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 safety and efficacy data from the Phase I/II PRISM clinical trial of intravitreal 4D-150 in patients with wet age-related macular degeneration. [Operator Instructions] As a reminder, today's call is being recorded. With that, I will hand the call over to August Moretti, Chief Financial Officer, who will make introductory comments.

Thank you, operator, and welcome, everyone, to 4D Molecular Therapeutics 4D-150 interim data webcast. A press release describing the results and development plans related to 4D-150 is accessible in the Investors section of the 4D Molecular Therapeutics website, and a recording of this webcast will be accessible on our website after completion of this call. 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, Managing Partner and Director of Clinical Research at Sierra Eye Associates and Clinical Associate Professor at the University of Nevada, Reno. Dr. Khanani is a principal investigator on the 4D-150 PRISM clinical trial. He will present the interim PRISM data today at the 2023 ARVO Annual Meeting. As a reminder, on this call, we will be making forward-looking statements regarding our clinical data from our PRISM clinical trial, product development plans, research activities and business plans. These statements are forward-looking statements and are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to materially differ from those forecasted. A description of these risks can be found in the Risk Factors section of our most recent Form 10-K and Form 10-Q, which are on file with the SEC. With that, I'd like to turn the call over to our CEO, David Kirn. David?

Thank you, Augie, and thank you, everyone, for joining us today. We're pleased to share with you updates on 4DMT's 4D-150 program, including positive interim clinical data from our PRISM clinical trial. As many of you know, our platform is based on directed evolution technology to design customized vectors with superior therapeutic profile compared to wild-type vectors. To date, we've demonstrated human clinical proof-of-concept for our platform with 3 vectors in 3 therapeutic areas. We're currently developing 5 clinical stage products for 7 patient populations, and our strategy is to become a fully-integrated large market genetic medicines company. Our efficient product design and development engine has powered a broad and deep pipeline. Each therapeutic area leverages a proprietary and optimized 4DMT vector plus our product development engine. Today, we'll focus on 4D-150 for wet age-related macular degeneration or wet AMD. This product is also being developed for diabetic macular edema or DME, and 4D-175 is our preclinical product for geographic atrophy. As a reminder, 4D-150 was designed as a single routine low-dose intravitreal injection to deliver a payload for expression within the retina that constitutively expresses 2 therapeutic products targeting 4 VEGF family members. Now, let's share our key takeaways for today. We're presenting interim data for all 15 patients enrolled in 3 dose exploration cohorts, 5 patients each at 3E10, 1E10 and 6E9 vg/eye. Over 12 months prior to enrollment, these patients were confirmed to be heavily dependent on anti-VEGF injection. Follow-up at the time of data cutoff on April 3rd was from 24 to 64 weeks. Key clinical data findings are as follows. Regarding safety and tolerability, 4D-150 was well tolerated at all 3 dose levels at all time points and in all 15 patients through 24 to 64 weeks. 14 of 15 patients had 0 evidence of inflammation by all 4 different eye examination endpoints. A single patient had only trace mixed cells at a single time point that resolved without intervention. No dose-limiting toxicities, 4D-150-related SAEs or hypotony were reported. Now for clinical efficacy data. Clinical efficacy data was available on all 15 patients through a maximum of 24 weeks. Clinical activity was demonstrated at all 3 dose levels. The dose response was observed in favor of the high 3E10 dose level based on supplemental anti-VEGF injections and central subfield thickness or CST on OCT scans. 80% or 4 of 5 patients in the 3E10 cohort were completely injection-free compared to 40% or 2 of 5 patients at each of the 2 lower dose levels. The reduction in annualized anti-VEGF injections for the high-dose 3E10 cohort was 84% with all injections being given to a single patient. The 3E10 cohort had the longest follow-up of all cohorts, with efficacy data available in all 5 patients through 36 weeks at the time of data cutoff. Durable clinical activity was observed. All 4 anti-VEGF injection-free patients at 24 weeks were still injection-free at 36 weeks. In addition, the mean central subfield thickness, or CST, continued to improve with a meaningful decrease of 92 microns. Mean BCVA remained stable. The single injected patient had such severe disease that they would not qualify for phase II enrollment. Extended follow-up beyond 36 weeks, and specifically, beyond 1 year was available for 3 patients in this cohort for up to a maximum of 64 weeks, and durable clinical activity and tolerability were observed. The Phase II dose exploration stage of the PRISM trial is enrolling briskly, and we're now over 50% complete with enrollment. We expect to complete enrollment of all 50 patients in Q3 this year instead of Q4. We expect to share initial data in the first half of 2024. Now, I'd like to turn the presentation over to Dr. Bob Kim, our Chief Medical Officer. Bob?

