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

Hello, ladies and gentlemen. Thank you for standing by, and welcome to 4D Molecular Therapeutics' Webcast Presentation of Interim Data from the 4D-150 Phase II PRISM dose expansion cohort in wet AMD patients with severe disease activity and high treatment burden. [Operator Instructions] As a reminder, today's call is being recorded. With that, I will hand the call over to Uneek Mehra, Chief Financial and Business Officer, who will make introductory comments.

Thank you, operator, and welcome to our webcast. We issued a press release describing the 4D-150 PRISM clinical trial interim results on Saturday, Feb 3, and the recording of this webcast will be accessible in the Investors section of the 4DMT website after the completion of this call today. With me today are Dr. David Kirn, our Co-Founder and Chief Executive Officer; Dr. Bob Kim, our Chief Medical Officer; and Dr. Arshad Khanani from Sierra Eye Associates, and the principal investigator on the 4D-150 PRISM clinical trial who will discuss the data. Dr. Khanani presented the PRISM interim data on Saturday, Feb 3rd at the Angiogenesis, Exudation, and Degeneration Conference. We remind you here, we may be making forward-looking statements. For further details, you can visit our website. With that, I would like to turn the call over to our CEO, David Kirn. David?

Thank you, Uneek, and thank you, everyone, for being here with us today to discuss these exciting results from the 4D-150 Phase II PRISM clinical trial. Our focus today is wet AMD, which is the leading cause of vision loss in the elderly in the U.S. and Europe and drives an $18 billion retinal diseases opportunity. 4D-150, our lead product candidate for retinal diseases is the first intravitreal genetic medicine with a dual-transgene payload targeting 4 VEGF family members. This gene therapy utilizes our modular R100 vector, which we have invented at 4D to deliver transgene payloads to the retina with a single routine low-dose intravitreal injection. We shared positive interim data over the weekend from the 4D-150 Phase II PRISM clinical trial in patients with severe disease activity and a high treatment burden. The results met all of our study objectives. 4D-150 demonstrated a favorable safety profile with no significant or recurrent intraocular inflammation. Stable vision and improved retinal anatomical control were demonstrated. Finally, robust reduction in anti-VEGF treatment burden was demonstrated, especially at the 3E10 dose level. We demonstrated an 89% overall reduction in treatment burden and 84% of patients received 0 or 1 injection and 63% remained completely injection free. We believe 4D-150 is the first investigational ophthalmology drug to receive both FDA RMAT and EMA PRIME designations. These designations along with these positive data enable us to rapidly advance our pivotal trial program with a Phase III clinical trial expected to initiate in Q1 2025. Our balance sheet is strong with approximately $300 million in cash as of the end of December 2023, which is expected to fund operations into the first half of 2026. I'd now like to walk you through a comprehensive overview of our 4D-150 clinical programs. In wet AMD, we have the Phase I/II PRISM trial, so we are pleased to report that we have completed enrollment for all 3 cohorts in 2 distinct patient populations. I'd like to note that our Phase I and our Phase II cohort enrolled patients with severe disease activity and a high treatment burden. This patient population has not been adequately studied in previous Phase II wet AMD trials, including those that have been recently reported. In contrast to this dose expansion cohort, the population extension cohort has a broad range of baseline disease activity and treatment burden patients. We also have the ongoing Phase II SPECTRA trial in a broad population of patients with diabetic macular edema. We're pleased to report that we've completed enrollment of 22 patients in the dose confirmation cohort ahead of schedule due to high patient and physician interest. We're very encouraged with the safety profile of 4D-150 to date, including the lack of any significant inflammation reported from the 110 total patients treated as of the January 19 data cutoff. Now let's dive into how 4D-150 addresses important unmet needs. On this slide, we review 3 major limitations with standard of care treatments, all 3 of which could contribute to vision loss over time. First, current anti-VEGF treatments are not durable. Recurrent lifelong intravitreal injection regimens even with recently approved anti-VEGF agents are a significant burden on patients, on their families, on physicians and on the health care system. These burdensome regimens also lead to chronic undertreatment often due to logistical challenges for patients and their caregivers. Second, the standard of care, even again, with recently approved bolus intravitreal injection agents results in oscillating peak-trough anti-VEGF concentrations that lead to variability in retinal subfield -- central subfield thickness or CST. This CST variability can contribute to vision loss over time. Third, VEGF-C is an important driver of wet AMD and can lead to persistent disease activity in patients treated with VEGF-A inhibitors, and this target is not addressed by any of the currently approved agents. In summary, all 3 of these limitations with standard of care, repeated intravitreal anti-VEGF therapies can contribute to vision loss over time. We designed 4D-150 to overcome all 3 of these limitations, thus addressing patients' unmet medical needs with the potential to preserve vision over many years. First, invented the proprietary AAV vector R100 here at 4DMT using directed evolution. R100 was designed for efficient penetration from the vitreous through the inner limiting membrane barrier, which blocks other AAVs to transduce all layers throughout the macular following intravitreal injection. We believe that the sufficient delivery at lower doses than our competitors should translate into a highly favorable safety and efficacy profile. We then designed and inserted a dual-transgene payload that expresses both the aflibercept protein and an RNAi molecule to inhibit VEGF-C. Thus, 4D-150 is able to target and inhibit 4 VEGF family members, VEGF-A, B, C and placental growth factor. With 4D-150, we address the durability limitations of the current standard of care frequently cited as the greatest unmet need in wet AMD. 4D-150 has the potential for multiyear durability by driving continuous local and steady-state expression of our 2 transgene products following a single routine intravitreal injection. This is in marked contrast to the incremental durability improvements of several weeks demonstrated by new agents such as Faricimab, high dose Eylea and many other investigational agents. We believe that 4D-150 is potentially highly disruptive and could dramatically reduce the overall treatment burden in these patients. Here, we share published data showing the detrimental effects of oscillating peak-trough anti-VEGF concentrations, which can lead to variability in central retinal thickness. On the left, we illustrate both high variability from poorly controlled disease and low variability from well-controlled disease. Extreme oscillations in retinal thickness and anatomical instability may contribute to long-term vision loss as shown on the right, where higher variability in the first year of treatment predicted for greater permanent vision loss for patients. The goal of 4D-150 is to provide continuous local and steady-state expression of anti-VEGF molecules to maintain stability of the retina. This stability should drive long-term vision preservation. A third limitation with current standard of care is that they do not inhibit VEGF-C, which is also a potential driver of wet AMD and increases in response to VEGF-A inhibition. To address this, we added a second payload component within 4D-150 to express an RNAi molecule to inhibit expression of VEGF-C. In summary, I believe 4D-150 is well positioned to be a market leader for VEGF-driven retinal diseases because it is designed to overcome all 3 of the major limitations with current therapeutic regimens. And this has the potential to preserve vision over the long term with a safe routine onetime intravitreal injection. I'd now like to hand the presentation over to Dr. Bob Kim to go over the trial design and baseline characteristics of the trial. Bob?

