Opus Genetics, Inc. (IRD) Earnings Call Transcript & Summary

Greetings, and welcome to the Opus Genetics Conference Call. As a reminder, this conference call is being recorded. I would now like to introduce your host, Jenny Kobin, Opus Investor Relations. Please go ahead.

Good morning, and thank you for joining us on today's call to discuss top line results from Cohort 1 of Opus Genetics BEST1 Phase I/II clinical trial. Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. Various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's annual report on Form 10-K for the year ended December 31, 2025, quarterly reports on Form 10-Q and our other SEC filings available on the Opus website. In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so even if our views change. Presenters from the Opus management team on today's call are Dr. George Magrath, Chief Executive Officer; Dr. Sally Tucker, Chief Medical Officer; Dr. Ash Jayagopal, Chief Scientific and Development Officer; Dr. Ben Yerxa, President; and Rob Gagnon, Chief Financial Officer, are also on the call and will participate in the Q&A session. In addition, following the prepared remarks, Dr. Mark Pennesi, Chief Medical Officer and Director of Ophthalmic Genetics at the Retina Foundation and Principal Investigator for the Phase I/II study will offer his insights on the results and be available for Q&A. The remarks on today's call will be accompanied by a slide presentation, which is available in the Events section of Opus Genetics Investor Relations website at opusgtx.com. A recording of this call will be available on the website later today. I would now like to turn the call over to Dr. Magrath.

Thank you, Jenny, and thank you all for joining us this morning. We are excited to share the current results from Cohort 1 in our BEST1 I/II clinical trial known as BIRD-1, which exceeded our expectations from this first-in-human cohort. At a high level, we have several key takeaways. Most importantly, OPGx-BEST1 demonstrated a well-tolerated safety profile with no serious adverse events, no dose-limiting toxicities and no intraocular inflammation at any of the visits. Our gene therapy has been well tolerated in this first cohort out to 3 months. Additionally, we saw evidence of biologic activity. When we began the trial, we thought we would see changes in subretinal fluid. But surprisingly, we saw a reduction in vitelliform material, the hallmark of best vitelliform macular dystrophy. Further, we ended up seeing functional improvements in all 5 patients. That functional improvement was directly paired with structural improvements at just a 3-month time point in 4 of the 5 participants. The combined functional and structural improvement in the same location in the retina, which we are defining as colocalization, gives us confidence as we continue advancing the development program. In August, we held a positive Type C meeting with the FDA regarding Phase I/II data, the Phase III clinical development program and our commercial manufacturing plans. We also discussed the potential pivotal trial endpoint in that meeting, and we aligned with the agency that a 3 decibel or greater improvement in microperimetry could be acceptable as a potential primary endpoint for a Phase III program. Because OPGx-BEST1 produced localized functional improvement in the treated viable retina, the FDA agreed that the same measure in conjunction with the patient-reported outcome may support a future pivotal trial. Our Phase III and commercial drug supply should be ready for use in early 2027. Until then, we have enrolled Cohort 2, the high-dose cohort. Initially, Cohort 2 was planned for 5 participants. We currently have enrolled 8 participants. The first has been dosed and is doing well. We expect dosing to be complete in Q4 of this year. Further, recent epidemiology research found that the number of BEST1 patients in the United States likely numbers around 23,600, while the global patient population is expected to number approximately 45,400 patients. The updated estimates are based on a survey of 150 retina specialists and ophthalmologists and optometrists and account for evidence that a majority of patients with best disease stay with their local retina physician are not genotype and are not counted in a lot of the databases. More information on this research is provided in the appendix of today's presentation. Today, I'll provide an overview of Opus and the BEST1 pathophysiology. Dr. Sally Tucker will describe our trial design and top line results. Then Dr. Ashwath Jayagopal will review individual participant case studies, and I will close with the program summary and our next steps. We have a deep pipeline built on a durable platform that is well funded into 2029 to advance these clinical programs. [ LCA5 ] is our most advanced program. This Phase III trial is fully enrolled, and we expect results next year. And if the results are positive, we would move quickly towards a [ BLA ] filing. That one is what we are going to talk about today. We also have [ RDH12, MerR2K and Re ] all entering the clinic in the near future. So it's an exciting time here at Opus. As you look across our pipeline, there's one consistent theme. There are no approved products to treat any of these inherited retinal diseases. These also represent diseases where we think we may see rapid evidence of target engagement and use a similar manufacturing platform. Importantly, we own global rights to all our gene therapy programs, and we believe each one has the potential to qualify for a priority review voucher. We are breaking new ground in each of these indications, and we are proud of the string of pearls pipeline we are advancing. Today, we're going to talk about BEST1 disease. As I mentioned earlier, BEST1 is a disease that affects 23,600 U.S. patients, and a majority of these have best vitelliform macular dystrophy or BVMD. BVMD is a type of autosomal dominant best disease that presents with this vitelliform material in the center of the macula that ophthalmologists refer to as an [indiscernible] lesion. This disrupts the vision and over time leads to macular atrophy. BEST1 typically begins when patients are in their 20s or 30s and they begin to have distorted vision. That distorted vision then turns into geographic atrophy and a permanent [ sitoma ] or blind spot over time. Our objective is to intervene when the disease is still in the partially affected stage and before it becomes atrophic. In Cohort 1 of our trial, the participants are all pretty close to atrophic because this is a first-in-human subretinal delivery of a novel gene therapy. Therefore, we selected patients that already had significant vision loss. As we gained experience, we were able to begin to enroll earlier stage patients, and you will see an example of that with our last participant enrolled. There's also a recessive version of the disease known as autosomal recessive best retinopathy or ARB, that is much less common and presents earlier in life. ARB patients have a more severe and diffuse phenotype, where instead of vitelliform lesion, they have many lesions spread throughout the macula. This is represented in 2 of our participants today. The BEST1 gene encodes for a protein in the RPE that creates a transmembrane calcium oxybate chloride channel. This channel opens and moves chloride ions through the basal lateral side of or PE, creating an electric gradient across the RPU cells, which normally pulls this vitelliform material into the choroidal circulatory system for disposal. These vitelliform lesions or deposits are most likely lipofusion and waste products in the photoreceptors that normally are trafficked out of the eye. But in Best disease, they're not transported out of the eye and they accumulate under the retina. As the patient develops a backup of these waste products, the photoreceptors begin to atrophy. As the photoreceptors atrophy, the patient enters the later stages of the disease and develops fluid over the lesion, which presents as what we call a pseudohypopion or subretinal fluid with a vitelliform material dispersed within it. As the photoreceptors further atrophy, the patient gets less and less of this vitelliform material being created because there's less metabolic activity. The material starts to fragment and then eventually goes away and leaves an atrophic spot, similar to what happens in geographic atrophy. As a first-in-human trial, Cohort 1 primarily enrolled participants in the later stage of the disease where the vitelliform material is fragmented. And as you will see in our data, OPGx-BEST1 had a meaningful impact in reduction of the vitelliform material in 2 of the BVMD participants. With that disease overview, I'd like to now turn it over to Dr. Sally Tucker, our Chief Medical Officer, to walk through the BIRD-1 clinical trial design and top line results.

