

Yes. And then as you think about -- let's say we're having this conversation a year from now, you're preparing to be a commercial-stage company. How are you equipped from a manufacturing and commercial -- I think Chris mentioned just you don't need hundreds of people, you need kind of more like dozens from like a sales perspective. So can you talk to us about manufacturing and commercial footprint?

Sure. So complex biologics manufacturing is critical. It's important to get it right early and not have significant changes as you develop the product if you can avoid it. And we've got a phenomenal AAV team. They've made, I think, more different AAV vectors by far than any other group in the world. And they've been on it from day 1 with a really efficient manufacturing process. And we made all our own material in-house up until Phase III and then roughly half of the second trial will be material from a CDMO that we've already tech transferred to, so there's a world-class, AAV-experienced CDMO. So that material is going into Phase III to make sure the bridging is done in Phase III. We'll do our qualification batches and then we'll be set for launch. And as we said before, the doses here are very, very small. So with one manufacturing run, you can make thousands and thousands of doses and stockpile those in advance of the launch.

Got it. And then I guess in our last minute here, what do you think investors misunderstand most about the company?

I'd say they -- well, I'd say they don't appreciate the massive opportunity that we have with an AAV in a large market indication. I think they've been programmed to believe that AAV is for rare disease, got to charge $1 million because you're only going to get to treat patients once and then the population is gone. We're putting that on its head and say with innovation, you can actually access high-incident-rate massive markets like a $20 billion retinal market with gene therapy. And we get why they don't get that yet or not all of them get it, certainly some do, but because it's never been done before. But when I think the penny drops that they realize, oh my God, the opportunity here to fully disrupt a massive market is -- it's a phenomenal business opportunity. So I think really, early story we're getting there.

Got it. All right. Great. Well, on that note, thank you guys so much for joining. We really appreciate it.

All right. Thanks for having us.