Thanks, David. Before we dive into the data, I'd like to share a quick overview of the wet AMD market and unmet needs. Prevalence of wet AMD is estimated by 3 million patients in the U.S. and EU. The market is rapidly growing with an annual incidence of 200,000 in the U.S. The global market for anti-VEGF therapies is over $12 billion annually. Approximately 1.5 million patients are currently on treatment. Key unmet needs remains despite existing anti-VEGF therapies. Efficacy duration is generally 1 to 4 months and frequent injections are needed to maintain efficacy. This limitation results in reduced adherence to treatment and suboptimal patient outcomes. We believe 4D-150 has potential to address these unmet needs. Our vector, R100, has advantages compared to wild-type vectors. As shown on the left, conventional wild-type AAV-based vector gene therapy has not been feasible with intravitreal injection due to blockage by the ILM barrier. As shown on the right, our vector, R100, was invented in primates for penetration through the ILM barrier to efficiently transduce and express transgenes within the retina, including the macula itself. On the left, we can see that R100 demonstrates significantly superior transduction of human retina RPE cells compared to the commonly-used wild type AAV2 in vitro. On the top right is an in-life image from a primate retina 26 weeks following intravitreal injection of R100, demonstrating widespread expression of the reporter gene GFP, including in the macula. 4D-150 is designed for a single-dose intravitreal injection to inhibit 4 key angiogenic factors driving wet AMD and DME. 4D-150 is comprised of the R100 Capsid and the dual transgene payload cassette. This payload expresses both aflibercept and the VEGF-C RNAi. On this slide, we see that 4D-150 has a biodistribution and pharmacokinetics that are highly differentiated from aflibercept. With intravitreal administration of a biologic like aflibercept, the highest concentrations are observed in the vitreous, with lower concentrations in the aqueous humor and the retina and choroid, as illustrated in the top row of the figure. Repeated intravitreal injections are necessary to maintain a concentration of aflibercept in the retina that is consistently above the therapeutic trough threshold. On the bottom, we illustrate conceptually the predicted biodistribution and pharmacokinetics of aflibercept protein expression patterns for 4D-150. 4D-150 injection results and sustained aflibercept concentrations that are highest in the retina and choroid, followed by the vitreous and lowest in aqueous humor. 4D-150 is highly efficient to driving aflibercept expression within the retina and choroid precisely in the tissues that are critical for clinical efficacy. 4D-150 also has potential advantages versus other AAV competitors. The top dose of the human Phase II dose range for 4D-150 is substantially lower than the top doses used by other AAV development candidates using suprachoroidal or intravitreal injections. The Phase I/II highest dose of 3E10 for 4D-150 is only 3% of the highest dose being utilized for RGX-314 by suprachoroidal injection and only 15% of the dose used with Ixo-Vec by intravitreal injection. In summary, we believe 4D-150 is highly differentiated from approved anti-VEGF therapies and other development-stage AAV-based therapies. We believe that 4D-150's intravitreal injection route in addition of 4 VEGF family members, anti-VEGF expression directly within the macula and promising safety profile give it the potential to become a best-in-class product. Now, let's move on to the interim clinical data. I'd like to turn the presentation over to Dr. Khanani. Arshad?

