4D Molecular Therapeutics, Inc. (FDMT) Earnings Call Transcript & Summary

Hello, ladies and gentlemen. Thank you for standing by, and welcome to our investor webcast today. As a reminder, today's call is being recorded. With that, I will hand the call over to Julian Pei, Head of Investor Relations and Corporate Finance, who will make introductory comments.

Thank you, operator, and thank you, everyone, for joining us this morning. Our team and a panel of key opinion leaders in retina are thrilled to spend some time with you today to share promising results and plans for advancing our lead asset 4D-150. The recording of this webcast will be accessible in the Investors section of the 4D website after the completion of this call. We remind you here that we may be making forward-looking statements. For further details, you can visit our website or our SEC filings. With that, it is my pleasure to hand it over to David Kirn, our Co-Founder and Chief Executive Officer. David?

Thanks, Julian. 4D-150 is a Phase III candidate designed to disrupt the retinal vascular disease market, valued at over $16 billion annually. Importantly, 4D-150 expresses aflibercept, the most used FDA-approved treatment in this class. And this molecule has been dosed roughly 65 million times to-date, in contrast to experimental molecules and/or formulations such as TKIs. 4D-150 is designed to address the primary unmet need with bolus anti-VEGF agents, which is reducing treatment burden and preserving vision. Our vision is for 4D-150 to be a backbone therapy that provides multi-year durability, forming the foundation of treatment for retinal vascular diseases. If successful, this would be the largest reduction in treatment burden ever achieved. None of this would be relevant without safety, especially for gene therapy in the eye, where the bar is high. Our targeted and evolved intravitreal R100 vector was invented with this goal in mind, and our data to-date suggests we have exceeded that. 4D-150 was also designed for rapid commercial adoption in the clinic as a single-dose routine intravitreal product that fits seamlessly into retina practices, including the buy-and-bill reimbursement model. We believe pricing flexibility will be driven by our low cost of goods. Our program is led by 4 industry leaders in retina therapeutics with over 100 years of experience at companies like Roche, Genentech and Novartis; they had leadership positions in development, approval and/or commercialization efforts for 6 of the 7 major retina products today, including VABYSMO, LUCENTIS and SUSVIMO. In contrast to external KOL-led programs, I believe we have the best industry experienced retina team in biotech today. Standard of care anti-VEGF therapies are effective but short-lived, requiring frequent, anxiety-inducing and burdensome injections into the eye. As illustrated on the left, an average patient receives approximately 36 eye injections over just a 5-year period. As shown on the right, each of these treatment visits, including travel, can take at least 4 hours for both the patient and their caregiver. Based on numerous surveys, the #1 thing that doctors and patients want is better durability and fewer injections. We envision 4D-150 being used as a foundational backbone therapy, reducing patients' treatment burden by 80% or more with the potential upside for many patients to remain injection-free for a year or more. This target product profile represents an unprecedented paradigm shift for the field. In PRISM, we've studied 4D-150 in a broad spectrum of patients. We started with the most severe, highest need and treatment recalcitrant population in Phase I and IIa on the far left. We believe this population represents approximately 10% to 15% of all patients with wet AMD, but they will be important for initial commercial uptake. In this population, we identified a subgroup with a strong correlation between higher baseline BCVA and fewer supplemental injections. We then studied 4D-150 in a broad population in Phase IIb, including both severe and a subgroup of recently diagnosed patients on the far right. As you'll see in the next slides, clinically meaningful and durable injection burden reduction was demonstrated across all of these populations with increasing effect sizes as we move from left to right. In the most severe patients, we demonstrated unprecedented and clinically significant treatment burden reduction of 83% over 1 year compared to patients' injection burden in the year prior to enrollment. On average, patients received less than 2 supplemental injections after having received roughly 10 injections in the prior year, 52% of patients required 0 or 1 supplemental injections. Importantly, the 3E10 dose cohort had superior treatment burden reduction versus all 3 different comparator groups we analyzed as shown on the right. Of all baseline characteristics evaluated, baseline BCVA had the strongest correlation with 4D-150 treatment burden reduction, specifically in this severe population. In the 50% of patients with the highest baseline BCVA, over 1 year, 73% of these patients required 0 or 1 injection and 64% were injection-free with a mean injection number of 1.1. Numerous publications have shown that progressive vision loss in wet AMD patients over many years is associated with retinal fibrosis, atrophy and cell death. This loss of retina integrity could impact transduction and gene expression, and we plan to explore this hypothesis further. Now let's move on to the Phase IIb. Over 1 year in the Phase IIb broad population, including both severe and earlier-stage patients, 70% required either 0 or 1 injection, 57% were injection-free and the mean number of injections was 1.0. Finally, at 1 year in the 50% of patients diagnosed within the last 6 months, which is closest to our target Phase III population, 87% required 0 or 1 injection, 80% were completely injection-free at 1 year, and the mean number of injections per patient was only 0.3. This remarkable injection burden reduction has not been previously described with any bolus anti-VEGF agents, including approved blockbusters such as VABYSMO or other experimental agents. As you'll see today, our Phase III population will be even further enriched for efficacy beyond this Phase IIb recently diagnosed population. Now here's our agenda today. Dr. Dante Pieramici will review the 52-week PRISM wet AMD Phase IIb data; Dr. Carlos Quezada-Ruiz and Dr. Anat Loewenstein will review the 4FRONT Phase III trial designs; Dr. Veeral Sheth will review our recent SPECTRA DME 32-week interim data; and finally, we'll wrap up with a 2-year durability update on aflibercept expression in PRISM patients, followed by a strategic outlook and audience Q&A led by myself and Dhaval Desai. Dr. Dante Pieramici will now review the PRISM wet AMD Phase IIb top line data. Dante?

