Ocuphire Pharma Inc Aktie

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 Phase 1/2 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. Ash 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 5 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. BEST1 is what we are going to talk about today. We also have RDH12, MERTK and MER 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 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 egg-yolk 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 scotoma 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 bestrophinopathy or ARB, that is much less common and presents earlier in life. ARB patients have a more severe and diffuse phenotype, where instead of one 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 RPE, creating an electric gradient across the RPE cells, which normally pulls this vitelliform material into the choroidal circulatory system for disposal. These vitelliform lesions or deposits are most likely lipofuscin and waste products for 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 pseudohypopyon 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 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 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 rescuable 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 PGI-S 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 co-localized in the areas of vitelliform material reduction. Both ARB 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 LCA5 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 vitelliform 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 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 inferotemporal 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 inferotemporal 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 1.5E9 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 decibel 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 contrast 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 Phentolamine 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 RHO program is also expected to initiate next year. In total, we expect 4 clinical data readouts in 2027, BEST1, LCA5, RDH12 and MERTK as well as expected initiation of dosing in 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 BEST1 study's principal investigator, Dr. Mark Pennesi. Mark is the Chief Medical Officer and Director of Ophthalmic Genetics at the Retina 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 researchers' 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.

Great. 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 [ Parodi ] 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 Konstantinos Biliouris with Oppenheimer.

Congrats on the data. 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 ARB patients was a reduction in the intraretinal fluid. And then what we saw in the BVMD patients was reduction of 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 vitelliform 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 scotoma on microperimetry. And what we saw was consistent with the Parodi group's natural history, which is that the changes really happen at the edge of the lesion and that 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 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 value.

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 bleb placement or the number of blebs? 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 [Technical Difficulty] sub-foveal, sub-RPE score in Cohort 2?

Yes. Great question, Biren. So a couple of things, right? So with the higher dose, we're hoping potentially maybe you can get a higher -- you can get transfection across a higher area of the retina. One of the feedbacks from the surgeons kind of across the board has been in BEST disease, you can raise a pretty large bleb and cover more area than, say, in an LCA patient. I think that -- so I think that the targeting of the blebs is being informed by the results that we've had to date and certainly will continue to be further refined as we get more and more data and we learn more and more about the drug. So I do think that there's going to be a lot more targeting towards the transitional area where we're seeing changes and towards the vitelliform material in this Cohort 2.

The second question, so the -- it's been a lot of fun because it's enrolled so fast like in Cohort 2, like we opened the thing up like I think the IDMC met like early August, and we've already got 8 patients in a 5-patient cohort. And Dr. Pennesi and the Retina Foundation have already treated the first patient. Of the 8 patients, 7 are BVMD, 1 is ARB. There are a number in that cohort that are earlier stage patients compared to what we've shown to date, there are some that are still advanced stage. I mean we are still learning about the product.

So for example, the ARB patient that Dr. Pennesi treated, it is still a pretty advanced patient. But some of the -- a majority of the BVMD patients that we scheduled are earlier stage. And I think that reflects what we would go for in the pivotal, right? In the pivotal, I think patients with big sub-RPE scars like our first BVMD patient may not be the perfect patient for that. Although that patient still had contrast sensitivity gain that was twice the threshold that's used in geographic atrophy studies. So I think it does help those patients, but it may not be the best for trying to get a homogeneous population for Phase III. Yes, thanks for that Biren.

Your next question will come from the line of Lili Nsongo with Leerink Partners.

Congratulations on the data. Maybe following up on kind of getting more or additional color on Cohort 2. So given that going into pivotal design, you will be excluding patients with sub-foveal scarring or fibrosis. Can you give us a sense of among the 8 patients that have been recruited, how many of them have -- among the BVMD patients, how many of them have advanced stage disease versus potentially earlier stage disease? And then thinking about the patient population as a whole, how should we think about the percent of patients that are diagnosed prior to reaching that stage of the sub-foveal scarring and fibrosis?

Yes, it's a good question. I don't have the exact numbers off the top of my head for that. I would say that -- I mean, a vast majority, if not all, of the BVMD patients do not have sub-foveal scarring in Cohort 2. And so I think that we're going to get -- as we get more and more experience with the drug, we're going to move earlier and earlier in the stage of disease. And so it is a process as we get more and more comfortable that the treatment -- that the risk-benefit profile is advantageous for patients. And so I think we'll probably do something similar to what we did for this cohort where we publish the demographics of the patients once the cohort is fully enrolled. So more to come on that, Lili. And again, that will obviously inform our Phase III design too, which will be likely very -- the data right now is suggesting we should skew that to earlier-stage patients.

Your next question will come from the line of Steve Seedhouse with Cantor Fitzgerald.

Congrats on the data. This is Nick on for Steve. For the pivotal study, is there a maximum number of loci that can be prespecified along the transitional zone? And also will the loci be selected on a patient level basis in a targeted manner to inform the physician at where to place the blebs?

Yes. So thanks. Great question. Yes. So the -- there's no maximum for the number of loci you can pick. So it just has to be at least 5. And so you could theoretically pick all 68, but we're going to be much more targeted than that. The second aspect of your question is, yes, absolutely. So we -- and Dr. Pennesi is always really good at this, but all the investigators do it. We sit down before every patient is dosed, and we sort of go through the surgical planning. And so now that we're informed on this transitional zone, the RPE transitional zone, I think we can make a more educated decision on where to place the surgical bleb. Now with that being said, surgery is surgery, so it can be unpredictable. So sometimes the blebs don't go exactly where the surgeon -- where you preplan them, but we are being very careful to enroll at sites that have a lot of experience like the Retina Foundation of Southwest and control that as best as possible.