Thanks, Bob. Here is the design of the Phase I/II PRISM clinical trial with 4D-150. The objectives of the trial are to evaluate the safety, tolerability and efficacy of 4D-150 in patients with wet AMD requiring frequent anti-VEGF injection. The clinical trial has 2 stages, the first is the open-label dose exploration stage, which included a total of 5 patients per dose cohort, 3E10, 1E10 and 6E9. The second stage is the Phase II dose expansion stage in which 50 patients are randomized to 1 of the 2 doses of 4D-150 or aflibercept in a 2:2:1 ratio. Patients received a single intravitreal injection of 4D-150 following an initial aflibercept injection. Topical corticosteroid prophylaxis was initiated 3 days prior to dosing, then tapered over 20 weeks. These patients received no oral, intravitreal or subtenon corticosteroids. After the first month, patients were followed every 4 weeks and the need for supplemental aflibercept was assessed at each visit using prespecified BCVA and OCT criteria. Key eligibility criteria are listed on the right. As a reminder, these are previously-treated patients requiring at least 6 prior anti-VEGF injections within the prior 12 months in the study eye and documented response to an anti-VEGF therapy. Phase II stage enrollment criteria require a higher range of BCVA than was the case in the dose exploration stage. The primary endpoint is safety and tolerability of 4D-150. Key secondary endpoints include change in BCVA and CST and the need for supplemental aflibercept injection using the criteria listed in the lower right. Here, we show the baseline characteristics of the 15 patients. Of note, patients in the 3E10 dose cohort had the most severe disease compared to the 1E10 and 6E9 cohorts as evidenced by the much lower visual acuity, much higher CST and higher need for anti-VEGF injections prior to 4D-150. The mean analyzed injection frequency for the 3E10 cohort was approximately 11. Moving on to the dose exploration data on all 15 patients at 24 weeks, this is the longest available time point for all 15 patients. Looking at overall safety, 4D-150 has been developed already to take without any DLTs or 4D-150-related SAEs. 14 of 15 patients had no inflammation noted by any of the 4 measures on eye exam. A single patient had traced mixed cells in the vitreous at a single time point which resolved without intervention. 14 of 15 patients completed the protocol-mandated 20-week topical corticosteroid taper and did not receive further steroids. A single patient was continued on topical corticosteroid beyond 20 weeks by the treating physician for noninflammatory asymptomatic pigmented cells. We have not observed any cases of hypotony, endophthalmitis, retinal vasculitis, choroidal effusions or retinal artery occlusion in this trial. This slide shows the primary ocular exam data for scheduled visits in all 15 patients following 4D-150 to date. The data here depicts SUN and NEI scores for inflammation which creates observations of white blood cells, flare and haze within the interior chamber and vitreous. Overall, 99.8% of the 480 scheduled assessment were negative for inflammation. Aqueous humor samples were obtained at Week 12 and tested for aflibercept levels to assess transgene expression. As Bob previously mentioned, 4D-150 was designed and developed for transgene expression in the retina and the choroid and not in the interior segment. As a background in primate, aflibercept concentrations were significantly higher in the retina and choroid than in the aqueous humor. Based on this modeling, we predicted the aqueous humor concentration above the limit of detection are expected to correspond with therapeutic concentrations in the macula. As shown here, 11 patient samples were evaluable at this time. Three patients and aflibercept injection prior 12 weeks which would confirm this assay, and therefore, were excluded from the analysis. One patient's result is pending. Aflibercept was detectable in 10 of 11 evaluable samples. A single sample from a patient in the 1E10 mid-dose group had undetectable levels. Of note, this patient still responded to 4D-150 and was supplemental injection-free at the 24-week time point. Mean aflibercept levels shown here clearly demonstrate a dose response. This slide shows longitudinal data on mean BCVA change for all 3 cohorts. Overall, the BCVA remained generally stable over time for patients in all 3 dose cohorts. This slide shows longitudinal data on mean CST for all 3 dose cohorts. Overall, the CST remain generally stable over time for patients in the 1E10 and 6E9 dose cohort. In contrast, the mean CST for the 3E10 dose cohort showed progressive improvement, with a decrease of 78 microns from baseline through 24 weeks. Here, we present data on supplemental anti-VEGF injections across all 3 dose cohorts through 24 weeks. On the left side of the figure, the data for anti-VEGF injections in the preceding 12 months is shown for all patients. Different colors represent different approved anti-VEGF therapies. On the right, anti-VEGF injections are shown over time for all patients following 4D-150. A white circle shows a visit at which a supplemental injection was not performed, whereas the red circle shows an injection based on protocol-defined criteria. The 3E10 dose levels showed the highest reduction in anti-VEGF injections. 80% or 4 of 5 patients were injection free at 24 weeks versus 40% or 2 or 5 for each of the 2 lower dose groups. Here, we summarize data for each dose cohort on disease severity at baseline plus supplemental anti-VEGF injection and mean CST changes through 24 weeks. Despite having the most severe disease, 80% of patients in the 3E dose cohort remain injection free, with 84% reduction in mean analyzed anti-VEGF injection rate and with a mean improvement in CST by 78 microns. Overall, these data demonstrate promising interim clinical activity across all 3 doses studied, with the dose response observed in favor of 3E10. Now, let's review data for the highest dose cohort, 3E10, with longer follow-up. This slide shows a safety summary for the 3E10 dose cohort covering Week 24 to 64. All patients had follow up through 36 weeks. Three patients that followed up beyond 36 weeks out to 56 to 64 weeks. 4D-150 continues to be well-tolerated. We have not seen any 4D-150-related SAEs or any cases of inflammation. This slide shows the same ocular exam data shown earlier, now through 36 weeks for all 5 patients in the 3E10 cohort. The blue boxes highlight the time period from 24 to 36 weeks. In this period, 5 of 5 patients had uniformly normal exams for all 4 inflammation assessments in both aqueous and vitreous. Shown here in white symbols, for patient 1, asymptomatic noninflammatory pigment itself were intermittently noted. Patient 3 had trace asymptomatic noninflammatory pigmented cells at a single time point. As previously described, 4 of 5 patients completed their protocol-mandated 20-week topical corticosteroid taper and did not receive further steroids. As mentioned in prior slide, 3 patients had follow-up beyond the time point shown on this slide, and no inflammation or 4D-150-related SAEs were reported. In terms of mean change in BCVA, you can see here that despite advanced disease BCVA remains stable in patients in the 3E10 dose cohort through 36 weeks. Mean BCVA was virtually unchanged. Moving on to CST. The slide shows longitudinally mean CST for the 3E10 dose cohort through 36 weeks. The mean CST for the 3E10 dose cohort showed progressive improvement through 36 weeks, with a decrease of 92 microns from baseline. This slide shows individual patient data for BCVA for all 4 injection-free patients. You can see that the 4 injection-free patients were all generally stable. Patient 1 had a BCVA reduction of 7 letters, which was associated with a worsening cataract. This slide shows individualization data for CST for all 4 injection-free patients. You can see that 2 patients had clinically meaningful reduction in CST. The other 2 patients were stable. In terms of supplemental anti-VEGF injections through 36 weeks, 4D-150 was able to completely eliminate the need for supplemental injection in 4 out of 5 high-need patients. Patient 5 has especially severe disease and was a suboptimal responder. This patient would have not qualified for the Phase II enrollment criteria based on a very low BCVA of 28%. In terms of long term durability in the 3 patients with long-term follow-up through 56 to 64 weeks, 2 of 3 remain injection-free and 3 of 3 have improved CST. Here, we show a case study from a patient in the 3E10 dose cohort. This was a high-need patient requiring 13 anti-VEGF injections in the prior 12 months. You can see the OCT images showing poor disease control with frequent anti-VEGF injections. After a single intravitreal injection of 4D-150, we saw a clinically-significant improvement in CST as well as 5-letter improvement in BCVA, showing the potential of 4D-150 in controlling disease activity in wet AMP. I will now hand the presentation back to David, who will provide closing remarks. David?