Thank you, George. I am pleased to present the Cohort 1 data from our Phase I/II clinical trial evaluating OPGx-BEST1 in late-stage participants with BEST1 disease. We are very encouraged by these results and have received positive feedback on this data from our medical advisers. First, let's review our trial design. This is a Phase I/II first-in-human study structured to be adaptable into a pivotal trial as the program matures. We are currently in the open-label dose exploration phase evaluating the safety and tolerability of a single subretinal injection of OPGx-BEST1 in adult participants with BVMD or ARB. We are presenting data today for Cohort 1, which was dosed at [ 1.5E9 ]. Cohort 2 will be dosed at a higher level [ 4.5E9 ]. Our primary objective is to assess safety and tolerability whilst identifying the right dose to carry into the Phase III portion of the study. Our secondary objective is to assess efficacy endpoints, which include microperimetry, best corrected visual acuity, low luminance visual acuity and contrast sensitivity. We planned for a minimum of 5 participants per dose level. In Cohort 1, we dosed 5 participants, 2 with ARB who now have 6-month data and 3 with BVMD who have 3-month data, all of which we are sharing the results from today. We expect to have 6 months data for the 3 participants with BVMD in quarter 2 of 2027. As George mentioned, due to investigator and patient demand, we have already enrolled 8 participants into Cohort 2 with surgery dates already planned for 7 of these, exceeding the original target of 5. We expect dosing to be completed in the fourth quarter of this year. As expected in an early safety study, Cohort 1 includes participants with more advanced disease with significant atrophy at baseline. Within this first cohort, we treated a 63-year-old woman with ARB, a 59-year-old woman with ARB and 50-, 45- and 31-year-old males with BVMD. These participants all had somewhere between 20/60 to 21/20 vision with the first sentinel participant having count fingers vision. The severity of disease decreased with each incremental participant with the last 31-year-old male being the least severe at baseline. The current study evaluates several endpoints. Microperimetry is a measure of retinal sensitivity that we can overlay onto the area of the lesion on imaging, allowing precise measurement of retinal sensitivity in areas where the vitelliform material resides. A recent natural history study by [indiscernible] evaluated microperimetry changes in BVMD patients over time. All patients in the study had a decline in microperimetry over time, with the decline almost exclusively located at the edges of the lesion. Best corrected visual acuity and low luminance visual acuity both test the central function of the macula. Contrast sensitivity is similar, but requires involvement of a larger area of the macula, which is why it has become popular in studies of geographic atrophy. To evaluate structure, we are using autofluorescence images, which highlight the vitelliform material as bright spots and loss of RPE as dark spots. We are also presenting OCT images, which provide a cross-sectional view through the retina at very high resolution. Slide 12 summarizes the key results from Cohort 1 to date. OPGx-BEST1 was well tolerated and displayed clinically meaningful improvements in functional endpoints that correlated with improvements in structural endpoints. Starting with safety, OPGx-BEST1 was well tolerated in all 5 participants with no serious adverse events, no dose-limiting toxicities and no reports of any ocular inflammation at any of the postoperative visits. In terms of structural changes, 80% of participants or 4 out of 5 had improvements with possible signs of improvement in the fifth. Among our BVMD participants, 67% or 2 of 3 had a decrease in the vitelliform material and both of our ARB participants treated had a decrease in the intraretinal fluid. One keynote about the structural endpoints is that they are co-localized in each of these participants to where there were improvements in retinal sensitivity observed. In terms of functional improvement, 100% of participants had a clinically meaningful improvement in at least one functional measure. Specifically, microperimetry improved in 75% of evaluable patients. Participant 101-101, the sentinel participant could not do microperimetry to their low vision at baseline. Of the patients that could do microperimetry, 3 out of the 4 had at least 5 low pI with a 3 decibel improvement or greater, which, as George mentioned, we talked about with the FDA as a potential pivotal endpoint. Best corrected visual acuity improved in 60% of participants with at least a 5-letter improvement. Low luminance visual acuity improved in 40% of participants, again, with at least a 5-letter improvement. Contrast sensitivity improved in 40% of participants with a 0.2 logMAR or 2 decibel or greater improvement. And of note, participant 101-106, our youngest participant, showed the largest functional gains, which was exactly what we were hoping to see. Our next youngest participant, 102-102, also had improvements, including measures in microperimetry within the treated area. While this initial data is limited in size and includes participants with advanced disease, we know that this disease progresses to atrophy. We hypothesize that we can save more photoreceptors and potentially have more rescueable retina if you can treat patients earlier on in the disease process. This is what we believe we saw in these participants and suggests the potential benefits of treating earlier in the disease course. We are very pleased with the safety data for OPGx-BEST1. There was no intraocular inflammation, no serious adverse events and no dose-limiting toxicities across the cohort. There were no treatment-related systemic adverse events and all ocular treatment-related adverse events were mild to moderate in severity. We saw no vital sign issues or safety lab findings of note. Based on this favorable profile, the independent data monitoring committee unanimously recommended that the trial advance into Cohort 2 at the higher dose. This slide summarizes where we saw clinically meaningful improvement for each participant in functional and structural measures. These include best corrected visual acuity, low luminance visual acuity, contrast sensitivity, microperimetry and OCT measures of intraretinal fluid or vitelliform material. Let me walk you through this table with a bit more context. Best corrected visual acuity improvement was defined as at least 5 letters of visual improvement as compared to baseline and compared to the fellow eye. This was seen in 1 ARB and 1 BVMD participant, 101-101 and 101-106. In participant 102-102, there was quite a large improvement in best corrected visual acuity at 2 time points prior to the 3-month visit. However, the gain was more modest at 3 months, thought to be due to an unrelated adverse event of dry eye. 102-101 and 101-104 did not have an improvement in visual acuity, likely due to the degree of subfoveal atrophy present. Low luminance visual acuity improvement was also defined as at least 5 letters of visual improvement as compared to baseline and compared to the fellow eye. Low luminance visual acuity improved in 2 out of the 5 participants. Contrast sensitivity with an improvement defined as at least 2 decibels or 0.2 logMAR improved in participants 101-101 and 102-101. Of note, 102-101 is one participant