Thank you, David. I'd like to start by discussing how to think about wet AMD patient population, since AMD is a heterogeneous disease comprised of different populations, which in turn is important to understand when designing clinical trials and interpreting results. First, you can see here on the X-axis, we have retinal CST, which reflects disease activity. Higher numbers mean thicker, more swollen retina and more active or severe disease. Normal CST is about 280 microns. On the Y-axis, we have the actual number of injections that patients received in the preceding 12 months as opposed to an annualized rate, which indicates their treatment burden and reflects how difficult their disease is to control. Now, when we look at baseline characteristics of other Phase II wet AMD trials involving treatment-experienced patients, we note that they had mean CSTs in the normal range, which is evidence of well-controlled disease at baseline. Average actual injections in the preceding 12 months was reported to be roughly 4 to 5 in some of these trials. Now, let's look at the patients enrolled in our Phase II dose expansion about a mean CST of around 440 microns and required about 10 actual injections in the prior 12 months. We consider these as patients with severe disease activity and high treatment burden who are among the most challenging to treat patients. We enrolled these patients by design in this Phase II PRISM cohort. Since these patients have the highest unmet need despite standard of care injections, we believe 4D-150 has the potential to be transformative for these patients. In addition, strong clinical activity in these hardest to treat patients should be predictive of strong activity in the broader patient population. As David mentioned earlier, we have recently completed enrollment of our population extension cohort to evaluate 4D-150 in a broader patient population as well. Here, we show the design of the Phase II PRISM dose expansion cohort, which is a multicenter, randomized clinical trial evaluating safety and clinical activity of 4D-150. We designed the inclusion criteria to focus on the highest unmet need patients based on disease activity measured by CST greater than or equal to 325 microns and presence of subretinal or intraretinal fluid as well as an anti-VEGF injection treatment burden of 6 or more actual injections in the prior 12 months. In addition, patients also required best corrected visual acuity at screening of 34 to 83 letters. After enrollment, patients were then randomized 2:2:1 to receive 4D-150 at a high dose of 3E10, a low dose of 1E10 or aflibercept 2 milligrams every 8 weeks control. This slide shows the clinical trial design. All patients received aflibercept on day minus 7. Patients in the 4D-150 arms initiated a 20-week prophylactic topical corticosteroid taper on day minus 1. Patients in sites knew if treatment was 4D-150 or aflibercept, but they were masked to the dose of 4D-150. Study endpoints include safety and tolerability, change from baseline in BCVA and CST and proportion of patients requiring supplemental aflibercept. The criteria for supplemental aflibercept are listed on the left. All arms were eligible to receive supplemental aflibercept if the criteria were met. Today, we'll be sharing a landmark analysis at 24 weeks for all patients based on a data cutoff of January 19, 2024. This table summarizes the key baseline characteristics of the 51 patients enrolled in our Phase II dose expansion cohort. Overall, the arms were well balanced. But of note, patients enrolled in the 3E10 arm had more chronic disease. I would like to point out that patients had a mean CST of 442 microns, highlighting severe disease activity. This was despite receiving an actual number of nearly 10 anti-VEGF injections in the prior 12 months, reflecting unambiguously highly active disease. These baseline characteristics are much higher than in other Phase II study extended delivery of anti-VEGF agents. I'd like now to hand the presentation over to Dr. Arshad Khanani, a lead investigator of the PRISM clinical trial to present the data. Arshad?