Thanks, Arshad. Today, we've presented promising clinical data on 4D-150. We believe 4D-150 has the potential to be a best-in-class genetic medicine for wet AMD. 4D-150 was well tolerated at all 3 dose levels. 14 of 15 patients had 0 evidence of inflammation by all 4 different eye examination endpoints. Clinical activity was demonstrated at all 3 dose levels, with a dose response observed in favor of the 3E10 dose level. At 24 weeks in the high-dose cohort, 80% or 4 or 5 patients in the 3E10 cohort were injection-free, with the reduction in annualized anti-VEGF injections of 84%. At 36 weeks in the high-dose cohort, 4 anti-VEGF injection-free patients remain injection-free and with a mean overall CST improvement of 92 microns. Mean BCVA remains stable. Finally, the Phase II stage is over 50% and ready, and we've now updated our guidance to complete enrollment in Q3 and expect initial Phase II data in the first half of next year. We believe this rapid progress signals the excitement of the clinical investigators about potential 4D-150 in patients with wet AMD. We just discussed our updated Phase II guidance. In addition, we expect to have Phase III planning discussions with FDA in Q4 this year. In regards to DME, we remain on track to initiate enrollment for the Phase II SPECTRA trial, with first patient enrolled targeted for Q3 and initial data in 2024. We're excited to expand into this indication given our positive interim efficacy data in wet AMD. We'll end with our growing ophthalmology portfolio. This slide reiterates our commitment to developing innovative genetic medicines for large market ophthalmology indications, including wet AMD and DME. We also recently announced the completion of an asset purchase agreement for short-form complement factor H which we believe, when combined with our retina tropic R100 vector, will be a differentiated product candidate for geographic atrophy, another large market opportunity. Before we move into Q&A, I'd first like to acknowledge and thank our investigators, clinical trial staff, patients and their families. Operator?