Thank you for having me here today. As David mentioned, I'll now focus on the Phase IIb cohort, which enrolled a broader patient population, all of whom were previously treated, 50% of whom were enrolled within 6 months of diagnosis, as shown in the far right column. This subgroup is the most comparable to our Phase III population. All had active Wet AMD confirmed on OCT by the Duke Reading Center, one of the top reading centers in the world. Here, we show the study schema for the Phase IIb population extension cohort of PRISM. Because this cohort allowed patients who received as few as 1 prior anti-VEGF injection before entering the study, all patients received a loading dose of aflibercept 2 milligrams at week minus 1 and the second and final loading dose at week 4 to control disease during the 4D-150 aflibercept expression ramp-up window over approximately 12 weeks. All patients had received a topical Durezol taper over a period of 20 weeks, starting at day minus 3. Supplemental aflibercept injection criteria were then applied, as shown on the right. Of note, the reference value for the BCVA and CST was the average of week minus 1 and day 1. Let's review the goal of 4D-150 would be in PRISM Phase IIb. Here, we highlight the aflibercept 2Q8 as a comparator arm from recent approval studies for VABYSMO and EYLEA HD. Aflibercept 2Q8 is the gold standard in wet AMD and starts with 3 loading doses followed by Q8 week dosing. Given PRISM Phase IIb patients were previously treated and received on average 4 actual injections prior to entering PRISM, we highlight the CST curves from week 16 and on. In these curves, we note; number one, the CST benefit remains unchanged on average compared to the benefit from the first 3 loading injections; and 2, 20 to 30 micron fluctuations are observed every 4 weeks from the waning effect of the aflibercept bolus therapy. Being able to achieve these results without repeated bolus therapy would address one of the largest unmet needs in retina. Similarly, for vision, we can see essentially all vision gains are derived from the first 3 loading doses. Again, the therapeutic objective in this population is being able to maintain these visual acuity gains over the long term without the need for frequent bolus therapy. Let's now review the Phase IIb top line 52-week results from all 30 patients treated with 3E10. The blue highlighted areas represents the benefit of loading bolus injections and 4D-150 transgene ramp-up. Therefore, we see the benefit of sustained anti-VEGF expression from 4D-150. All patients in the 4D-150 arm are represented by the solid blue line, with a subset of supplemental injection-free patients being represented by the dashed line. The solid blue line includes patients who required supplemental injections as indicated in the row of blue numbers below the CST figure. The vision and CST improvements from prior bolus treatment were maintained through 52 weeks, achieving the primary therapeutic objective. Through 52 weeks, patients in the Phase IIb portion of PRISM demonstrated sustained improvements in mean visual acuity. This was accompanied by sustained anatomic control over the same time period with a lack of monthly 20 to 30 micron oscillations that are observed in trials with standard of care bolus therapy. Here are the swim lane plots for this population. Through 52 weeks after 4D-150, 70% of these patients required 0 or 1 supplemental injection and 57% were injection-free. On average, patients received only a single supplemental injection over this time period. Of note, only 2 of 30 patients shown at the bottom required greater than 2 supplemental injections, representing approximately 40% of all supplemental injections given through 52 weeks. We'll revisit this in a moment. There was no control arm in this cohort. However, a projected standard 2Q8 aflibercept arm that would be used in the Phase III setting would result in 6 injections through 52 weeks. In contrast, patients in the 4D-150 received only 1 supplemental injection on average. This represents an 83% reduction in treatment burden. Now, let's review OCT images and best corrected visual acuity for a few case studies. In blue, you can see a patient who received 4 monthly anti-VEGF injections and entered PRISM at 446 microns on CST. The average patients in Phase III has baseline of approximately 360 microns. After receiving 4D-150, the patient remains under excellent control and is injection-free through 52 weeks. On the bottom of this slide, in pink, you can see a patient who is recalcitrant to anti-VEGF intravitreal injection. Despite having received 6 monthly anti-VEGF injections, they presented with baseline CST greater than 600 microns and a large PED. Through week 24, as seen in the pink box, the patient had received 6 bolus aflibercept injections and the CST continued to worsen. This type of patient is rare and will not be eligible in the Phase III trial. Moving on to the recently diagnosed subgroup of the Phase IIb cohort, which is made up of 50% of those patients and are more comparable to the Phase III population that is planned. Similarly, the vision and CST improvements from prior treatment were maintained through 52 weeks, achieving the primary therapeutic objective. Through 52 weeks, patients in the Phase IIb portion of PRISM demonstrated sustained improvement in mean visual acuity. This was accompanied by sustained anatomic control over the same time period. Again, here are the swim lane plots for this population. At 52 weeks, 87% of these patients required 0 or 1 injection and 80% were injection-free. On average, patients received 0.33 supplemental injections over 1 year. As previously shown, a projected standard 2Q8 aflibercept arm would result in 6 injections through 52 weeks. In contrast, patients in the 4D-150 arm received only 0.33 supplemental injections on average, which represents a 94% reduction in treatment burden. We know that efficacy is only enabled by safety in wet AMD, and the 3E10 dose remains well tolerated across all populations with no 4D-150 related serious adverse events with up to 3 years of follow-up. No patients had 4D-150-related hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions. 2.8% of patients receiving the 3E10 dose experienced transient 1 plus vitreous cell that resolved by the following visit. Importantly, 99% of patients were able to complete their steroid taper on time. And as of the last data cut, 99% of the patients remained completely off steroids. In summary, in the Phase IIb cohort of PRISM, we saw robust and clinically meaningful reductions in treatment burden in a broad population. Importantly, we saw durable improvement in CST with fewer fluctuations and sustained best corrected visual acuity improvement. Most importantly, all of these results were achieved with 4D-150 continuing to be well tolerated through up to 3 years of follow-up. I'm looking forward to the imminent start of the Phase III program. I'll now hand it over to Carlos and Anat for more information on Phase III.