Your next question will come from the line of Francois Brisebois with LifeSci Capital.

Can you guys hear me okay?

Yes, Franc.

Okay. Great. Yes, congrats on the data. I'm just wondering, we touched a little bit on this in the prior questions here with the higher dose Cohort 2. I was just wondering how -- in terms of picking, how confident are we that, that is the right higher dose just based on the fact that the vitelliform changes were probably exceeded expectations just on the fluid there. Does that change anything about the dose? And do we need to see kind of improvement somewhat at a higher dose? Or are we good to go to the Phase III here based on what we've seen?

Yes. I think that is an interesting question. I think that in my mind, if we sort of see these same results, if we were to see these same results sort of repeated at 6 months, I think we would feel pretty good about the low dose. But I'm certainly curious about the high dose. And I think it will be interesting. Ash, do you want to talk a little bit about the pharmacodynamics of it or potential pharmacodynamics?

Well, it's really exciting to see signals of efficacy at such a low dose. But as you know, BEST1 is a heterogeneous disease, over 500 different mutations. And every patient may present differently in some way or the other. And it's nice to explore dosing flexibility to cover every situation, phenotype we might encounter. But I would just kind of leave it at that to look forward to exploring dose escalation.

Your next question will come from the line of Debanjana Chatterjee with Jones.

You hear me?

Yes, we have Deb.

Congratulations on the encouraging data. Just to clarify, the microperimetry endpoint, is this going to be a responder analysis where response -- a responder being defined as at least that they show 3 decimals of improvement at each of the prespecified loci or is this going to be an average across the 5-plus loci cluster? And just curious on -- for the Cohort 2, since you have already enrolled, have you prespecified these points already?

Good question. So it's an average at the patient level, right? So you take an average of the spots that you prespecify for each patient. But at a study level, it's a responder analysis. And so for a patient to be a responder, they have to have an average of 3 decibel or more improvement over a prespecified area of 5 loci in conjunction with the PRO. And then that patient would be classified as a responder. And then you would just obviously compare between your sham arm. And so for the Cohort 2, so yes, Sally, do you want to talk a little bit about some of the changes you've made for Cohort 2 and the learnings from this?

Sure. Okay. So in Cohort 2, as George has already indicated, I think the learnings from Cohort 1 we'll be utilizing to discuss with the investigators to help planning of where the bleb is placed, where we think that we'll see the optimum response to placement of the drug. We are not prespecifying the loci formally in our analysis in the Cohort 2. That's not part of our Phase I/II. However, we will be utilizing the data and prior to surgery, talking with the investigators where we expect to see those improvements and see if that is mirrored, and that will help us in determining the best route forward for the pivotal and how we select those loci.

So we will be practicing the pre-specification in Cohort 2, like we will be doing that and testing ourselves on that to try to get better in advance of the Phase III.

Your next question will come from the line of [ Andre Goditel ] with Guggenheim Securities.

So I just want to go back maybe to the endpoint for the Phase III. Specifically, how is this 3 decibel threshold determined. It's quite significant line to 7 that was the previous bar. And kind of related to that, what's the chance of observing that just by chance I guess close to just related to specificity of test retest reliability of microperimetry, if you have any information on that?

Yes, yes. I would definitely point to the natural history of microperimetry and BEST disease study that was published in IOVS this year that showed that -- I mean, there were no 3 decibel improvers that I could see in that study. So I think the 3 decibels is a pretty high -- still a pretty high bar with a fairly low chance of a -- of a false positive. Dr. Pennesi, you have a lot of experience. Would you like to talk about test retest and sort of how you think about microperimetry?

Yes. No, I would agree with what you said. And the reality was that the previous requirements were just completely unrealistic. And this is still a difficult endpoint to hit by chance, but one that is more within the realm of reality.

This concludes the question-and-answer session. I will now hand the call over to George Magrath for closing remarks.

Great. And thank you, everybody, for joining us today. We're incredibly encouraged by these early results at the low dose to see that the drug product is -- it has been well tolerated with no inflammation seen in the patients and that there is potential to really modify the actual core of the disease on OCT from the cellular fluorescence and also on function with microperimetry and BCVA. And so we look forward to continuing to gather data to responsibly develop this program and try to get this to the patients, which turns out there a lot more than we originally thought. So thank you all for joining us today, and this concludes the webcast.

Good morning, and thank you for joining us today to delve into our gene therapy pipeline with a focus on our earlier-stage programs. As a reminder, this event is being recorded.

Before we begin, I'd like to remind you that during today's call, we will be making certain forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements. Please refer to our annual and quarterly reports and our other SEC filings available on our website.

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 these go even if our views change.

Recording of this event and the accompanying slides will be available in the Events section of the Opus Genetics Investor Relations website later today. So we have a really terrific lineup of speakers and are really grateful for all the key opinion leaders joining us today to share their expertise on the treatment of inherited retinal diseases, including targeted indications for Opus. For reference, you can access speaker bios on the right side of your screen or via the button in the top right corner.