[Operator Instructions] Your first question comes from the line of Salveen Richter of Goldman Sachs.

Congrats on the data here. 2 questions here. One, how comfortable are you that you've reached long enough follow-up that you can understand safety profile at the high dose? And then how do you think about the risk of late onset inflammation occurring? And then secondly, how do you think about the improvements in CST with the slight decline BCVA at the high dose? And I recognize BCVA is more meaningful, but just if you could put that in context in addition to the loss of BCVA letters at the higher dose in the context of how patients might perform on aflibercept as move into larger trials here.

Well, thanks, Salveen, and good morning. So first of all, I think the safety signal here is very strong. We have safety data out to 36 weeks on all 5 patients with a high dose level and out beyond a year in 3 patients, and we've reported really no inflammation, no serious adverse events related to 150. No hypotony, so I think this is the cleanest safety profile that's been presented with genetic medicine and -- in the eye. And I think if you look at the history of retinal gene therapy, if you're going to see inflammation, you are always going to see it at an earlier time point. So there's any examples of inflammation popping up randomly well beyond 6 to 9 months. So I think we have clearly checked the box that this is extremely well tolerated after a single intravitreal injection, which is a game changer for this field. And that safety data is particularly important, large market indications such as wet AMD and DME. In terms of the CST, our hope was at a minimum, it would stay stable. The fact that in patients who've received no injections over approximately 9 months that their CST continues to improve on 4D-150. I think it's just a remarkable biological sign of clinical activity and really, I think, bodes well for the future of the product. In terms of the BCVA, it's absolutely stable within the noise of the assay. We did show that in patients who have not been injected, the mean is close to 0 and absolutely overlaps with 0, so we're very pleased with the overall BCVA stability as well.

Your next question comes from the line of Nalin Tejavibulya.