Thank you, Bob. I'm pleased to report today that 4D-150 met all objectives we set out to achieve in this severe and difficult-to-treat patient population. As a single routine intravitreal injection, 4DMT achieved a favorable safety profile with no significant or recurrent inflammation. We signed 89% overall reduction in anti-VEGF treatment burden, 84% of patients receiving 0 or 1 injection and 63% of patients remaining injection free in the 3E10 dose arm. In the aflibercept control arm, we saw substantial CST fluctuations on OCT, while in the 4D-150 arms, we saw minimal fluctuations showing the potential of sustained expression from a single injection of 4D-150 in patients with severe disease activity and high treatment burden. In addition, Phase I data shows the potential of long-term disease control with 4D-150 through up to 2 years of follow-up. Now let's review the recent data I presented at Angiogenesis. For any new treatment, safety is a priority. In terms of safety, 4D-150 demonstrated a favorable safety profile with no significant or recurrent intraocular inflammation. Notably, high-dose 3E10 group had no grade 1 or higher inflammation. 97% of patients completed the 20-week topical corticosteroid taper on schedule. At the low dose, only a single patient had 1+ mixed anterior chamber cells at week 16, which resolved by the next visit. The patient completed their steroid taper by week 26. All patients are currently off steroids through up to 48 weeks of follow-up, with no patients having to resume steroids after their taper was completed. There were no 4D-150 related SAEs or study eye SAEs. There were no cases of hypotony, endophthalmitis, retinal vasculitis, choroidal effusions, or retinal artery occlusions. Comprehensive ophthalmic examinations were done at every visit to look for interior chamber cells or vitreous cells. Each row represents a patient, each column represents a visit, and each box represents the SUN score for that visit. Again, no clinically significant or recurring intraocular inflammation was observed in this trial. Looking at BCVA, stable visual acuity was observed through week 24 in this wet AMD population with severe disease activity and high treatment burden. Because patients are eligible to receive supplemental aflibercept at any time point and patients receiving aflibercept received an injection every 8 weeks, the difference versus aflibercept was averaged at week 20 and 24, consistent with many other studies. Looking at those results, a mean change compared to a aflibercept was -1.8 and +1.8 letters for the high and low dose arms, showing that the visual acuity was stable in all groups with 95% confidence intervals or lapping at every time point. Let's look at CST to evaluate for disease activity as measured by OCT. Patients on their aflibercept arm showed high variability and fluctuations of up to 100 microns in their CST. This variability is more than that has been described in other wet AMD trials, highlighting that this trial enrolled patients with very severe disease activity. Now looking at the CST in the 4D-150 treated patients in contrast to the fluctuations in retinal thickness observed in their aflibercept arm, CST remained relatively stable through the 24-week period in both dose levels of 4D-150. At the 3E10 arm, the overall magnitude of change from baseline to week 24 was similar to that in participants receiving bimonthly injections of aflibercept. Also, it appears that the CST and the 3E10 dose at all time points was lower than aflibercept control, very close to the trough and the CST seen 4 weeks after aflibercept injection, highlighting the benefit of sustained expression with 4D-150. Here, we show the robust reduction in treatment burden for these patients. At the high dose level, we observed an 89% reduction in mean analyzed anti-VEGF injections. At the low dose level, we observed an 85% reduction. Here are the swimlane plots for individual patients showing the pre-enrollment anti-VEGF injections on the left and the supplemental anti-VEGF injections on the right for both treatment arms. At week 24, the annualized anti-VEGF injection rate in the high dose group was reduced by 89%, 84% received no injection or only one injection and 63% of patients remain injection free. The low dose also demonstrated similarly strong reduction in treatment burden. Now, I would like to share some specific patient examples to highlight the benefit of 3E10 dose of 4D-150 in these chronically treated patients. First patient is the one who was on monthly ranibizumab injections. Second one is a patient who received monthly aflibercept injections. And the third patient who was receiving bimonthly Faricimab. As you recall, these patients were required to have fluid at screening, which indicates that they were not well controlled on these treatment regimens. After 4D-150, all of these patients have been injection-free. As a busy retina specialist, I am excited to see these results. These data highlight the benefit of a single intravitreal injection of 4D-150 in these highest treatment burden patients with wet AMD. Finally, we would like to provide an update from the Phase I dose exploration cohort of PRISM and specifically durability in our injection-free patients at the high-dose level. Safety continues to be maintained in all 15 patients with no new inflammation since the last update. In terms of durability, the 3 patients in the high-dose arm that for injection-free beyond 1 year remain injection-free through week 80 to 104, highlighting the emerging long-term sustained benefit of 4D-150. We come back here to the summary slide. 4D-150 achieved all of our objectives in this clinical trial, including safety, efficacy and long-term durability. I am excited to work with the team at 4DMT on the Phase III planning for this promising onetime dual-transgene intravitreal therapy. I will now hand it back over to David to discuss the next steps.