Today's agenda is divided in 2 parts. In part 1, we will provide a brief company introduction and scientific overview. Then one of our KOL guest speakers will discuss each disease followed by a summary of our scientific approach for the corresponding indication. We will review our clinical development strategy and approach followed by our first Q&A session on these programs that will be entering the clinic later this year and into 2027. Please note that any time during our presentation today, you can submit a question using the Ask a Question button on the top right corner of the screen.

In part 2, we will provide a brief summary of the clinical trial data from our lead programs, LCA 5 and BEST 1. We will highlight the recent epidemiology work we commissioned to better inform the disease prevalence of our 7 current indications. And finally, we are excited to host a panel discussion with several industry experts to discuss patient recruitment and retention in inherited retinal diseases. We will then open the call back up for questions. So I'd now like to turn the call over to Dr. George McGrath, Opus' CEO, to kick off our program.

Thank you, Ben, and good morning, everyone. At Opus Genetics, we're focused on accelerating groundbreaking gene therapies for inherited retinal diseases. We're advancing a portfolio of 7 AAV gene therapy assets built on validated science and a proven delivery approach pioneered by our co-founder and guest speaker today, Dr. Jean Bennett, whose work led to the first approved IRD gene therapy. We hold first-mover advantage across multiple indications supported by broad IP protection, orphan drug exclusivity potential and rare disease regulatory pathways that offer flexibility and potentially accelerated approval.

Our approach emphasizes streamlined time lines, capital-efficient development and the ability to progress multiple clinical programs in parallel. We're fortunate to collaborate with leading scientific and clinical innovators in gene therapy, many of whom are here with us today. By building a portfolio that spans multiple rare retinal diseases, we believe we can capture meaningful share in a multibillion-dollar market and deliver multiple approved therapies for patients with severe genetic eye disorders.

As you will hear today, our validated scientific approach and early clinical success give us strong momentum as we expand into our next group of promising programs. We're currently targeting 7 inherited retinal diseases caused by genetic mutations. As you think about the indications we're focused on, there are 3 primary buckets of IRDs, the bestrophinopathies, bleber's congenital amaurosis and retinis pigmentosa. We have chosen these programs specifically since they have common approaches that we can leverage, including cell biology, delivery method and clinical trial design. Then we can differentiate as needed for each disease.

For example, LCA mutations are typically earlier onset conditions in children, and they are also more macular focused, while the retina pigmentosa mutations have a more concentric loss of peripheral vision. All of these programs are fairly straightforward subretinal IRD gene therapy programs. And one of the reasons we pick these indications is because we can potentially see a rapid proof of concept in clinic. We will go through much of this today as we look towards several clinical trial initiations and data readout in the next 12 to 18 months.

We really are building a differentiated gene therapy pipeline. Our company is essentially built as a platform to develop these gene therapies and advance them in a very capital-efficient and time-efficient manner. For LSA-5, we are currently enrolling participants in the run-in portion of our Phase III clinical program. This program has received multiple regulatory designations, including the Regenerative Medicine Advanced Therapy, or RMAT, -- and most recently, we were accepted into the new Rare Disease Evidence Principles, or RDEB program focused on ultra-rare diseases.

For BEST1, Dr. Mark Panesi presented our data on the Sentinel patient at the Macula Society in February, and we look forward to presenting our first full cohort of data in September. Our key focus today is to provide you with the disease profile and scientific rationale for our next 3 programs. RO, RDH12 and MerTK that are all progressing into the clinic.

Here on Slide 10, we've laid out our planned time lines. And importantly, current cash runway into 2029 will support 5 clinical development programs through multiple inflection points. We are really entering a pivotal time for the company. Based on early success we've had with LC5 and BEST1 and our recent fundraising activities, we are now in a position to accelerate RDH12, MERTK and R in the clinic. This increases our total addressable market in a significant way and gives us multiple shots on goal. We are now funded to achieve readouts in our BEST1 and LC5 programs and also generate clinical data from these additional programs coming online.

Currently, we expect as many as 4 clinical trial readouts in 2027. It is important to note that all of our programs treat various forms of rare pediatric diseases with the potential to receive priority review vouchers if approved.

It's my honor to introduce our first guest speaker, Dr. Jean Bennett. She is the inventor of Luxturna, which is the first gene therapy approved in the U.S. to treat inherited retinal diseases. She is one of our -- the scientific co-founders of Opus Genetics and remains a key member of our Board of Directors.

Today, Dr. Bennett will provide an overview of IRD drug development and discuss the concept of structure function association that underlies all of our programs.

Thank you so much, George. It's my pleasure to be here. I thought to set the stage for the next set of talks, I'd give you a little bit of background about the rationale for selecting the various targets that we've selected. Obviously, the optimal targets have to affect -- have to target the affected cells before they've degenerated. Otherwise, you can't treat them.

Ideally, lack of function disease is optimal since one can then reactivate the function and rescue the disease. We want transgene cassettes that will fit within the small cargo capacity of the adeno-associated virus or AAV, and that AAV must transduce the target cells efficiently. The disease has to be severe enough to be able to detect improvement and ideally in a fairly rapid time frame so that we can see this improvement quickly.

We need the relevant animal or cell models to be able to develop proof of concept to be able to go forward and ideally select diseases which are relatively prevalent, so we can find enough patients to be enrolled in the clinical trials. The more challenging diseases are those that are developmental conditions, for example, those that begin the whole process -- degenerative process in utero, those would be very difficult to treat.