Thanks, Dante. We're excited to move forward into Phase III with our forefront program in wet AMD and believe that 4D-150 has the potential to significantly improve the treatment of wet AMD for our patients. And today, we're honored to be joined by Dr. Anat Loewenstein from Tel Aviv Medical Center, who is a member of our esteemed Ophthalmology Advisory Board to discuss our Phase III program. Thank you, Anat, for joining.

Thanks, Carlos. So, based on what we know about aflibercept, which 4D-150 expresses, and the results of the PRISM trial as well as what we know about the burden of the management of patients with monthly or bimonthly treatment with anti-VEGF, I'm sure that most retina specialists in the world are pretty excited to participate in a trial like this.

Thank you. The 4FRONT program consists of 2 Phase III studies with identical trial designs with differences in the population to be included, as noted in the slide. The primary objective of both studies is to demonstrate non-inferiority in the mean change in BCVA from baseline to week 52 of a single injection of 4D-150 compared to aflibercept 2 milligrams on a 2 8-week regimen after 3 loading doses. And of course, one of our secondary endpoints will also be the injection burden in both arms.

Yes. I think the design of the study makes a lot of sense. It will enroll -- the 4FRONT-1 study will enroll treatment-naive patients. It will be conducted in North America. And the 4FRONT-2 will enroll a mixed population, giving us a lot of more information, consisting of 60% treatment naive and 40% previously treated patients. All of them -- all the previously treated patients were diagnosed within 6 months of the screening, and this study will be conducted globally. The key inclusion and exclusion criteria are aligned with that of most recent Phase III studies that led to global approvals of other products and, of course, learnings from [ Freedom ] trial. In the next slide, we'll go into some more details.

Both 4FRONT studies are multicenter, randomized, double-masked, aflibercept Q8-week comparator controlled studies. Patients will receive their first aflibercept loading dose at the week minus 5 visit. And 4 weeks later, at the week minus 1 visit, patients will be assessed for response to aflibercept by an independent reading center and only patients who meet this criteria will then be randomized. Anat, what do you think about the inclusion of the treatment response into the 4FRONT program?

Thank you, Carlos. I think actually, it's very important to include this responsiveness into the inclusion criteria. You're right, not all the trials include this requirement for treatment response for intravitreal therapy. However, if we're looking on a long-term sustained anti-VEGF delivery platform like 4D-150 or any other long-term treatment, I think it's really important to include that patients need to be responsive to the anti-VEGF therapy prior to inclusion. This is needed in order to be sure that the patients that are enrolled in the trial are likely to benefit long term from this long-term expression of aflibercept.

Absolutely. And any other comments around any impact on patient or physician excitement?

Yes. Carlos, I don't think it's an issue because the vast majority of patients are responsive to anti-VEGFs. And the physicians are used to give anti-VEGFs. So, I think, both the patients will be eager to participate and the physicians will be eager to enroll. And I don't think it will be a big issue. Also, the physicians wants to make sure they are not exposing the patients long term to something that they are not responsive to.

I agree. I agree. Thank you so much, Anat. About 400 patients who meet the response criteria will then be randomized in a one-to-one fashion at the day 1 visit to one of the treatment arms. Patients in both arms starting 3 days before their day 1 visit will start a topical corticosteroid drop in a taper that -- as it was used in the PRISM study. Patients will then complete their third and final loading dose at the week 4 visit. Anat, in our clinical practices, patients always use different drops for different indications, including that of steroids. What do you think about the steroid regimen we have and the patient perspective on this?