Thanks, Dr. Khanani. The excellent results we showed today validate our belief in the potential of 4D-150 to be a highly disruptive product in the neovascular retinal diseases market and paves the way for Phase III development. Given the robust clinical data and ongoing discussions with the FDA and EMA, we have decided to run a Phase III non-inferiority trial based on BCVA, evaluating 4D-150 versus a control arm of aflibercept 2 milligrams every 8 weeks. The non-inferiority margin for FDA and EMA is 4.5 and 4 letters, respectively. Based on the totality of the results to date, we have selected 3E10 vg/eye as our pivotal trial dose. We expect to enroll approximately 225 patients per arm. We expect to enroll a broad population of wet AMD patients, including patients with severe disease activity and a high treatment burden. We're also thrilled to have received both RMAT designation from the FDA and PRIME designation from the EMA for 4D-150 and wet AMD. These designations enable increased collaboration between the 2 agencies and an opportunity for expedited product development. To our knowledge, we're the only ophthalmology product candidate to ever receive both designations. We expect additional regulatory interactions in Q2 this year, and we plan to provide an update on these discussions to finalize the Phase III design in Q3 2024. We expect to initiate our Phase III clinical trial program in Q1 2025. Now, looking ahead to Phase III, we applied our preliminary Phase III eligibility criteria for CST and BCVA to the Phase II dose expansion cohort. The criteria focused on patients with CST less than 500 microns and BCVA of 40 to 78 letters. This excluded 4 outlier patients from the aflibercept arm and 4 outlier patients from the high dose arm, but still represented overall a high disease severity and high treatment burden population. Of note, the patients on aflibercept every 8 weeks were still not well controlled on this study in this population. When we compare both arms, we see BCVA for the high dose, 4D-150 was 3.3 letters higher than aflibercept. We also see a near 100 micron benefit in the high-dose arm versus aflibercept on CST. The mean CST over time is stabilized in the high-dose arm versus the oscillating CST and aflibercept control arm. This data once again highlights promising sustained disease control with high-dose 4D-150. We also continue to see excellent reductions in anti-VEGF injections as shown on the right, with a 90% overall reduction in annualized injection rates, 88% of patients receiving 0 or 1 injection. We believe these data are highly supportive of our advancement of 4D-150 into Phase III trials. I'd now like to conclude by highlighting the upcoming milestones for our ophthalmology program. As you can see on this slide, we have many important upcoming milestones in 2024. Before I open up the call to questions, I want to take a moment to thank the entire 4DMT team for their remarkable innovation, execution and dedication. I'd also like to deeply thank our investigators, clinical trial staff, patients and their families. Thank you. And I'm happy to now open the call up to questions. Operator?

[Operator Instructions] Our first question comes from Josh Schimmer from Cantor Fitzgerald.

Congrats on the early exciting data. Three quick questions. First, what are the gating steps to starting the Phase III trial? Second, which manufacturing are you going to be using? Do you to expect this role for the wet AMD indication be in-house or will be using a CDMO? And where are you in terms of scaling up for clinical and commercial supply? And then the third question is for those patients who didn't -- who did need additional injections of anti-VEGF therapies, is there any way to discern whether it was an issue with maybe the original transduction in those patients just not being as robust or whether the treatment effect was wearing off, or whether they just had to active a disease process for the therapy to really impact this meaningfully?

Thanks, Josh, for the question. I'll answer the CMC question first and then turn it over to our CMO, Bob Kim, for the Phase III gating question and the response question. On CMC, I think one of the great strengths of this company is we have an incredible CMC team. We manufacture all our clinical trial material in-house in our own manufacturing facilities. For this study, we'll be manufacturing the material in-house at commercial scale and with the commercial process such that we'll have a seamless transition to a CDMO in the future down the road for commercial supply using the exact same process and at commercial scale. So we feel really good about that, and that won't be gating for Phase III initiation. I'll now turn the questions -- other questions over to Bob regarding Phase III gating and responses.

Yes. So regarding steps towards Phase III, we've had some very productive initial interactions with both the FDA and EMA. And as we've shared, we have a general alignment on the initial study design of a noninferiority study. There are some details that we are going to be working out with these agencies, and this will be facilitated by the RMAT and PRIME designation that we've obtained. So basically, at this level, we're just sorting out details. Regarding your question about rescues, I think we're not worried that there's differences in transduction. We think that wet AMD is a heterogeneous disease and that some of these patients just have disease, as you put it, that's just too active to overcome.

Our next question comes from Nalin from Jefferies.

Congratulations on the results. For DME, previously, you stated that the starting dose in Phase II was going to be 5E9 vg/eye. And now it looks like you're evaluating 1E10 and 3E10. Could you please talk us through that decision? Is it a reflection of good safety profile? Or maybe is sufficient efficacy seen in DME so far at 5E9 or perhaps is this an attempt to go at a higher dose for potentially increased durability to avoid redosing?