The first 1, for DME, the disease etiology is different from wet AMD. DME patients tend to be younger and have systemic disease. That can make them more susceptible to inflammation compared to wet AMD where patients are old and have more -- much more confined disease to the eye. For Phase II SPECTRA, could you please provide more details on what patient age groups you would be looking to enroll? And do you think that the 20 weeks of topical treatments would be sufficient or would you potentially need the kind of similar oral plus topical regimen that was used in the XLRP program? And for the second question, could you please provide clarity on whether the patients who did not have significant reduction in treatment burden, if you would consider redosing those patients?

Well, thank you, Nalin, for the question. So in terms of the SPECTRA study for DME patients, we're really excited about this opportunity. To our knowledge, it will be the only genetic medicine company treating patients in this important and very large and growing market with high unmet medical need. One of the exciting things here is that historically, agents that have worked in wet AMD had been effective -- have also been highly effective in DME. If anything, DME patients tend to be a little bit more responsive at even lower doses of these agents -- these anti-VEGF agents than in wet AMD. So we're thrilled with that potential. We're also thrilled with the safety profile that we've seen to date, with 14 out of 15 patients showing 0 inflammation and 1 patient having trace mixed cells at a single time point. So I think we have a very, very strong safety and tolerability profile and efficacy and clinical activity profile going into the SPECTRA study. You correctly point out that these patients are younger and will have broad enrollment criteria initially. And we are really pleased with the performance of our steroid regimen. We're using a simple all-topical regimen, which is important in diabetics. Not -- if you can avoid it, not to use systemic steroids, oral steroids or the like. So we're thrilled with an all-topical regimen. We don't use oral steroids or subtenon injections or other maneuvers, and we think this is going to hold up in DME. Importantly, in DME will be starting down at the 5E9 dose level, which we think has a strong chance of having clear clinical activity and tolerability. So it will be less than 1% of the dose that showed hypotony and other significant inflammation problems with the Ixo-Vec product candidate. So we think we're in a really very good dose range to be in for safety. We believe it's a strong likelihood of clinical activity. In terms of the wet AMD and redosing, again, as a first in human study, we always start with the most advanced patients. These patients are extremely advanced, particularly that Patient 5 in cohort 1 with a baseline BCVA of 28 was a clear outlier and would not qualify for Phase 2 on that basis, and had 13 injections in the proceeding year. So really, I think that patient was very useful for safety data which was confirmed, but it's not relevant for Phase II. With regards to redosing of patients who need an additional boost, that's certainly something we could consider in the future and we may explore that. But at this point, we don't think that's necessary, and we're excited about the signal we're seeing.

Your next question comes from the line of Josh Schimmer of Evercore ISI.

Thanks as well for the detailed presentation. A lot of useful information in here. First, I just want to reconcile the answer you gave to Salveen about the un-injected patients in the high-dose, certainly all being stable in terms of visual acuity. But what I thought you said was a patient who had a deteriorating cataract. So I guess, does that imply there was 1 patient who had deteriorating vision, and that might have been from the cataract as opposed to the underlying disease that was a little bit hard to manage?

Thanks Joshua. So we presented individual patient data for the 3E10 cohort out through 36 weeks for patients who are completely injection-free to see how 4D-150 manage those patients. And so as we show, we have a patient who had 0 letter changes, 1 with a single letter change and one with 5. The 1 patient -- and these are -- sorry, plus 5 and plus 1. So in fact, 3 patients were stable or slightly improved within the noise of the BCVA assay. We did comment on the 1 patient, Patient 1, had progressive cataract and dropped from approximately stable with approximately minus 2 or 3 letters down to minus 7. And with surgery of that cataract, we expect that to pop right back up. So overall, the BCVA data in patients who've not been injected for approximately 9 months, these are either stable or slightly improved.

So does that -- what happened to the BCVA of the patient who actually did require subsequent anti-VEGF antibody injections and then high dosing?

You're saying that patients who did require injections?

Correct, yes.