Yes. I think that -- I don't think that patients will be concerned at all about topical eye drop regimen. Almost all my patients when they come for their monthly or bimonthly injections, they say, don't you have a drop that I can take that will make me not need all these injections? So I think that knowing this about our patients, knowing that the PRISM trial had this excellent results in terms of reducing the treatment burden and that the patients were able to taper down the steroids and 99% of them or more did not need to resume the steroids following the tapering down. I think it's not going to be a big issue. Patients really don't like to come to the monthly injections, and even if they are a little more sparse than every month, they would prefer to take drops and have less injections, maybe one injection, even if the price is to take the drops. And actually, this has been shown also experimentally that patients do prefer eye drops for fewer injections. Basically, I think fewer injections, albeit the need to take eye drops is what makes 4D-150 such an attractive clinical candidate, both for the patients and for us, the retina specialists.

Now, we can see the whole schema for the trial design. All patients in both arms will be assessed for disease activity at every visit and sham injections will be given to patients in the 4D-150 arm every 8 weeks for the purpose of masking. Patients in both arms who meet the disease activity criteria will be eligible to receive supplemental injections, which we will review in a moment. We will continue to follow patients for the 2-year duration of the study. So Anat, given the patient population, given the response criteria, given the disease activity assessments, what do you think about the study design?

Well, I actually think it's a very good design. We have the very compelling results of the Phase IIb. And now having the Phase III population enriched for potential multiyear efficacy based on the learning from the PRISM trial makes it very compelling to participate in the trial. I really like the masking approach, which includes the identical topical prophylaxis regimen given on both arms. I think it's really important. And also the fact that the supplemental injection criteria are identical on both arms. This is actually done to protect both the visual acuity and the supplemental injection reductions, as will be discussed later in our slides. But I think that if you really want to know the difference between 2 treatment regimens and you want to keep the masking, I think it's really important to have the prophylaxis and the supplemental treatment criteria identical for both arms. Otherwise, we might be biased.

Great, Anat. Here are the disease activity criteria we used in PRISM on the left and the criteria we will be implementing in our 4FRONT Phase III program on the right. Taking into account the learnings from PRISM, the data from other anti-VEGFs used across multiple populations and our experience in drug development, we've evolved the patient population, the trial design and disease activity criteria in the 4FRONT program. In totality, we're confident that the updates in design for 4FRONT will maximize the probability of successful registrational studies that replicate the strong treatment burden reduction we've seen in PRISM. And we will be working with the retina community to bring this promising therapy to patients as soon as possible.

Yes. I think what is important here is, actually that there are many possibilities or many options to have supplemental injection criteria. So, both the letter loss and increase in central subfield thickness, or if it's a higher, more than 10 letters or more loss of -- in vision, then it is a criteria by itself or of course a macular hemorrhage. I think that there are -- here, all the options an investigator would need for supplemental therapy should these events occur.

The team at 4D has worked extremely hard to reach this important milestone, and I want to express my thankfulness to all of them. And given the global enthusiasm to participate in the 4FRONT program to date and the rapid enrollment we've seen in PRISM and SPECTRA, we're confident in our ability to share top line results by the second half of 2027.

Carlos, I think it is a pivotal moment for patients around the world who really will soon have the opportunity to enroll in the 4FRONT-2 global clinical trial and to get an intravitreal genetic therapy. I'm really delighted to have had the opportunity to work with you, Carlos, and all your 4DMT team on bringing this trial to life.

I will now hand it over to Dr. Veeral Sheth, who will review the 32-week data from Part 1 of the SPECTRA study in patients with DME, which was released in January of 2025. Veeral?