Thanks, Nalin, for the question. I'll answer that quickly. It's all about safety. We've seen great safety at 3E10. We're thrilled that there were no grade 1-plus or higher episodes of inflammation of the high dose in this study. And we've now treated 110 patients across all of our studies with various varying degrees of follow-up, and we've seen no significant inflammation across the 110 patients. So we're thrilled with the safety, and that allowed us to very quickly go to the 1E10 and 3E10 doses in DME.

And as a follow-up -- sorry, second question, could you please talk us through your statistical assumptions for Phase III with 225 arm -- sorry, 225 patients per arm, what is that accounting for? Is it going to be 4.5 letters for EMA guideline?

Good question. So you pointed out the different non-inferiority margins at the different regulatory agencies have required and the 4.0 margin is more challenging than the 4.5. So the 225 patients per arm is -- should -- provides adequate power to cover the tighter 4.0 inferiority margin.

Our next question comes from Salveen Richter from Goldman Sachs. We'll return to Salveen, and we'll take a question from Jonathan Miller from Evercore.

Congrats on the data. I wanted to ask about that look at the Phase II data when cut by the Phase III inclusion criteria. Now the Phase III obviously includes a broader population than this Phase II, is it fair to assume that among patients with less severe disease at baseline than were included in this Phase II, maybe some of that lessening of the sawtooth or the benefit on BCVA might be less apparent in those patients where there was less disease at baseline. Is that the right way to think about it? How do you expect the various endpoints to change as you look at a broader, less severe at baseline population?

Thanks, Jonathan. I think we'll have our CMO, Bob Kim answer that question.

Right. So I think regarding the sawtooth pattern, it was quite dramatic. The magnitude of the swings was -- it approached 100 microns. And that's kind of unprecedented regarding the swings that described in other anti-VEGF studies. I think as we -- and it reflects the extremely, I think, refractory disease in these patients. As we broaden the population, I think we would expect the swings perhaps to be a bit smaller on average. But nevertheless, we expect the stabilizing effect on fluctuations to persist in 4D-150 treatment.

Great. And on maybe some of the other end points, would you expect VEGF injection freedom to be higher? Would you expect VEGF injection burden to be -- how would you expect those other key endpoints to change?

So regarding injections, it's kind of hard to improve on a 90% reduction in the annualized injection rates. We're hopeful that we might see an improvement in the injection free rate, but we'll be exploring that in our population extension cohort. And hopefully, we'll be able to share that with you later this year.

Our next question comes from Matthew Caufield from H.C. Wainwright.

Obviously, a very exciting update. So with the minority of patients not injection-free through 24 weeks, what are your thoughts around prospective redosing down the line? And is this something at all that you're potentially thinking about for Phase III?

Thanks, Matthew. Sure. The injection free rate is 63%. So that's well over 50% injection-free. And 84% of the patients had either 0 or 1 injections. But perhaps Arshad Khanani would like to comment further on that point.

Yes, absolutely, David. Good morning, everyone. So I think we know that it's a very variable heterogeneous disease. And in this highly severe patient population with a very high treatment burden, that's why I highlighted those patients that these were worst of the worst patients in our clinic. And I think as it goes into broader patient population, we expect those numbers that David just gave to actually improve in my opinion, because I've seen that in other studies with sustained delivery as we participate in all the clinical trials that are happening. In terms of redosing, I'll pass it to Bob. I don't expect to read those gene therapy. I think as long as I am helping the patient either completely resolve their disease or decrease their treatment burden significantly, I think this treatment has the potential to be broadly utilized in a busy retina practice. But Bob can comment on redosing of 4D-150.

Right. At this time, the benefit that we're seeing in the severe population is actually very exciting. The fact that we're seeing any supplemental injection-free patients regard as a big success. And those patients who are receiving rescues for the most part seem to be doing much better than they were beforehand. So we're -- in this population, we're delighted with the activity that we're seeing. Something that we will be exploring at some point, it's something both the regulatory agents have asked us since wet AMD can affect the fellow eye is that we will be coming up with a plan to address second eye treatment.

Our next question comes from Salveen Richter from Goldman Sachs.

Can you hear me?

Yes.

Perfect. Congratulations on the data here. Just 3 quick questions for me. One is whether there's any efficacy data beyond week 24 that you can provide to help us better understand the longer-term outlook here? And then could you comment on physician feedback at the medical meeting? And then finally, how you're thinking about positioning the drug on the forward here in the treatment paradigm?

Well, I'll take the first one quickly and then turn it over to Arshad for the next question. So in terms of safety and efficacy, this is a 24-week landmark analysis, but this is obviously an open study, and we feel very good about what we're seeing beyond 24 weeks and feel like the durability has been excellent overall with 4D-150, including in our Phase I patients out now 1.5 years to 2 years with stable CST and BCVA and those patients remain injection free, those 3 patients from Phase I. In terms of safety, we've given high-level safety update through week 48, which is the most follow-up that we have on these patients. And again, there's been no significant inflammation or recurrent inflammation and all patients remain off of steroids, which is really a remarkable safety profile. I'll now turn it over to Arshad Khanani for the other -- to answer the other questions.