Yes. So that patient was bounced around a lot. Their baseline BCVA was 28, which is low, and that patient bounced around anywhere from a decrease to the criteria of getting another injection, which was 10 letters up to -- within the range between 0 to 10. So very severely advanced disease would be excluded and certainly no evidence of toxicity in that patient, no evidence of retinal damage, but highly variable BCVA readings in that patient.

Got it. And so then in the high dose arm, you had -- you had that patient who didn't seem to drive significant benefit. And then on the other hand, you had 1 patient who had a fairly dramatic improved reduction in CST. Do you have the aflibercept intravitreal levels that might help correlate why 1 patient did so well and 1 patient didn't?

Yes, it's a great question. So overall, the main aflibercept in this cohort was approximately 250 and with a range of about roughly 60 to 600, and so patients were well above the threshold that we had targeted for activity. I think above that threshold -- and we did see a dose response in terms of dose aflibercept levels at the mean cohort level and we did see a correlation with efficacy. So we think being in that range of dose is important. But beyond that, on a patient by patient basis, we don't see that that predicts as long as patients are again in this therapeutic range. The patient who got injections, Patient 5, again, the significant outlier would not be enrolled in Phase II. They got 13 injections the proceeding 12 months, so that suggests they don't have any evidence of any sort of durable aflibercept benefit. And so I think patients like that who are not going to respond to the protein and have BCVAs well below the Phase II cutoff are highly unlikely to respond, and those will be patients that we exclude going forward. And so Josh, if I wasn't clear, that patient did have expression.

Your next question comes from the line of Kostas Biliouris of BMO Capital Markets.

Congrats on the data. A couple of questions from us. The first 1 is on the trace mixed cells that you saw in 1 patient. Can you confirm whether this is the same case as the one you described in the previous result in November, or this is a new case? And then I have a follow-up.

It's the same case. There was a single episode at a single time point of traced mixed cells. Again, in these very advanced wet AMD patients, it's possible these trace cells would be picked up periodically. Just even in patients on standard anti-VEGF therapy, that's something we're looking at. But no, this is the same case. And otherwise, 14 of 15 or 100% inflammation-free and well over 400 evaluations.

Okay. And can you talk a little bit about how the aflibercept levels in the highest dose compared with the aflibercept levels of patients who are under Eylea?

Right. So I think what's important is Bob Kim's demo showed in the presentation, our biodistribution and mechanism of action is very different from standard protein Eylea. So in contrast to Eylea where you get these spikes and then troughs, spikes and troughs with poor adherence out in the real world and breakthrough disease and progressive damage to the retina, what we have is a stable -- what we believe is a stable expression of aflibercept in the anti-VEGF-C directly in the macular where it's needed. So in primates, when we look at levels in the retina, they're very significantly higher than they are in the vitreous and what we see in the aqueous is really the tip of the iceberg. And so what we're targeting is to be in a dose range that is equivalent or above the trough levels at 8 weeks with the aflibercept protein in the retina. And so when we do those calculations, we get approximately 25 nanograms per ml and the aqueous, we'd predict for therapeutic levels in the retina. Obviously, the error bars in such assays are pretty wide, so it's possible -- they definitely cross 0, so it's possible to still have efficacy in a patient who's undetectable as we showed at that patient at the mid-dose 1E10 was still injection-free at 24 weeks despite being undetectable at 12 weeks. So I think that's how we think about this. So the amount in the aqueous is really irrelevant. What matters is what's being expressed in the retina. I think what we're seeing here is that we're above the threshold for efficacy in the vast majority of these patients.

Congrats on the data again.

Next question comes from the line of Mani Foroohar with SVB Securities.

Apropos the nonresponder in the 3E10 cohorts, this was on a baseline of 28 letters. Can you walk us through, given what we know about the injection criteria, what triggered those rescue injections because apropos having a relatively low baseline letter, putting on a 10-letter loss should be relatively difficult. Was it a question of fluid? What drove the injection volume in that patient? And then I have a follow-up.