Thanks, Carlos. SPECTRA is the 4D-150 Phase II DME study that was originally planned to be conducted in 2 parts. The first part focused on establishing a safety and efficacy signal in diabetic eye disease as well as looking at doses for further evaluation. Similar to the early studies in AMD, SPECTRA enrolled patients with advanced disease with approximately 75% being previously treated. And despite that, the mean baseline CST in these patients was approximately 500 microns at baseline. Patients in all dose groups received 2 loading doses of aflibercept 2 milligrams followed by a dose of 4D-150 and then a final loading dose of aflibercept for a total of 3 loading injections as compared to 5 loading doses commonly administered in typical Phase III studies for DME. The supplemental retreatment criteria were set conservatively based on an increase of 50 microns. Today, we will review data from week 32, which was released in January 2025. At 32 weeks, where data was available for all patients, no cases of IOI were observed at any dose. On this slide, each row represents a patient and each column represents a study visit. The left-hand side represents anterior chamber findings and the right-hand side represents vitreous chamber results. Green is indicative of a lack of inflammation and the white starred boxes represent missed visits. All patients completed the 16-week steroid taper on time with no patients requiring reinitiation of therapy. Over 32 weeks, we see clinically significant gains in mean best corrected visual acuity of 8.4 letters and 7.1 letters in the 3E10 and 1E10 arm, respectively, illustrating a nice dose response. This increase in BCVA is in line with expected visual acuity gains at week 32 in Phase III studies of anti-VEGF agents for DME. Over 32 weeks, clinically significant reductions in central subfield thickness of 194 microns and 153 microns were observed in the 3E10 and 1E10 arm, respectively, again, illustrating a dose response between the 2 doses. Similar to the BCVA findings, the reductions in CST are in line with expected improvements in retinal anatomy at week 32 in Phase III studies of anti-VEGF agents for DME. Here are the swimmer lane plots for both groups. Starting at week 8, study eyes were eligible to receive supplemental aflibercept injections shown here in green. At week 32; 5 of 9 patients in the 3E10 group were supplemental injection-free, 3 patients received 1 supplemental injection each and 1 patient received 2 supplemental injections. The mean number of supplemental injections over 32 weeks was 0.55 for 3E10 and 1.41 for 1E10. There was no control arm in this cohort. However, compared to a projected standard 2Q8 aflibercept arm that would be used in the Phase III setting, clinically significant reductions in treatment burden would be expected. The mean number of injections 0.55 seen in the 3E10 arm over 32 weeks represents a theoretical 86% reduction in treatment burden after the loading period compared to aflibercept 2Q8. On the left-hand side of the table, we see baseline characteristics of the 3E10 subgroup, the dose which will be utilized in the Phase 3 program. Compared to aflibercept 2Q8 arms in Phase III DME studies, patients in the 3E10 arm were on the high end of the CST spectrum and had more patients that were previously treated. Despite this and having received 2 fewer loading injections than in typical Phase III studies seen here in the green rectangle, patients in the 3E10 group experienced mean BCVA gains and CST reductions in line with aflibercept 2Q8 arms from major Phase III DME studies. Here is a 50-year-old male patient from the 3E10 cohort. At presentation, CST for this patient is 447 microns and BCVA is 53 letters. After receiving 4D-150 and the week 32 time point, the patient remains injection-free with a stable reduction in CST of 244 microns and an increase in BCVA of 5 letters. This represents a common DME patient in retina practices. These patients tend to be of working age, unable to receive regular treatment. These are exactly the type of patients that could benefit from a medicine like 4D-150, which has the potential to control disease for an extended period of time without the need for repeated intravitreal injections. Additionally, with longer-term follow-up, I look forward to seeing if we are able to control underlying diabetic retinopathy and reduce the incidence of future vision-threatening events. So in summary, 4D-150 continues to be well tolerated in DME with no patients in SPECTRA experiencing an IOI event. Clinically significant, stable and durable improvements in line with response from historical Phase III studies were observed in BCVA and CST despite having received 2 fewer loading doses and presenting with higher baseline CSTs. Both results were achieved with an 86% treatment burden reduction compared to a theoretical 2Q8 aflibercept arm, which will be utilized in future Phase III studies. Finally, based on a review of data from SPECTRA and PRISM and in conjunction with the 2 proposed Phase III AMD studies, the FDA has agreed on a registrational path forward for 4D-150 in DME with a single Phase III study. I'll now pass it to David.

Thanks Veeral. I'll now share an update on the aflibercept expression from 4D-150 through up to 2 years of follow-up after dosing. Durability is a major advantage for gene therapy over other modalities. For example, AAV gene therapy in the retina has shown clinically-meaningful durability through 4 to 10 years of follow-up in multiple clinical trials. We've shown that 4D-150 clinical activity is durable based on CST, BCVA and injection burden reduction with some patients out to 2.5 years, as previously presented. Now, let's look at aflibercept expression from 4D-150 as a biomarker to study durability. After a single intravitreal injection, 4D-150 mediates expression of aflibercept directly from the retina tissue itself, as shown on the right in this figure, and aqueous concentrations following diffusion are lowest, as shown on the left. Samples taken in the aqueous, as shown on the left of the figure, are expected to contain only a small fraction of the area under the curve or the tip of the iceberg. PK modeling showed that therapeutic concentrations of aflibercept in the retina can result in detectable aqueous levels, but sensitivity is low and false negatives are likely. However, in patients with detectable aqueous aflibercept levels, we can follow concentrations over time to determine durability of gene expression. These interim data demonstrate durability of 4D-150 mediated aflibercept expression for up to 2 years for samples analyzed to date in PRISM patients receiving the 3E10 Phase III dose. For this analysis, we excluded patient samples that could be contaminated with aflibercept from loading or supplemental injections within the prior 20 weeks. 43 patients had at least 1 sample that was evaluable and 67% of these patients had detectable aflibercept levels that could be used to evaluate durability in this analysis. On the left is a bar graph to assess population level durability. The mean aflibercept concentrations for all evaluable and detectable samples at each time point are shown. The number of evaluable samples decreases over time due to variable follow-up and supplemental aflibercept injections. No significant change in aflibercept expression was evident at any time point from week 24 through 2 years. The slight increase in mean concentrations over time may be due to variable patient follow-up. The right panel shows patient level data on durability; 5 patients had an aqueous concentration in the quantifiable range above 30 nanograms per ml and at least 2 evaluable samples consecutively. None of these patients had significant changes at any time point and no patient had a subsequent sample with aflibercept undetectable. In summary, both patient level and population level data clearly demonstrate durability of aflibercept expression from 4D-150. We expect this to translate into durability of clinical outcomes as we'll update later in the year. We expect to begin enrollment in 4FRONT-1 next month and initiate 4FRONT-2 in Q3 this year. We expect top line data from both programs in the second half of 2027. We will also provide a durability update from the PRISM Phase I/IIa and IIb trials of 2 and 1.5 year data respectively, in Q4 of this year. For DME, the 52-week data from SPECTRA will be presented at a medical meeting in Q3 of 2025. We look forward to continuing to showcase the durability and clinically significant potential of 4D-150 across both wet AMD and DME patient populations. Before I open up the call to questions, I want to take a moment to really thank our investigators, our clinical trial staff, patients and their families, and of course, the entire 4DMT team for getting us to this point today. I'll now open the call to questions. Operator?