Thanks, David. So when I presented the data, I got numerous messages right away after the data was presented. And I think the #1 thing, as I said, for our field is safety is a priority. And the reason is we have agents that were great and have a good safety profile. So any sustained delivery product that is going to be widely adapted has to have a very favorable safety profile. And looking at the data we have seen with Phase I and Phase II patient population, gives me quite confidence that the safety profile we have seen is very, very good. And the reason is not just that patients receive 20 weeks of steroids, and we saw only 1 patient with mixed cell in the low dose, but rather that there was no reinitiation and that's something that's key for the field because you don't want to have a gene therapy that will decrease intravitreal injection burden, but you stay on steroids for several years. So I think that's the key. So I think the safety data was very, very exciting. And then piggyback to that, looking at the efficacy in these severe patients, we have these patients in our clinic on a daily basis. And no matter what you do, you give them monthly anti-VEGF injections of potent drugs like Faricimab and Eylea and they still have fluid and they fluctuate throughout. They will have less fluid a week later, but at 1 month, they have severe amount of fluid. And seeing that stability of OCT is very exciting because in clinical practice, that's how we treat disease. So overall, very, very positive feedback from my fellow retina docs that attended the angiogenesis meeting virtually. So I'm really thrilled to be a part of this. And together, we are going to hopefully change the course of treatment for our patients by taking this program in later phase studies. And I'm excited to be a part of the Phase III trial that's going to launch Q1 of next year.

Our next question comes from Geulah Livshits from Chardan.

Congrats on the data. So you mentioned the safety that you've seen so far across 110 patients. I think the FDA has some recommendations regarding the size of the safety database at the relevant dose, [indiscernible] guidance, I think it's around [ 400 ] or so. So can you talk about how your current set of programs will let you get there at the 3E10 level?

Thanks, Geulah, for the question. We'll turn that over to Arshad Khanani and then Dr. Bob Kim. Arshad?

Yes. I mean I think you have to look at the totality of data. And I think what we have seen in gene therapy program is that if there is a safety issue, it will show up within the first year, if not earlier. What usually happens is that as patients are tapering steroids to over time, if there's a safety issue the inflammation will recur. So in this case, we have not seen that. And I think that's why I feel confident in the safety data set we have so far because gene therapy, the safety is dependent on vector. And this vector is retinotopic. We are not seeing too much transfection in the front of the eye. This vector can as dual-transgene, and we are using very low doses and that really helps also. And the prophylaxis regimen, the topical steroid appears to be working very, very well. So if we had any safety issues, it will show up during the tapering or right after the tapering and we have not seen that so far. So I think that is, to me, shows that the safety we have seen so far gives us confidence to move forward. And I'll pass it to Bob for the other answers.

Thanks, Arshad. From a regulatory point of view, generally, I'd say, these guidelines are that you need at least 400 treated patients and 300 patients treated at or above the to-be-marketed dose for in the case of wet AMD, at least 12 months. So we mentioned a Phase III sample size of about 225 patients per arm. And if you were to have 2 studies, you'd have 450 patients. So that's well above the requirement. And all the patients that we've treated in our Phase I/II PRISM study will count as well. And for safety, also the patients in DME will be relevant. So no problem covering the safety requirement.

So thanks for the question. And just to reiterate, I think for Phase III, really, at this point, it's about aligning EMA and FDA on final details of the protocol. And then it's all about operational start-up, which will take about 5 months to 6 months once that protocol is finalized. Thanks for the question, Geulah.

Our next question comes from Mani Foroohar from Leerink.

A little more on operational question. Wet AMD studies, the pivotal setting can be quite broad, and obviously, this is the sizable global market. How should you think about the geographical footprint wherein you'd study patients? And how do you think about the puts and takes around whether or not sort of a global commercialization partner in at least some geographies make sense?

Thanks, Mani, for the question. So I'll answer the operational question quickly, and then we can speak to opportunities for business development outside of that. So we have the opportunity to run either global studies or U.S. only followed by global study. There are 2 studies. I think right now, we're believing that our program will be global and that, that would support global regulatory filings. We're committed as a company to commercializing 4D-150 and our other large market ophthalmology products in the U.S. on our own. That's core to our business plan. But outside of the U.S., we see opportunities for potential partnerships. And I'll turn it over now to Uneek Mehra, our CFO, to comment on that.

Yes. Thanks, Mani. I think we've indicated earlier publicly that we have an interest in finding the right partner ex U.S., both from a capabilities perspective on the development and more importantly, on the commercial side. As you've rightly noted, ex U.S. market is a pretty big market. It's a large market disease even in those geographies, so Europe, Japan and some of the Asian continents present a great opportunity. We have received significant interest in terms of partnership interest and we are prosecuting those both on the dimensions of those capabilities, the ex U.S. Thank you.

Great. And just one quick follow-up. We're going to be -- you're going to be accumulating a fairly substantial database of patient experience in this market, which obviously reflects applications of this -- of your vector across other ophthalmology indications. Beyond those places where current anti-VEGF therapies are used, how do you [ finish ] -- how do we think about indication expansion into other areas of ophthalmology?