And there are also some technical challenges with large genes fitting them into the small cargo capacity of the AAV. -- ideally, we want disease that progresses fairly quickly because we don't want the trials to have to take 10 years or longer. And it's more challenging if we don't know much about the natural history of the disease or if there's asymmetric disease or if it's extraordinarily rare. So shown in this graph is a diagram of the numbers of genes which when mutated cause retinal degeneration.

Over time, the first ones were identified in around 1990, choroideremia and rhodopsin were some of the earliest. And as you can see now, the number has expanded to more than 348 identified genes, and that's in large part, thanks to the human genome project. When we first started and others first started considering gene therapy, gene augmentation therapy, the only 2 genes that were known were rhodopsin and choroideremia. RPE65 or retinal pigment epithelium 65 kilodalton protein encoding gene were some of the earliest ones identified, and those have been targets of clinical trials, choroideremia and RPE65 were targets of Spark Therapeutics and other people, including those that you'll hear later today have been involved in trials for choroideremia.

But shown here are additional diseases, which have been identified over the course of this progress in the gene identification. And these are targets that OCU has selected that fit the characteristics that are listed in this slide in terms of optimal targets.

In the next slide, we -- obviously, if the retinal structure is relatively preserved, even though visual function is already impaired, it becomes possible to deliver the gene to rescue the function in a therapeutic window when these are still -- the cells are still viable enough to be able to function.

And if one can pick the right patients and choose the meaningful endpoints for clinical trials, one can potentially demonstrate benefit. And that's exactly what has happened with Luxturna, which was the reagent that was developed to treat RP65 deficiency. In the next slide, I'd like to show you 2 of the targets that Opus has initiated studies on. One is -- they're both forms of labor's congenital amaurosis. This is a severe early onset form of retinal degeneration, one of the most severe forms of retinal degeneration because it affects children and infants. LCA 5 and RDH12 are both diseases which are first manifest in photoreceptor cells, unlike RP65, which is the gene target of Luxturna. And these are both sillyopathies. They're very rare.

But by imaging, we know that there are photoreceptors that are still available and treatable in childhood and young adults. And so that satisfies one of the requirements. There are animal and cell models that can be used to demonstrate proof of concept. However, compared to RPE65, these are more severe and earlier onset. And so we hypothesized that by treating children, we could actually intervene well with the disease and potentially even prevent the disease. And shown to the right are some of the children who are the first to be identified with these diseases.

The top one is one with LCA 5 and underneath our EH12 children when they came to visit my laboratory. In the next slide, one of the reasons why these 2 diseases are so dear to my heart is because of the patient and family partnerships that have been made over decades. And starting with LCA 5, a labor's congenital amaurosis conference was held in 1998 that was developed and formulated by parents of a child with LCA.

At that point, they didn't know what the cause of his disease was. And they fueled the efforts of academics and really an international consortium to try to figure out what was the cause of this and other forms of LCA. And their child's gene was identified in 1997 -- well, the child was born in 1997. But after this conference, his gene was identified some 10 years later in 2007. That picture on the lower left shows the team at Nyagan in the Netherlands who had discovered this gene. And that fueled a consortium to try to develop a treatment for this particular disease. The family continued to fund projects, including generation of a mouse model of this disease, which was made at Jackson Labs by Patty Nina, sent to my lab. And together, we all developed a reagent, which we showed could actually ameliorate the disease in this mouse model.

In our lab, we set up a GMP facility to generate AAV. And then we were lucky enough to partner with Opus Genetics and develop a clinical trial. And shown in the lower right is the team that delivered the first gene therapy for LCA5 in 2023.

In the next slide, I'd just like to close by telling you what I think the status of retinal gene therapy is. There's abundant safety data. There are more than 140 different retinal gene therapy clinical trials that have been initiated.

There are gene therapy centers around the world and thousands of eyes have been injected. We have a lot of safety data -- there are numerous disease targets that have been tested and are in the process of being tested in the clinic with a variety of strategies, excellent safety data. And now there's familiarity with gene therapy surgical techniques, vector handling and storage, genotype, phenotype correlations, development of outcome measures all over the world. And it's a very exciting time.

There are more than half a dozen retinal gene therapy clinical trials, which will read out within the next year, hopefully giving us additional approved gene therapy products besides Luxturna. Now where are we with Luxturna, also known as voretigene, the neparvovec rizzzle. This is the treatment for RPE65, which is now approved not only in the United States and the European Union, but in numerous countries and continents around the world.

There is a great deal of long-term durability data that stems from the clinical trial that was run to approve this drug. It's more than 9 years in counting of this durability data. And the real-world efficacy is very similar to that reported in clinical trials. So we're really optimistic that Opus is going to contribute further to development of treatments for these currently untreatable conditions.

So I'd like to hand off the next session to Dr. -- actually, let me give this slide. There are numerous obstacles to retinal gene therapy that have been overcome, just as a continuation of where we are. In the 2000s, when we began with LUXTURNA, there was no path. There were no regulatory guidelines. Everything had to be derisked, including the safety of subretinal delivery of AAV and dosing of AAV.

There was a lack of genotype patients because there was no reason to genotype them. There was no treatment, no clinical trials in progress. No one had enrolled pediatric subjects for gene therapy clinical trials. We didn't know the status of immune response, whether this would cause rejection or inflammation. And we had no guidelines from the FDA, including whether or not it was going to be necessary to inject the second eye, the contralateral eye, what we needed in terms of control groups, et cetera.