Our first question will come from Tommie Reerink with Goldman Sachs.

This is Tommie on for Salveen. And congratulations on this data. So, for the 2 Phase III wet AMD trials, beyond meeting the primary endpoint, what can you lay out, what gives you confidence that it will be compelling for payers and physicians? Could you see any need to see multi-year Phase III data for durability to get stakeholders to be comfortable here?

Well, thanks, Tommie, for the question. I'll give you my perspective first, and then we'll turn it over to Anat and Dante. Yes, we think this target product profile is extremely attractive given the significant reduction in treatment burden, which is the #1 unmet need in the field and the safety to-date. So we think we're very well positioned for commercial uptake and success with patients. I'll now turn that question over to Dante first and then Anat.

Yes. I think I'm very enthusiastic about this. We've had some incremental changes or improvements in the durability with the recent anti-VEGF agents have been approved. But I think that based on the data that I'm seeing here, this would be much more than an incremental improvement in the durability. So, yes, I think that from a commercial standpoint, doctors will be pretty confident looking at 2-year data, 1 to 2 year data that shows durability and safety, of course, in these patients and the maintenance of visual acuity in the long haul that they would be quite enthusiastic to go ahead and institute this in their clinical practices. Anat?

Yes. As a retina specialist, I can tell you that even with the longer duration drugs that we have today, still the need for injections is really too much for the patients. And I think both the patient community and us, the retinal physicians, we really look forward to a much higher reduction of treatment burden. And the mere idea of using -- we all think that maybe such a very long-term treatment should be genetic and to have such a treatment that is given intravitreally, I think, is extremely compelling for the retina specialists because most of the other things, almost all needed some complex surgeries. So I think it's extremely compelling for us.

Our next question will come from the line of Daniel Giraldo with Bank of America.

I was just wondering if you could maybe elaborate a little more on the recently diagnosed patients you had in the trial and maybe if the baseline characteristics kind of compare to what you would expect to see in a larger Phase III trial where you would have maybe more variability for treatment-naive patients? And maybe just one clarification for the anti-VEGF response you're looking at. Is that going to be after a single injection of aflibercept? And then, if so, what percent of patients do you expect to get a response after just 1 injection?

Thanks, Daniel. We'll have Dante answer the first question and then regarding the response criteria for Phase III, we'll turn it over to Carlos next.

Can you repeat the question? I'm sorry, the recently diagnosed -- can you go ahead and repeat that caller? Yes.

Yes. I'm just wondering, just based on the baseline characteristics for those patients, how do you think that could extrapolate to a larger trial? Do you think you would expect to see sort of similar baseline characteristics once you start enrolling the Phase III where you would -- since you're enrolling treatment-naive patients, you would have more variability in terms of response or anti-VEGF needs for those patients?

Yes, it's a good question. And I think that we get some hint of this. If we look at -- when we first look at the very broad population of patients in PRISM, you see what kind of a response we get as far as reduction in treatment burden. And as we move to a more naive population, which is what we'll see in the 4FRONT-1 program, we're seeing that we can get the same excellent control with even a more significant reduction in treatment burden and a higher percentage of patients with just one-time treatment. So, I'm enthusiastic that as we move into an even more naive population, they'll have an induction phase, so we'll get them up to excellent levels of visual acuity and anatomical control and that we'll be able to maintain this control with probably even a higher percentage of patients in this naive population of needing only 1 injection and a significant reduction in treatment burden as we've seen progressing from the broader to the more naive population.

Thank you, Dante. And for the second part of the question, the vast majority of the patients achieve their greatest BCVA and CST improvements after the first injection, as Dante mentioned at the beginning of his talk. So the mean change in shows about a 30% CST reduction, and therefore, we only expect to exclude a small proportion of patients that are highly heterogeneous and suboptimal responders with this criteria.

Our next question will come from Gena Wang with Barclays.

I have one question regarding the safety and one question regarding the protein biomarker. So, regarding the safety, it looks very clean. And you do have a 2 out of the 71 treatment treated in grade 1 inflammation. So maybe can you give a little bit more color at what time point [ you did ] see it's a 1 single timepoint? And what was that single time point when it happened? And any color on the 1 patient that still requires steroid? My second question is regarding the protein biomarker data. I know you only select the patient with less than 20 weeks -- sorry, more than 20 weeks without any rescue injection. What percentage of these patients were injection-free patient -- and also, do you see any correlation regarding the protein expression and the BCVA and CST?