Well, we think the R100 has vector shown great safety and activity across a range of different disease indications, including not only wet AMD but also in rare monogenic diseases. And we're also excited about 4D-175, which is our geographic atrophy agent for -- that will be entering clinical trials in the second half of this year. So we think that this should be great read through with the R100 vector in terms of safety and activity and also just speed of development. The manufacturing process for each of these products is identical. And this is a very modular platform that we can leverage for efficient development.

Our next question comes from Kostas Biliouris from BMO.

Congratulations on the great data. Maybe a couple of questions from us. One, on the BCVA -- sorry, on the CST trajectory. I'm wondering what do you think the steady state of CST will end up being given what you see there? And would it be ideal to be at 0, given that you have a loading Eylea dose at the beginning? And any comments around the steady state of CST that you would like to see here would be helpful? And then I have a follow-up.

Thank you, Kostas for the question. Arshad, would you like to take that question?

Yes, absolutely. As clinicians, we are -- our goal is to stabilize CST. And as you saw, the fluctuations are significant in the control arm. So you know that these patients are the most severe and have very high treatment burden. So when I look at the CST curve, I'm looking for relative comparison to aflibercept and where the CST of 4D-150, 3E10 is landing. So if you look at those graphs, you see that the CST achieved with 4D-150 is actually close to the trough that's seen 4 weeks after the aflibercept injection. So that tells me that you're having steady state of anti-VEGF that is controlling the disease. We all know as clinicians, that peak and trough in CST shows, of course, uncontrolled disease but also can lead to visual acuity decline over time. So when I'm looking at the [ trans ], I'm actually looking at the comparison. And then if you look at the Phase III population by excluding the outliers, you see a huge difference between the group. So I think that's what I'm comparing with because this is the patient population that is so severe that sometimes you can't even control them. Many of us even try every 2-week injections in this kind of patient population and they are not controlled. So overall, looking at that, I think we are getting a very steady state and very good disease control. And I think that's why I'm excited that in patient population that is going to be broad, we'll be able to do even better than aflibercept that what we have seen in the Phase III subset analysis.

Very helpful. And maybe a follow-up, and sorry if I missed that, but have you looked at aflibercept levels in patients who received gene therapy? And if so, have you observed any differences among patients who maybe the rescue injection versus those who are injection -- rescue injection fee?

Thanks, Kostas. The answer in Phase I, we looked at that and we reported out data at 12 weeks of aflibercept expression. We saw a really nice dose response there and levels that were consistent with preclinical modeling for a high degree of efficacy at those levels. Now what's important about this therapy is what we are achieving is sustained continuous steady state local concentrations in the retina, which is really a game changer as compared to this bolus anti-VEGF therapy with the peaks and troughs. So as Dr. Khanani mentioned, that should translate into long-term vision preservation that we're very excited about. And I think a lot of this data has led to excitement at a high speed of enrollment in these Phase IIs. And maybe Arshad, I don't know if you'd like to comment on speed of enrollment in these Phase IIs and how that might translate to Phase III.

Yes, absolutely, David. I think there was so much excitement about this program that we had many patients who are waiting in the back of to enroll at a record time. If I have a patient that is getting anti-VEGF injections, their first question is, is this a lifetime disease? Do I need to come every month or every other month, even with second-generation treatments like Faricimab, we have a good subset of patients that require frequent injections monthly or every other month. And I think as we plan Phase III and recruit, we will actually start planning in advance because I know that it's going to recruit really fast because these are previously treated patients, they know what injection burden looks like and having a treatment that can eliminate the need for any future injections in more than 50% of the patients and decrease the treatment burden significantly. And this is an in-clinic treatment. So I think this is going to enroll very fast as we launch it. And I think just looking at even your DME program, we had patients waiting because it enrolled the initial cohort so fast. So I'm excited about the fact that physicians are excited because we all have these patients that have a very high treatment burden, and they want to do anything to eliminate that.

Our next question comes from Lisa Walter from RBC.

Great. And congrats again on the data. So first one, we have seen one of your competitors at [ Baram ] this morning doing a pipe, and their data is obviously coming on Thursday. Just wondering what are your expectations for that data? And how are you thinking about differentiation versus them? Any color on that much appreciated.

Thanks, Lisa. We're confident that our therapy has shown a high degree of safety with a very clean safety profile. We think that's why we're getting such great high rates of enrollment and why we achieved both RMAT and PRIME designation, we believe we're the only ophthalmology asset to ever have those 2 designations. So we're very excited about the future and operationalizing Phase III. We don't worry so much about our competition here. We think our product speaks for itself. We think we're the only product that's shown this kind of activity in this patient population with very severe disease activity and a high treatment burden, and we think it's highly differentiated product profile. Thank you for the question.

Got it. I have one follow-up. Just on your Phase III, I know you've already flagged that 2 mg aflibercept once every 8 weeks is a possible control arm, which is in line with the FDA's guidance document, but given how standard of care is evolving, I'm wondering if you are also considering Vabysmo or Eylea HD as a control as well.