who did not improve in best-corrected visual acuity due to the significant degree of subfoveal atrophy. From the dry macular degeneration community, we know that contrast sensitivity is a more sensitive measure in patients with significant atrophy. Microperimetry improvement was defined as at least 5 loci within the treated RPE transitional zone, improving by at least 3 decibels. Functional gains were seen in participants 101-104, 101-106 and 102-102. We will describe the treated RPE transitional zone in more detail shortly. But in brief, this is the area of retina on the periphery of the lesion between the area of atrophy within the lesion and a more normal retina in the periphery of the macula. We are also pleased to report improvement on OCT in 4 of the 5 participants. In our 2 ARB participants, the intraretinal fluid improved in both. Vitelliform material is the hallmark of best vitelliform macular dystrophy. And the vitelliform material definitively improved in 2 BVMD patients and with changes observed in the third. Considering that the presence of vitelliform material is a hallmark of the disease, as George mentioned earlier, we believe this is a really important finding that provides evidence of biological activity in both ARB and BVMD. As you can see, our 2 less severe BVMD participants had broad improvement across visual acuity, microperimetry and OCT. This chart shows mean change in best corrected visual acuity from baseline out to 3 months with error bars representing the standard error around the mean. The solid orange line indicates all treated eyes and the dotted orange line indicates all fellow eyes. As you can see, the trend moves favorably from baseline through to the 3-month visit, consistent with the participant level improvements we just walked you through. Now if you look at the teal blue lines, which represent the treated eyes with definitive structural improvement, 4 out of the 5 participants, you start to see a larger or more exaggerated improvement from baseline in the treated eyes compared to all eyes. This again reinforces our belief that administering OPGx-BEST1 in earlier-stage disease may have a greater impact. Looking ahead to the Phase III portion of our trial, we expect that participants with significant subfoveal atrophy, scarring or fibrosis will be excluded from the study and as such, be earlier on in the disease process. Enrichment in this way may allow for greater functional responses. Now I'd like to turn to microperimetry. Microperimetry is an important endpoint because it lets us evaluate retinal function in specific locations within the lesions and 75% of evaluable patients in Cohort 1 had meaningful improvement. As you'll recall, after our recent FDA meeting, we believe similar improvements in a Phase III trial could be used as a primary endpoint if prespecified and accompanied by a [ PGIS ] improvement. First, I want to spend a moment defining the key term I mentioned earlier, the treated RPE transitional zone. This is the area of the retina that surrounds the area of central atrophy. Essentially, if you look in the periphery, this is normal retina. If you look in the center, this is the more compromised retina. There is a slice that goes around the retina circumferentially that is the most impacted by this disease. This is where we saw the improvements in participants after 3 months of treatment at the edges of the lesion. If we further segment that into the treated RPE transitional zone, this is the area where OPGx-BEST1 was actually administered and is the area of intact photoreceptors around the central area that is partially compromised. These are able to be treated with the gene therapy subretinal bleb. And this is the area we discussed with the FDA regarding the pivotal trial and where a 3 decibel improvement in this treated RPE transitional zone could be acceptable as long as we prespecify at least 5 loci in this area. In Cohort 1, 75% or 3 out of the 4 evaluable participants had clinically meaningful retinal sensitivity improvement in the treated RPE transitional zone. We are particularly excited by this data because we saw that the improvements co-localized with the structural changes in the treated RPE transitional zone. Further, as shared earlier, we received agreement from the FDA that a 3 or more decibel improvement in at least 5 loci with a patient-reported outcome would be acceptable. And it would be our intention to choose the loci that correlated with this treated RPE transitional zone. We were really pleased to see structural improvements and functional gains in this first cohort treated at the lower dose. In the majority of BVMD participants, multimodal imaging shows a meaningful reduction in vitelliform material that was evident across imaging modalities, not solely on OCT. Specifically, 67% or 2 of 3 BVMD participants had a reduction in vitelliform material, and all 3 BVMD participants had clinically meaningful improvements in at least 1 visual function measure, with the largest gains colo colocalized in the areas of vitelliform material reduction. Both ALB participants had a reduction in intraretinal fluid on OCT and both had clinically meaningful improvements in visual function in the areas where the fluid decreased. A fluctuation in fluid was observed in the sentinel participant. However, since visual acuity was maintained, that fluctuation is not considered clinically meaningful. More broadly, functional gains appear largely independent of subretinal fluid. At the onset of this trial, we expected subretinal fluid to be the first parameter to change since that has traditionally been the metric used in other retinal diseases. Instead, subretinal fluid was largely unchanged, whereas the vitelliform material itself, which is the hallmark of BVMD, was reduced. This appears to be driving the functional gains observed, and this result exceeded our expectations going into the study. Functional improvement correlated with structural improvement, meaning retinal sensitivity improved specifically in the treated RPE transitional zone at the edge of the lesion where fluid was minimal. In addition, the fixation moved from outside the lesion to within the lesion in all 4 evaluable participants. Areas of the RPE transitional zone treated within the subretinal bleb showed the highest functional gains. These findings are informing future enrollment since earlier-stage participants showed the greatest structural and functional improvement, again, suggesting earlier intervention may yield improved outcomes. Beyond imaging and functional data, post-treatment participant feedback remains central to evaluating this program's impact. Moving a participant from counting fingers or from very limited vision to usable vision is meaningful, life-changing, an outcome consistent with what was previously observed in the LCA 5 program and now again in this study. Therefore, this slide shares personal experience from all of our participants treated to date from Cohort 1 in their own words. All were happy they were included in the trial with 4 of the 5 noticing improvement and multiple participants requesting their second eye be treated. It's encouraging to see the functional impact we're able to make for individuals living with this potentially blinding disease. This is the metric that matters most in the end. Now I'll hand the program over to Dr. Ash Jayagopal, our Chief Scientific and Development Officer, to review several participant case studies.