Thank you, Gena, for the question. So with regards to the safety, this is unchanged from our previous presentations but with now more follow-up up to 3 years. So we're thrilled with this tolerability profile. The 2 patients, out of more than 70, you had the 1 plus vitreous cells that was presented previously, but it was approximately a few weeks in and was a single time point and then resolved spontaneously by the next visit. So really a very, very mild and overall very well tolerated. In terms of the aflibercept levels, we have a very rigorous biomarker team at 4D, and they wanted to ensure that there was no chance that a prior aflibercept supplemental injection, whether loading or supplement could contaminate the results and give us a false positive, and that's why we use that 20-week threshold to say, "Hey, anything within 20 weeks could confound results." And that's why we did this. We believe it's the most scientifically rigorous way to go. And we're thrilled with the strong durability we've shown. I mean it's amazing to see it hasn't changed at all over -- up to 2 years. This is consistent with other AAV gene therapy programs in the retina, which have shown stability of expression and efficacy out to 4 to 10 years. I think it's too early for us to make any correlations between the exact level that we see in patients and the supplemental injection burden reduction. We see it broadly across all patients, even if aflibercept is below the level of detection. But over time, we'll look for that correlation and we'll update you once we have that.

Our next question will come from Mani Foroohar with Leerink.

I guess I have a broader one. Obviously, this is a market with a number of approved products, biosimilars, et cetera. Some attempts to add longer duration/less frequently dosed products, although certainly not in the same duration as a gene therapy approach. For the KOLs more broadly, where do they see 4D-150 fitting into the treatment paradigm initially upon approval and longer term? Is this a place we're primarily going to be looking for new patients that are diagnosed, patients that have a high injection burden, those who are most responsive to anti-VEGF least responsive. Like where and amongst which patients would you initially adopt, and where and amongst which patients would you use long term?

Thanks, Mani. Great question. Why don't we turn it over to Veeral initially and then Anat and Dante?

Yes. Great question. I think -- I think the data from the Phase III study is going to help really inform kind of where we position this. But at the same time, you can say if we're going to decrease treatment frequency, I think that's the real benefit to patients. So, as someone that's been part of these clinical trial programs in the past, I can tell you the feedback from the patients is, they want fewer injections, but they don't want to trade that off for outcomes. And at the end of the day, vision is very important for these patients. And so, let's say, for example, we see in this patient population, treatment naive in particular, that this treatment in particular does really well, reduces treatment burden significantly. I don't see why I wouldn't have this conversation early on in a world where this exists as one of those many options, as you discussed with that patient early on. And so I think treatment-naive patients, certainly, this is a conversation I will have. I think we have to see kind of how patients that are a little more difficult to treat respond to these treatments. I think we can easily see if this is going to still reduce treatment burden in those cases. I think this is still another option for those patients that are really more difficult to handle and manage that have been previously treated. So I could see it positioned there as well.

Thanks, Veeral, Anat?

Yes. So if you're asking where it will be in our armamentarium of treating our patients, I think that the first -- like with every other new treatment that has been shown as safe and effective in pivotal trials and then approved and then we start to use it. We first start with patients who are not responding well enough to other treatments. That is at least my routine. So I would first start with patients who are frequent flyers on other treatments or didn't respond well even to the newer regimens that we have. But as I get comfortable, I think it's a suitable treatment to give it to my patients who are early on during the management of their disease, because as we mentioned before, there isn't a single patient that I'm treating that is not asking, doctor, don't you have something with which I could get less injections and so forth, and also in some way reducing the risk of infection and not only reducing the burden. So, I think that even though I'll start with patients who are -- who need a lot of injections, I think later on, I'll be comfortable to continue with more -- with newer patients.

Thanks, Anat, Dante?

Yes, I think Anat really summed it up well. If you look at how retina specialists typically address a newly approved medication, we sort of dip our feet in the water. And so we're going to use this in these harder-to-treat patients. But I do think it's the PRISM data -- I mean, sorry, the Forefront data looks good. The patients are going to get 1 or 2 anti-VEGF injections, which is typical for the induction anyhow. And we're going to start a conversation with the patients during these injections that, "Hey, we have this other option here. It's an injection, you're have to use some steroids for a few weeks afterwards." But if the data looks good, we're going to reduce the burden of therapy by 80%, and there may be a 50% chance this is the only -- the final injection that you'll need for an extended period of time. So, I think that many of the patients given that option and knowing that it's a safe option, probably will go ahead with it. So, we'll be treating the more naive patients, I think, in a short order, assuming that the data looks good and the safety is comfortable for us and our patients.

Thank you, Dante. Next question?

Our next question will come from Jonathan Miller with Evercore ISI.