Yes. We're comfortable with the standard, Eylea. It's very clear from FDA feed and the EMA feedback that, that's an acceptable and appropriate regimen. And I'll turn it over to Bob Kim, our CMO.

Yes. So the noninferiority margin, it's kind of like the antibiotic problem. You need a reference drug. And so the agency has designated ranibizumab and aflibercept as reference drugs where there's a non-inferiority margin established about 4.5 letters. The problem is drugs that follow are noninferior to one of those drugs. And what the agency tries to avoid is noninferiority to noninferiority, stacking noninferiority. So at the moment, we're not aware that there's any noninferiority margin established, for example, for Vabysmo or high-dose Eylea. So we kind of have to work with one of those reference drugs at the moment.

Next question comes from Josh Schimmer from Cantor Fitzgerald.

So during the conference session a couple of times, the idea of home OCT monitoring came up. Just curious to better understand what would be involved with home OCT monitoring and how feasible do you think that will ultimately prove to be and what time lines there might be for that becoming an option for patients.

Thanks, Josh. Arshad, do you want to take that one?

Yes, absolutely. So in a prospective clinical Phase III study, you want to see those patients on a routine monthly basis in most cases. I think mostly the OCT is exciting. But I think that's something that can done into long-term follow-up studies are as a sub-study in the Phase III. So we still need the OCT data. We still need to do the examination of the patient. So OCT is exciting, but it's not something they utilize in pivotal studies as a primary modality to monitor fluid but rather more in the extension phase or as a sub study to look at utility. And as you know, a large DRCR trial is happening looking at the use of home OCT. Now once this product is commercialized, absolutely. I think the goal would be that we know that patients, majority of them will not need injections. So if a patient gets one treatment and is doing well, they can monitor themselves at home OCT and as soon as if there is any activity, we can call them back in clinic. So that's going to reduce the treatment burden even more. And that's why sustained delivery and gene therapy is very exciting because you can use home OCT to kind of even decrease the burden even more. And I think that will lead to better and stable visual outcomes in the real world for our patients. So a very exciting idea.

So would there be expensive equipment that patients need to have at home? How would they be trained to use the device appropriately?

Yes. So those are questions that are out of the context for this, but we are doing those in sub studies and other programs where the company that makes the OCT, trains and sends the equipment. So not part of this discussion. And I think they have their own validating studies going on to get a home OCT approved. So that would be some discussion that will be more geared towards that company's planning. But here, I think we see a sustained delivery effect, which will decrease treatment burden and any technology we can use to decrease treatment burden in combination of gene therapy is very exciting.

Our final question, we'll return to Mani Foroohar from Leerink.

I think there's a lot of debate around, as mentioned, some of the ways this market could evolve with home OCT. Can we talk about presuming that, that does not result in the broad shift in the market and practice patterns continue to look kind of like what they look like now? How frequently would patients be brought back into the clinic based upon this product profile?

Arshad?

Yes, absolutely. So I think home OCT is not going to change the number of anti-VEGF injections that we are giving with Vabysmo high-dose Eylea, it is going to help patients who have already received gene therapy or sustained delivery to even come less often to our clinics. So I think in terms of utilization of gene therapy is not going to change. Remember, home OCT is just showing fluid accumulation at a nanoliter level, and then you can bring those patients in. So I don't expect clinical decision-making changing because of home OCT, but rather decreasing treatment burden for our patients who are utilizing sustained delivery. But if a patient needs to come in every month or every 2 months to get their bolus anti-VEGF injections, home OCT is not going to change it. In terms of like how often I'm going to follow these patients, obviously, I'd like to follow them during their steroid taper stage. And then at that time, we'll be collecting OCT data and then seeing how the disease is stabilized. I'm very confident that once the disease is stable in the first 4 months to 6 months after getting 4D-150, then I think you can kind of find which patients need to come to clinic or not and majority of them were not required to come in clinic. And at that time, we can launch home OCT to kind of let the patient monitor and then bring them in when the fluid accumulates. So I think this will really help patients come in very minimally to our clinic because of the sustained delivery that we are seeing in sustained disease control. And then I think physicians will independently based on their specific patient individualize the follow-up. But I do see significant decrease in treatment burden, utilizing home OCT once the patient is stable and well controlled with 4D-150.

There are no more questions in the queue. I would like to hand the call back over to Dr. David Kirn for closing remarks.

Thank you, operator, and thank you to all of our analysts for the excellent questions today and really stimulating discussion. Thank you to the audience and also to our 4DMT team for participating today. In summary, we're very excited about 4D-150 and its ability to potentially disrupt and transform the wet AMD market. We see clean safety and now approximately 110 patients treated to date, a high degree of efficacy in severe disease activity and high treatment burden patients. And we're excited to be operationalizing the Phase III clinical trial for initiation in Q1 2025. Our goal has been to disrupt and transform the treatment of wet AMD, and we think that this 4D-150 data to date gives us confidence that we're on that track, and we'll make that a reality for patients. So thank you all for your time. And again, thank you, Dr. Khanani for your support today in this call.