Thanks, Sally. I'll now walk you through a few individual participant case studies in more detail and then turn it back over to George to close with our next step for the program. Participant 101-106 is a 31-year-old male with advanced stage disease. He had 7 loci improving by at least 3 decibels, all of which were located within the treated RPE transitional zone. In this area, we observed a 3.125 decibel mean improvement from baseline with the same area in the fellow eye improving by 0.5 decibels. This participant's improvement, therefore, exceeded the 3 decibel success threshold. The fundus autofluorescence imaging on the far left shows hyperautofluorescent vitelliform material surrounding the lesion. At month 3, the lesions have largely resolved. The change is not complete as some residual findings remain visible on fundus autofluorescence, but the improvement is substantial and clearly visible. On microperimetry, functional gains were measured in the same area as the resolving lesions as seen in the middle section of the slide. We observed this on the superior region of the microperimetry sensitivity map over the resolving lesions, supportive of improved retinal sensitivity measured in decibels. These findings are supportive of microperimetry as a clinically meaningful functional endpoint in BEST1 IRDs. The OCT images on the right side demonstrate resolution of the vitelliform material. The second participant, 102-102 is our 45-year-old BVMD participant. As shown with 101-106, he had a significant number of loci improved by 3 or more decibels within the treated RPE transitional zone, which is located at the top right of the grid within the yellow box. This zone improved by an average of 3.5 decibels from baseline, while the similar area in the fellow eye improved by only 0.5 decibels. A finding seen across several participants and most pronounced here relates to fixation represented by the blue plot on the left side of the slide. In participant 102, 102, we also observed improvement of retinal sensitivity assessed by microperimetry in the RPE transitional zone with markedly improved centering of fixation from baseline to month 3 as shown in the imaging. At baseline, the area of retina used by the patient for fixation was located well outside the core lesion near the nasal macula close to the optic nerve. By month 3, however, fixation had shifted back toward a central macular location, which may signal a deviation from BEST1 natural history in which fixation can progressively move toward the lesion edge over time. The vitelliform lesion at the edge of the affected area within the transition zone is resolving as shown within the yellow boxes on the OCT and magnified at the bottom of the slide. Again, this correlates vitelliform material resolution with improved retinal sensitivity. A sub-RPE scar is also visible in this participant. This is not expected to change and has not thus far. The subretinal fluid is similarly unchanged. This reinforces the observation that functional improvement can be observed independently of fluid, but also can be associated with resolution of the [indiscernible] material at the lesion edges as shown in these cases. Participant 102-101 presented with central atrophy, visible at baseline as subretinal, sub-RPE hyperreflective material surrounding fluid. At 1 month, we did not observe any significant change in this material. However, by 3 months, some consolidation and reduction of the vitelliform material is apparent. The series of consecutive OCT rasters is presented here to show how clearly the retina is evolving, but how findings are not yet conclusive to this case. Functionally, this participant had a significant improvement in contrast sensitivity that peaked at 4 decibels. Returning to participant 101-101, the sentinel participant previously discussed at the Macula Society meeting, the earlier resolution of fluid was associated with an improvement in visual acuity, and that improvement has been maintained. The recorded values of 0.24 and 0.18 logMAR reflect modest fluctuation within intravisit BCVA variability for this disease. On OCT, there is disruption of the retinal architecture in both the inner and outer retina at 6 months. Fluid fluctuation was also observed in the untreated area. Fluctuation in fluid is a recognized feature of BEST1 disease, so these findings continue to evolve. Given the continued improvement on multiple functional measures, we do not believe this fluctuation is clinically meaningful at this time. Our second ARB participant, 101 104, was able to complete microperimetry. Similar to the 2 BVMD participants, she had significant clusters of loci, which improved by 3 or more decibels from baseline. As with our other 2 BVMD participants, these loci were clustered in the transitional zones where intraretinal fluid reduced. Her improvement was 3.3 decibels in this area, while only 2.3 decibels in the similar area of the fellow eye were observed. As an ARB participant, she had intraretinal fluid in the infrarotemporal location. This location was readily accessible for treatment, allowing a substantial subretinal bleb to be placed directly over the area of fluid. Over 6 months, this participant showed a clear reduction in intraretinal fluid going from 48 microliters at baseline to 7 microliters at 6 months. As we observed with our other participants, microperimetry improved markedly in the infrarotemporal quadrant, consistent with its close proximity to the subretinal bleb. In addition, fixation in this participant is also improving as shown by the decreasing size of the concentric circles honing in on usable retina. Central and stable fixation is important for visual function. In BEST1 patients, a recent natural history study showed progressive worsening of fixation over time. And so it is great to see the opposite effect so far in our participants. In summary, we have cleared 4 key milestones on the path to a pivotal trial for OPGx-BEST1. First, across 3 months of follow-up in the BVMD participants and 6 months in the ARB participants, the low dose at 1.5 E9 vector genomes per eye was well tolerated with no intraocular inflammation observed at any visit. Second, we believe there is evidence of biological activity with initial efficacy observed on both functional and structural endpoints. 100% of participants demonstrated improvement in one or more functional endpoints. And we observed a structure function correlation with structural changes that were correlated to where functional improvements were observed. Next, we held a constructive Type C meeting with the FDA, reaching alignment on CMC plans and potential endpoints for the pivotal trial. And finally, we are excited that 3 out of 4 evaluable participants in our low-dose cohort had more than a 3 decibel improvement in the treated RPE transitional zone at 3 months. Now I'm pleased to turn the call back over to George to wrap up and highlight next steps.