There was no natural history data and no relevant outcome measures and certainly no potency assays with which to measure the quality of the product. In 2007, when we began our first retinal gene therapy clinical trial, there was only one approved outcome measure, and that was reading the eye chart.

Now there are numerous potential outcome measures, including the outcome measure that was developed during the process of testing Luxturna. That's the multi-luminance mobility test. And they're now virtual reality tests -- there's perimetry, there are anatomical features and also changes in disease progression. So it's a very bright future for retinal gene therapy.

And now I'd like to turn the table over to Dr. Fan, who will tell you about RDH12. Thank you very much.

Thanks, Dr. Bennett. That was such a great overview of how far we've come with gene therapy and IRDs, of course, you've been so pivotal to all of that. Let's get into the slides in the interest of time. I'm just going to start reviewing this disease, RDH12, which is truly one of the most devastating forms of early onset retinal dystrophies or degenerations that I see in my clinic. D12 is interesting because it draws a lot of parallels to the severity and intensity of vision loss to RPE65. We know RDH12 accounts for up to 10% of all LCA cases. That makes the global prevalence over 30,000 with a high concentration in the Middle East and North Africa.

There are still quite a few patients in the U.S., probably underestimating it at about 2,500 patients. But surely, as we know about all IRDs, the true prevalence is probably a little bit higher. These are images of a patient I see of my clinic, a young patient. As you can see on the images on the right, that you have essentially severe peripheral retinal atrophy. But what's unique about this retinal degeneration as opposed to a disease like retinitis pigmentosa is that you have more macular atrophy, which is central involvement early on in life.

And so what you often see in these patients is they'll present in childhood with a diagnosis of retinitis pigmentosa, but then you kind of watch them progress very quickly into losing central vision in addition to peripheral vision, and that can be truly devastating for this patient population.

Let's go to the next slide. Not to bore you with the scientific mechanism of action of RDH12, but essentially, as Dr. Bennett was saying, this enzyme and this gene has its function in the photoreceptors as opposed to the retinal pigmented epithelium. So you can see that the job of the photoreceptors, the outer segments is to process light and clear toxic byproducts like alltansretinol, which then can be recycled into the visual cycle. But if you're unable to clear those byproducts, what happens is that the byproducts will build up, they'll dimerize, they'll create oxidative stress and damage to the photoreceptors in forms of entities like A2E, lipofusion and that kind of thing.

And so we know in RDH12, this process is very severe and will damage photoreceptors if left unchecked, leading to early vision loss in the disease that we call liver's congenital amaurosis or LCA.

Let's go to the next slide. One of the most interesting things that we have found about RDH12 is, in some ways, it is parallel to RPE65, but in other ways, it is not. So the way that it is similar is that it has profound vision loss early on in life.

We know that maybe in your teens or childhood, you're about 2,200, but it can steeply decline very quickly thereafter hitting counting fingers or even hand motions or life perception in your 30s and 40s, which is truly devastating and much more severe than a lot of other inherited retinal diseases.

Drawing your attention to the diagram on the right, you can see that the OCT image of the patient of RDH12 has more disorganized anatomical layers of the retina as compared to the image of the OCT of R65. However, we have found on electrophysiology that there is better co-mediated sensitivity in patients with RDH12 despite the anatomical disorganization of layers as compared to RPE65, which may suggest because the pathobiology is relatively similar that perhaps these cones are rescuable because they still maintain pretty good sensitivity despite what we see on exam and also on imaging to be more severe retinal disorganization or potentially retinal atrophy.

And so there is a therapeutic window here for us to produce a therapy that may mimic that of Luxturna that may be able to treat patients similar in some ways to RPC35 and maybe optimistically be able to rescue in maybe a more efficient way or better way this co-mediate sensitivity before it causes damage to the central vision.

I'm going to pass it over to Ash now so we can review the scientific overview. Ash is the Chief Scientific Officer of Opus. Thanks.

Thanks, Dr. Fan. OPGX-RDH12 is an AAV8 vector designed for a onetime subretinal administration to deliver functional copies of the RDH12 enzyme to photoreceptors in order to restore visual function using a photoreceptor-specific promoter. And in our studies, mouse model of RDH12 deficiency was used to test OPGX-RDH12 to test for expression as well as function of RDH12 in the mouse retina.

And we demonstrated with Dr. Bennett that OPGX-RDH12AAV restores RDH12 enzyme expression in the mouse retina as shown on the right panel, and in a dose-dependent manner, also restores enzymatic activity and function approaching that of wild-type mouse retina levels. And the RDH12 deficient or as we call it, a knockout mouse model is also highly susceptible to light damage due likely to acceleration of phototoxic stress and subsequent photoreceptor apoptosis.

So left untreated, these RDH12 knockout mice treated with high-intensity light exposure to the retina degenerate as shown by thinning outer nuclear layers where the photoreceptor nuclei reside, and you can see that on the top panel. However, AAV8 encoding for RDH12 expression in this published study was capable of preventing this retinal degeneration.

And furthermore, mouse behavioral testing used to assess visual function also improved with AAV gene therapy for RDH12 as shown on the bottom half of the panel. And we, therefore, are well poised to now investigate OPGX-RDH12 safety and efficacy in clinical studies.

And so with that, I would now like to turn the call over to Professor Robert McLaren to discuss MERTKRDs.