Yes. Thanks, Mani. So as I said, that patient is an outlier would not qualify for Phase II. These are the sorts of patients that we put on Phase I first in human study. That patient had injection criteria that were determined either by CST or BCVA, primarily CST, but had crossed that threshold on both criteria at different time points. And again, I think if you look at the responsiveness to the aflibercept protein itself, there's no evidence this patient is driving any sort of durable benefit from that either, with 13 injections the preceding 12 months going into this and even further injections on study. So this patient appears to relatively refractory to any sort of durable benefit from aflibercept protein.

Okay. That's helpful. And as one digs into the data, how does that inform your sense of what the universe of patients that are appropriate for this therapy would be? Because if one starts excluding those most severe patients/nonresponders, how we're going to find them from the potential commercial opportunity? Like what proportion of currently treated wet AMD patients would fall into that sort of too far gone, too low, too low BCVA, how we want to define that population?

Yes, it's a great question. I think given our safety profile and the simple intravitreal injection, we have an opportunity to have a very broad label. I think clearly, the vast majority of patients are having clinical activity, with 4 out of 5 in the study still being injection-free at approximately 9 months. And let's not forget, even these patients were very advanced and very severe disease with high-need wet AMD. So I think we'll be able to treat the majority of high-need patients as well as now that we have this sort of this clinical activity and tolerability signal, we can move into earlier-stage patients as well, and eventually even treat patients soon after diagnosis. So I think the population, as we show more and more data, will allow us to go earlier and earlier stage. So we think at the end of the day, we should be able to treat the vast majority of patients with wet AMD.

Great. That's helpful. And if -- we don't have the slides. I know it will be released later on today. If you guys could slide back to the slide with the patient level BCVA in -- for the patients in the highest dose cohort, the first cohort, I've had a couple of inbound investor questions around what rescue injection would look like if one applied something like a minus 5 letter, perhaps more restrictive metric, which could be appropriate for patients which have -- that have a lot more vision to save. It's hard for me to do that math without the raw data on hand. And what would that do to the injection-free rate -- I'm sorry, what would that do to the injection reduction rate if one applied the negative 5-letter bar?

Yes. Well, as I said, there's clear, strong clinical activity here. Robust aflibercept detection in the aqueous, which bodes very well for high-level expression of the retina. The injection criteria that we're using are very standard. They're identical to some other studies in the field and they were set by key opinion leaders that we relied on to set those criteria, so these are rigorous criteria, 75 microns or more progression and 10 letters or more on BCVA. Some studies will use 2 consecutive 5-letter changes, 5-letter worsening as a cutoff, but that is, again, 2 consecutive. So we think these are robust. We don't think that using something -- other criteria in the field would change these results significantly, and we think these are robust, strong criteria for detecting clinical activity. I think also, in addition, the decrease in the CST actually, we certainly hoped, as part of our target product profile, to see a stabilization of CST. We actually saw a significant improvement in 2 patients and strong, stable disease in the other 2 with a mean decrease of 92 microns. So that's -- and those are patients who had 0 rescue injections over the course of 9 months. So I think that clearly signals strong clinical activity even these patients with very, very advanced disease.

Great. And just 1 last question I just got in from an investor who listening in. Can you confirm there were no changes in the intraocular pressure for all patients off steroids?

Yes, we can confirm that.

Great. Thanks guys on the Phase II.

This concludes the question-and-answer session. I will now turn the call over to Dr. Kirn.

All right. Well, thank you for your attention and your excellent questions today. We're excited about these interim data. We're also excited by the enthusiasm that physicians are showing in terms of enrollment on the Phase II, with that now being more than 50% enrolled and completion targeted for Q3. Which is, again, an update of our guidance from Q4, now moving forward to Q3 for completion of enrollment and we look forward to sharing Phase II data from this study in the first half of 2024. So thanks, and have a great day.

This concludes today's conference call, you may now disconnect your lines.