Thank you, Ash. As our manufacturing team finishes the Phase III and commercial drug product batch, in the clinic, we are progressing quickly through Cohort 2, which is 3x the dose of Cohort 1 at 4.5e9. Based on investigator and patient interest, Cohort 2 has already enrolled 8 participants, most of whom are BVMD participants. The sentinel participant for Cohort 2 at the higher dose is an ARB patient who has already been dosed and is doing well. We expect to complete dosing of Cohort 2 in the fourth quarter of this year, assuming all participants complete assessments as scheduled with top line data expected in Q2 of next year. In parallel, dialogue with the FDA remains ongoing. Potential endpoints could include a 3 [ decel ] or greater microperimetry improvement across at least 5 prespecified loci in a well-controlled trial in conjunction to a patient-reported outcome. BCVA, [ LLVA ] and contra sensitivity are all potentially acceptable endpoints as well. We've also aligned with the agency on Phase III and commercial CMC activities with the Phase III drug product expected to be ready in early 2027 ahead of the pivotal trial. We have already started the planning process for the pivotal trial and expect to begin dosing next year. Looking at our near-term catalyst calendar, in October, we have a PDUFA date for our [ phenolimine sNDA ] in presbyopia, our commercial partner program. The LCA5 Phase III trial is now fully enrolled and dosing of the Phase III participants is expected to begin in the fourth quarter with a readout expected next year and a potential BLA filing to follow. Dosing is also expected to begin in Q4 for RDH12 and in Q1 of next year for [ MerTK]. The [ MerTK ] program will be conducted in Abu Dhabi in collaboration with the Department of Health and the Cleveland Clinic. The ROE program is also expected to initiate next year. In total, we expect 4 clinical data readouts in 2027, BEST1, [ LC5, RDH12 and MERTK ] as well as expected initiation of dosing the BEST1 pivotal trial. To support these programs, our current cash runway extends into 2029, funding 5 clinical programs through to potential product approvals and priority review voucher opportunities. I'd like to take a moment to thank the team and all the investigators, clinical staff and most importantly, the participants who have committed their time and energy to advancing a potential treatment for this blinding disease. We're particularly grateful for the expertise and leadership of our F1 study's principal investigator, Dr. Mark Pennesi. Mark is the Chief Medical Officer and Director of Ophthalmic Genetics at the Foundation of the Southwest, and he is the principal investigator for our Phase I/II study. We are thrilled to have him on the call today to provide clinical and research perspective on this early data set. Mark, can you start us off with your overall impressions of the results to date?