Thanks very much, Ash. And also thank you to Jean for a very helpful summary of the history of the retinal gene therapy, which I've been following myself for over 20 years now. So I'm Robert MacLaren, Professor of Ophthalmology in Oxford, and I've been involved in gene therapy trials for a number of conditions, choroideremia, X-linked retinitis pigmentosa, which take a lot of my time at the moment and also the work we've been doing with age-related macular degeneration.

Now MERTK is one of those inherited retinal diseases that can be very severe in early onset and cause what we refer to as labor congenital amaurosis and others very, very poor vision from birth. But more often, what we see is missense changes where patients have a disease that is clearly causing the vision impairment, but still some ability to see things and read the chart. And this particular condition is caused by a mutation in the gene that encodes a protein that is involved with the phagocytosis of photoreceptor disks. And most significantly, the MERTK gene is expressed in the retinal pigment epithelium. And we know this cell, in particular, is readily transducible with low levels of AAV compared to photoreceptor transduction, again, which helps us in terms of predicting the clinical trial outcomes in terms of safety.

The prevalence worldwide, I have patients in my clinic and oxate,' particularly high in the Middle East. And my colleague, Alan Alka originally did a MERTK gene therapy trial at the Kingollyye Hospital in Riyadh. And the reason for that was that it was funded by a family, the Aldi family, who unfortunately have MERTK in the family and was really done almost like as an off-label treatment. I was very much hoping that Fazan would continue the program. And in fact, I invited him to Oxford to come and speak about the results of the trial, but it's sort of faded away, unfortunately, at that stage.

But we do have some very good examples from that paper that he published on the safety and in some case, efficacy of the treatment administered to a small cohort of 6 patients. So the phenotype, very, very similar to all of these inherited retinal diseases. If you look at the picture on the bottom right, kindly provided by Ken, again, I'm going to comment on your image, I hope you don't mind. But there is some debate about whether we can see subretinal clumps in the subretinal space. And you can see in the bottom right, the retina, the subretinal space.

There is certainly good data from the models, the animal models that these are photoreceptor allogments of clump there. And it's one of those things that we look for potentially as a phenotype to identify patients and try and narrow down the genetic testing. So the ability to phagocytose the other segments is all part of the visual cycle indirectly. And so not surprisingly, these patients have night vision loss, peripheral vision loss. And indeed, the actual clinical features are very similar to those seen in many of the other inherited retinal diseases. So if we could go to the next slide, please. So this just shows a little bit more about the mechanism.

And you can see that the MERTK receptor is on the surface of the retinal pigment epithelium. So we can translate a lot from the luxtoma program, which is also targeting retinal pigment epithelium to MERTK. And we might expect to see, as indeed we have seen with other inherineases is when you put back a protein that has a critical role in maintaining the structure of the photoreceptor, particularly the outer segment, then you can expect to see an improvement in the outer segment structure. And we've seen that with OCT scans as well. And if you improve the outer segment structure by liamans, you can also expect to improve the retinal sensitivity, which is very important because that gives you a functional endpoint.

And functional endpoints are much easier to achieve with a small number of patients than anatomical endpoints in which one would have to wait quite a long time to see a difference in slowing degeneration in a treated eyes compared to untreated eyes. We know that the functional endpoints are well established. I mean it's going to be low lumous visual acuity, best corrected visual acuity, microperimetry. These are the tests we do all the time on our patients, and they're all recognized as being useful tests by the regulators for clinical trial approval. And ideally, we'd like to see something within 1 year improvements, which would justify approval of the treatment. So if we could go to -- so the failure of the MERTK results in accumulation of this outer segment debris in the subretinal space. And there is undoubtedly a window where the function is impaired, but the cells are still there, potentially could be reversed with a clinical trial outcome measure seen very quickly after gene therapy. And that is seen in the animal models.

Next slide, please. So again, this just explains a little bit about what I said, the functional loss, okay? So any disease in which there's a loss of function before you get degeneration has a potential opportunity for reversal of functional loss by gene therapy, which gives us a nice clinical trial outcome measure. The reduction in vision, as I said, in most cases, we see it in childhood teenage years. Most patients manage reasonably well. But they do lose vision, and we do have a large cohort of patients who are treatable. And these patients will, in general, have had relatively normal development.

They may have problems with in childhood with night vision, but they will be able to use a visual system and gives us an opportunity, a relatively large window in their lifespan where we could perform the intervention, as I said, because primarily of the preserved structure as well. And the phenotype on the right-hand side, again, I mean, to be honest with you, it's very, very similar to all retinal degenerations. But what you have to look at, if you're familiar with the structures of the OCT scan is the bottom scan. And you can see the black line, which is basically the outonuclear layer in contact with the reflected line, which is the retinal pigment epithelium. And this outonuclear layer is relatively well preserved.

In other words, the photoreceptors are still there. They're probably largely nonfunctional because the other segments cannot grow. They're not being properly fanocytos. There's debris in the subretinal space, but the cells are there. And when the cells are there, there's a capability of regeneration following gene therapy. And by the way, the reference we've got at the bottom there is the guarding reference, which is the clinical trial led by Cal's a geneticist when he was working in Saudi Arabia. So I think just check. That's pretty much all from me.

So I'll hang around for questions afterwards, and I'll gladly hand over to Ash to go through the molecular biology of the treatment. Thank you.