I'd love to ask more color on the new inclusion criteria details you've given for Phase III. In particular, I know you flagged that 1 patient in the broader Phase II that would have been screened out. But are any of the patients that required injection in the newly diagnosed subset of the Phase II, would those patients have been screened out by these new inclusion criteria? And then -- yes, and then I have a follow-up.

Thanks, Jonathan. Just quickly to answer that, yes, a few of those patients would have been screened out, including at least one who was receiving a few injections. Yes, so we do believe this new criteria will be even tighter and give us even better patient population for injection burden reduction.

And then I'd also like to ask on the supplemental injection criteria. You've added this vision plus anatomy criterion. You've loosened the anatomy-only criterion, I guess. Would you characterize these criteria as tighter or looser versus the Phase II, first of all? And second of all, are there any patients in the Phase II with the old rescue criteria that got a supplemental injection that would not have gotten that injection on the new criteria?

Sorry, just coming off mute. Jonathan, thanks for the question. So I think -- we believe these are optimized for the new patient population based on learnings from PRISM. And a number of those Phase III studies that we talked about with VABYSMO and SUSVIMO are actually designed by our team members. So they have a great degree of comfort with these and knowledge. And these are really set to protect BCVA as a primary endpoint and to maintain that high reduction in treatment burden we achieved in PRISM. So we would expect those not to change significantly. And when we apply those to our current PRISM patients, we don't see a meaningful change at all, if we were to apply the Forefront criteria. It's a little bit apples and oranges, but the best analysis we could do, there'd be no change. Bob, do you want to add anything to that?

Yes, the -- again, it's like apples to oranges in 4FRONT-1 and we're going to be talking about 100% naive patients. But when we do try to apply these criteria, we do filter out a few patients again from the Phase IIb recently diagnosed group. So it is a -- these are tighter eligibility criteria, but in terms of injections, as David said, there's not really a meaningful change.

Our next question will come from Clara Dong with Jefferies.

Congrats on the update. For the doctors on the call here, when you look at the numbers of injection-free rate and treatment burden reduction from the different patient subgroups, if you have to pick which number is more important for you for making treatment decisions? And also in a broad population here, there were 2 patients had supplemental injections based on investigator discretion. So, wondering whether you could provide some details on whether the decision was based on their vision or [ atomical ] change?

Thanks, Claire, for the question. So I think importantly, in an earlier-stage trial, physician discretion is allowed, but that is no longer allowed in Phase III, which is pretty standard. So it will be very, very rigorous BCVA and CST criteria to maintain that rigor in Phase III. In regards to which treatment burden reduction number is most important, whether it's overall treatment burden reduction or some specific injection-free number, maybe we'll turn it over to our experts. So maybe we'll go Veeral, Anat, Dante again. Veeral?

Yes. That's a great question. I think for me, it's overall treatment reduction burden because I think that's the way I counsel my patients. Whenever we talk to a patient about a new treatment, really, you want to set the expectation. And for the patients we've enrolled in these trials, for example, really what I think excites them about these treatments is just less injections over time. So that's really the one that matters more to me.

Anat?

Yes. I actually agree. I think that what patients are expecting now is mostly the treatment reduction. And I think that the way that the supplemental injection criteria is built in this trial, we'll really do that because -- or prove it because there are many options to give supplemental therapy. You can give supplemental therapy if you have a significant reduction in vision, it significantly increases CST or a smaller reduction of both, or any other threatening complications. So I think, if you take all of this into consideration and still there will be a reduction of burden, it will prove it for our patients, and it will achieve the goal.

Thanks, Anat, Dante?

Well, one of the things I always counsel patients is that I can't predict, at least based on intravitreal injections at baseline, what patient is going to need a lot, what's not. There's a lot of variability in this disease. But if I can tell a patient that with this product, we can reduce, on average, the treatment burden by 80%, I think that, as Veeral mentioned, I think this is very powerful. I think also to tell them that you might have, say, a 40%, 50%, 60% chance of not needing another injection is sort of the icing on the cake for me because that's the home run. But patients would like to hear that as well, and there'll be patients that achieve that. So, I think both of these are important things to discuss with patients as well as discussing the variability of response that we see, but that we can reduce, on average this variability, at least the treatment burden for these patients.

Thank you, Dante.

Our next question will come from Lisa Walter with RBC.

Congratulations on the data. I'm just curious if you have had an opportunity to share the wet AMD results with any strategics? And if so, what has the feedback been like?

Thanks, Lisa. It's clear to us, there's significant interest on the strategic side with potential partners. I think as a company, we're going to have to make a decision as to when and how to partner, if at all, but there's certainly significant interest. And I think the pharmaceutical companies in this space really get this target profile and think it's attractive for patients and attractive commercially. So there's certainly quite a bit of interest, and I'll leave it at that. Thanks for the question.

And there are no more questions at this time. I'd like to turn the call over to David Kirn for closing remarks. Well, thank you, everyone, for joining us today. We appreciate your interest, and thank you to Veeral, Anat, and Dante for joining us today and for your support. We'd also like to thank investigators, their staff, patients and their families, and finally, our dedicated and relentless team at 4D. Please do reach out to me or our IR team if you have any additional questions, and have a great day.