Sure. Thank you. It's a pleasure to be here today. And I think as many of the analysts might know, I'm a skeptical person. So I'm very happy to report that I'm quite encouraged by these results for several reasons. I've been involved with probably over 15 different gene therapy studies. And first off, I think the safety data is really solid and encouraging. Specifically, we're not seeing any signs of inflammation, which has been one of the biggest barriers for gene therapy in the past. And I think partly the reason for that is that we are at a low dose, in fact, probably 10x lower than the low dose that many other therapies use. And the fact that we're starting to see efficacy or promises of efficacy at such a low dose is really encouraging. Furthermore, I think that I can add a little color to some of the patients, and I've been impressed by what my patients have said. In particular, I would point out patient 106 who showed the improvement in the microperimetry. And -- when I saw the improvement in the microperimetry, I asked the patient if he had noticed anything. And what he told me was that he felt that his blind spot had actually gotten smaller, which is exactly what you would expect someone to say based on those microperimetry results. And so I thought that was very impressive. Additionally, I'm really excited by the alignment with the FDA on the change that 3 decibel mean change of 5 points anchored to a patient-reported outcome can be considered to be clinically meaningful. And this is just a huge accomplishment, not only for this program, but I think for all programs in inherited retinal degenerations. And I've been wanting to tell the world about this because I think this really lowers the bar in terms of what we need to demonstrate to the regulators. And some of our patients are already meeting that, and I think there's still room for improvement in Cohort 2. Thank you.