Thank you, Dr. McLaren. Our clinical candidate, OPGX-MERTK is an AAV2 vector designed also for onetime subretinal administration to deliver MERTK gene within RPE cells. And in this case, it uses an RPE-specific promoter. The capsid used AAV2 is the same as that used in the approved product for digene neparvovec or Luxturna, which as Dr. Bennett elegantly described, has now had a long track record of improving clinical outcomes in patients with RPE65 associated IRDs.

So the MERTK deficient mouse model, which has been published and established for some time now, allows us to study the efficacy of MERTK gene therapies in a relevant context. This mouse model rapidly loses photoreceptors and concurrently loses visual function, but this decline can be prevented through subretinal injection of AAV and coding for MERTK.

Specifically here, gene therapy-treated mice exhibited improved outer nuclear layer thickness as shown on the top right panel and improved electroretinogram or ERG functional responses as shown on the bottom right panel. And furthermore, using another model, this case, a rat model of MERTK deficiency called the RCS or World College of Surgeons rat model of retinal degeneration, we demonstrated that the clinical candidate, OPGX-MERTK was capable of dose-dependently reducing photoreceptor degeneration in this model when compared to a control injection, which had no therapeutic response as outlined by the blue dash line on measures of outer nuclear layer thickness. So with that, we look forward to investigating the safety and preliminary efficacy of OPGX-MERTK in clinical studies.

And with that, I would now like to turn the call over to Dr. Lejla Vajzovic to discuss ADRPRO IRDs.

Thank you. Thank you very much, Ash. Good morning to you all. It's truly a pleasure to be here with all of you. It's really a pleasure to be included with such an outstanding, really world-renowned experts and clinicians, scientists and industry leaders. It's super excited to be here because the future of, I think, care of IRD patients is looking really bright. And I commend the Opus Genetics team for working so hard to provide more options for our patients in the future.

As mentioned, my name is Lejla Vajzovic, I'm Professor of Ophthalmology, Pediatrics and Biomedical Engineering with tenure at Duke University. As a clinician and surgeon who has been taking care of pediatric and adult retinal patients with IRDs and who has been delivering the gene therapy surgeries for the last 15 years at Duke, I'd like to provide some more perspective on RO specifically associated retinitis pigmentosa, what I see in my clinic, how these patients progress over time and what's really the essence of the disease and why this may be a great therapeutic approach to treating these patients.

So let's dive into RO-associated retinitis pigmentosa and one of the most common inherited retinal degeneration that we encounter in our practice. There has been more than 290 disease-causing mutations that have been identified and RO variations account for approximately 20% to 30% of autosomal dominant retinitis pigmentosa cases that we see. Importantly, this is not an ultra-rare disease. Currently, estimates suggest approximately 8,800 affected individuals in the United States and more than 30,000 across the global markets.

From a clinical perspective, these patients often first present with night blindness and difficulties in dim environment. So this is really the first complaint we will hear very much from our patients. Over time, they experience progressive peripheral vision loss while maintaining the useful central vision for years to come. I think this combination of meaningful patient population, prolonged disease course, I think, makes an especially attractive target for therapeutic delivery.

Next slide, please. Well, let's dive into biology itself. Well one of the aspects that makes RO particularly compelling is that we understand the disease biology exceptionally well. Row encodes rhodopsin, the critical photopigment with the rod photoreceptors that really enables vision in the low light conditions. When mutation does appear, the resulting protein can misfold or function abnormally, triggering cellular stress and progressive photoreceptor degeneration. Importantly, many dominant role mutations act through toxic gain of function or dominant negative mechanism.

As a result, these therapeutic approaches most address the mutant protein itself rather than really adding another copy of the gene. So we really want to address that mutant protein than just kind of multiplying and adding new copies. So deep understanding of this disease biology really provides us with stronger scientific rationale for targeting gene therapy approaches for certain.

Next slide, please. I think one of the most encouraging aspects of R-associated disease, it's often relatively slow progression. This disease typically begins with raw destruction during the childhood. As I mentioned earlier, it presents with night blindness and peripheral visual field construction over time. But the cone, the central vision degeneration is typically the last one to occur in this disease course. We do understand that there are 2 classes, 2 broad phenotypes that have been described here. Class A patient experience is more of a severe disease with early functional loss, while Class B patients often maintain broad function and preserve retinal structure well into the adulthood.

I think this distinction is important because many patients, again, retain viable photoreceptors for years, creating meaningful opportunity for us to intervene therapeutically and hopefully stop their degeneration or at least slow it down. I think the structural and functional data shows that there is definitely room for intervention and the disease progression can very much, as mentioned earlier, in other diseases can be measured as such with imaging and functional testing, providing us now tools to really understand and how to develop clinical trial designs, follow the patients and ultimately report on outcomes.

I think before I transition back to Ash, I just want to summarize. I believe Rove represents one of the most compelling opportunities in inherited retinal diseases because it truly combines 3 key characteristics for me. First, we have well-understood disease mechanism; second, meaningful and identified patient population that we can treat. And third, we have a therapeutic window where the photoreceptors remain present and potentially are amenable to interventions. Those characteristics, I think, make RO an attractive target for gene therapy, especially in development.

And with that, I'm going to turn it back to Ash to discuss really their OpusRO program. Thank you so much.

Thank you, Dr. Vajzovic. In this case, we're talking about the clinical candidate, OPGX-RO. This is an AAV5 vector. And like the others, it's for onetime subretinal administration for patients with autosomal dominant retinitis pigmentosa associated with RO mutations. OPGX-RO is a mutation-independent single AAV construct for silence and replacement. And this is designed to replace mutated rhodopsin proteins with a functional nontoxic copy, and the vector targets rod photoreceptors using selective promoter technology.