[Operator Instructions] your first question comes from the line of Ritu Baral with TD Cowen.

Congratulations on this data. Actually, I have a question for Dr. Pennesi around the evidence of the movement on the retinal fixation. The change in retinal fixation in your experience, was that also related to anecdotal improvement in these patients or potential improvements on any PROs that you officially or unofficially measured? And does it change how you view the functionality of the retinal tissue underneath at least the vitelliform deposits, if not under retinal fluid? And then I've just got a very quick follow-up on the Phase III.

Sure. So I think that fixational data is really great supportive data. Change -- improvement in fixation is not something the regulators will necessarily take as an endpoint. But I think it can support other endpoints, specifically when we see an improvement in fixation or if we see a shift in fixation, say, to a treated area from a less functional area. And I think there's evidence of that. This is still early. It's only 5 patients. But if we were to see that over additional patients, that certainly does lend evidence to a treatment effect.

Got it. And if we could just review the -- that composite responder analysis, George, can you remind us what are the deltas needed on the 2 individual points? And what is the delta needed on the overall responder rate for success per your alignment with FDA? And is any placebo rate expected given the way that the responder definition was put together?

Yes, Ritu, I'll start with that and then maybe let Dr. Pennesi and Sally talk because they were in the meeting as well with the FDA. The alignment right now is that we will prespecify an area of at least 5 loci on the microperimetry. And we would -- the data suggests we should try to pick the area of what we described as the treated transitional zone or treated RPE transitional zone. And you need to have at least 3 decibel average improvement in that area. And then the second part of the alignment really was interesting, and that's with it being in conjunction with a patient-reported outcome. The suggestion that we've been working through with the FDA is using the PGI-S Patient Global Impression Severity score. It's a single question, well validated, very well accepted by the FDA. But we also had discussions with them about developing a best one specific question. And we've been -- we've actually done some work in the background with Dr. Pennesi already, like to sort of kick off maybe doing something similar to what we did with LCA5, where we validated an LCA5 specific questionnaire. But it's really interesting. As far as your aspect of the placebo rate or the sham rate in this case, the [ Pyroti ] group in Italy published earlier this year in [ IOVS], an article on the natural history of microperimetry and best disease. And over a 5-year follow-up, none of their patients had an improvement in microperimetry. And quite frankly, the interesting thing is like the declines in the patients all happened in this so-called RPE transitional zone in the paper, they call it the edge of the lesion, but I think it's essentially the same thing or very similar to what we're discussing here. And so I think the fact that it's a sham-controlled study where you have to have both an improvement in something that's rather objective with microperimetry and a patient-reported outcome makes the bar for a placebo effect or a sham effect rather high, right? Like I don't think we'll see a big number of false positive responders. Mark, what do you think or Sally?

Yes. I'll just echo that I think the change of going from needing a 7-decibel change on 5 prespecified points to a 3 decibel change anchored to a PRO is really a huge improvement. And I've seen many times over the years, patients who clearly have shown an improvement, but don't meet that 7-decibel measurement. And we just knew that, that was an unrealistic measurement. We've been saying that for years. And so to finally get alignment to lower that to a 3-decibel change really is an accomplishment.

Your next question will come from the line of Kostas Biliouris with on Oppenheimer.

Maybe 2 quick questions from us. One is about the 20% fluid removal bar that you had previously communicated. Can you explain what was the basis for that and whether fluid removal matters at all moving forward? And then I have a second follow-up.

Yes. Thanks, Kostas. I'll start off and then I think we think we can involve others too because a lot of people have been thinking about this. So yes, the pathology, the phenotype is really rather different between BVMD and ARB. And what we saw in both ARV patients was a reduction in the intraretinal fluid. And then what we saw in the BVMD patients was reduction of the vitelliform material that's kind of the hallmark of that vitelliform macular dystrophy. And what we did not see was any change in the subretinal fluid. And I think that that's -- that the -- I think that speaks directly to the pathology. In this disease, the fateophorm materials typically appears first. And then as you get to later stages of the disease, like Stage 4 or so and the photoreceptors begin to sort of be very stressed, then the fluid shows up on the scene. The fluid tends -- in our patients, at least, the fluid tends to pool in the center area of atrophy where there's a pretty deep [indiscernible] on microperimetry. And what we saw was consistent with the [ Pyroti ] group's natural history, which is that the changes really happen at the edge of the lesion and that the vitelliform material going away there. And so it will be interesting to see over time, right, what happens with the fluid. I mean it's only 3 months so far. So the fluid may change over time. But I think at this point, it's -- in my mind, honestly, I mean, it's just a scientific curiosity because the fact that we were able to modify the vitelliform material in 2 out of the 3 patients was really, really pretty cool. And so I think that that's my thought on it right now. I mean I'd be interested in -- I mean, Ash, what do you think from a biology standpoint and then maybe Dr. Pennesi.

Sure. There are passive and active transport mechanisms for the RPE to remove fluid from the subretinal space that they're designed to do. One thing we need to look for is whether the RPE are metabolically stressed by the vitelliform material and aging in late-stage time course of the disease and whether there's resolution of that fluid resorption capability once the vitelliform material is removed. And like George said, it will be interesting to see how the time course evolves with respect to fluid, and it's at a very early stage right now, and we'll be watching closely to see if we can prove out that hypothesis.

Yes. I would also add, have we seen fluid resorption without any improvement in microperimetry, that might be a sign of biological activity, but it would not necessarily be clinically meaningful. So the fact that we're seeing improvement in microperimetry is actually a more important metric.

Great. And maybe a second question. We see impressive qualitative correlation between microperimetry improvement and vitelliform material reduction. Is there any way to understand the potential quantitative correlation between the 2? Is it a way to quantify the reduction of the vitelliform material because the qualitative correlation seems very impressive.

Yes, Kostas, it's a great question. And it's something that can -- that should be able to be done. I think that we can use the OCT sort of 3D reconstruction of those slices to potentially try to quantify that. It's not anything that I'm aware that anybody has really done before. So our team is working on that. It's -- I think it's going to be important for the program. And my presentation in October will be a little bit some of the early work we've done in conjunction with Retina Foundation of the Southwest with Dr. Pennesi, Dr. [ Birch ] and others on trying to mathematically correlate measurements on the OCTs with the changes in microperimetry. Thank you, Kostas. Yes, it's a good question.

[Operator Instructions] Your next question will come from the line of Biren Amin with Piper Sandler.

Maybe for Cohort 2, can you talk about with the higher dose, are you doing anything that's different compared to the lower dose in terms of blood placement or the number of blood? And also, what can you tell us about the 8 patients as it relates to their disease profile and how they compare to Cohort 1? Specifically, would you exclude the one patient that you had in Cohort 1 and [indiscernible] score in Cohort 2?