We've been fortunate to have demonstrated preclinical safety and efficacy in 2 large animal models of ADRPRw as previously reported. Here, in the canine model in collaboration with Dr. William Beltran of the University of Pennsylvania, we have tested safety and efficacy of the clinical candidate in this model of ADRPRO mutations. The canine model is a mastive, English mastive with a naturally occurring point mutation in row and expresses nearly equal amounts of wild-type and mutated row proteins and captures well, we think the structural degeneration observed in Class B human ADRP patients, as you see on the top right.

Within the first 2 years of life in this model, there is a substantial loss of photoreceptors. However, this time course can be accelerated even further with light exposure to enable the study of therapeutic interventions within an efficient window. In fact, with a 1-minute light exposure protocol, rapid photoreceptor loss down to even a single row of outer nuclear layer nuclei can be observed as early as 2 weeks post light exposure in the ADRP row, but not the wild-type canines. And you can see that on the bottom right panel. So this accelerated degeneration model has been useful for us to test our clinical candidate.

So here, on the left panel, we can see that the retinas post injection of subretinal AAV and light exposure treatment have exhibited significant outer nuclear layer retention in the treated areas. So the dash lines are actually showing demarcating the subretinal blood boundaries here. And immunofluorescence on the right panel shows rhodopsin and cone staining with conarstin in green and red, respectively. That histology and immunofluorescence confirms our observations in vivo. And what we're seeing here is photoreceptor cell body retention with observation of rod outer segments as well, which was only observed in the subretinally treated areas, not the proximal untreated areas.

So in the addition to the canine model, we have also tested on the next slide, OPGX-RO safety and efficacy, in this case, in a humanized swine model of ADRPRow, and this was in collaboration with Dr. Maureen McCall of the University of Louisville. This model exhibits a human p23HR variant, which is highly prevalent in North America. And the retina in this model rapidly degenerates by postnatal day 60, such as there is only residual rod structure and function followed by subsequent cone degeneration. And thus, this also, we believe, accurately models the structural and functional degenerative time course that we see in ADRPR patients.

We observed that OPGX-RO here, as shown on the right, preserves rod photoreceptor structure and reduces the aforementioned degeneration. And specifically, if you look in the untreated panel on the bottom left, untreated rods are sparse. They are dysmorphic and rhodopsin is mislocalized in these retinas. However, when we treat with OPGX-RO, we see that it's capable of dose-dependent preservation of rods as shown in the upper right panels -- and in this case, you're starting to see proper localization of rhodopsin and preserved cell morphology.

Not shown here, but also previously presented was preservation of the rod isolated full field ERG in treated animals, but not untreated animals. We also have observed preservation of cone structure throughout the study as shown on the upper right panels. And this is also correlated with preserved cone ERGs, again, not shown here, but previously presented. And so with that, we look forward to investigation of OPGX-RO in clinical studies.

And on that topic, I will turn the call over to Dr. Sally Tucker, our Chief Medical Officer.

Thanks so much, Ash, and good morning, everybody. As Ash said, I'm Sally Tucker, Chief Medical Officer. If we go to the next slide. As mentioned earlier, when we consider the IRDs we're targeting, that fall into 3 separate buckets. We have the vestroonopatpies, which includes both ARB and BVMD. These patients with ARD generally occurred much earlier on than BBMD. And the progression can be slow and often variable.

It results in a defective calcium chloride channel that results in functionality dysfunction of the RPE that results in cone loss, patients often complain metyphoxia, decreased central vision and photophobia. And then in the other 2 buckets, we have LCA and retinitis pigmentosa. LCA, which we have touched upon already, generally occurs from a much earlier onset. Patients are born with the LCA and it affects vision much earlier on and in many cases, from 1 to 2 years with many patients being blind early on. Whereas in retinitis pigmentosa, the vision loss can occur in the adolescents to adulthood.

So there can be progression over years. However, regardless, with these patients, they have abnormal red cone functionality, decreased central vision, night blindness, visual field loss that results in tunnel vision and for many patients, niceness. And as we indicated previously, our goal is to reinstate the functionality of the retina in those patients that have structure so that we can then see vision improvements in a relatively short time period.

We go to the next slide. This indicates the signs and symptoms of the various IRDs that we're targeting. And what you can see here is that the signs and symptoms really key in the development and design of the protocols for all of our IRD programs with us addressing either structural endpoints or key functional endpoints. So you can see here with many of the signs, we're really focusing in on fuunalystography, funder autofluorescence and SVOCT. -- as Dr. MacLaren indicated, it can be that these changes occur over a longer time period. However, with the symptoms, we're focusing in on better corrected visual acuity, low luminance visual acuity, FSP, microperimetry, contrast sensitivity, virtual reality, MLMT, perimetry, static perimetry and kinetic visual field testing.

And then in addition, we also can look at pupilometry and quality of life parameters as well, which are important to consider in those symptoms that might be more hard to quantitatively assess. Our clinical designs follow a data-driven dose exploration approach. So what does that mean? Well, with any Phase I/II study, the primary purpose is to determine safety.

We want to ensure that the drug delivery is safe and is well accepted by the patients that it is administered to. But we're also wanting to see an efficacy, and we're wanting to see as maximum efficacy as possible. So what we will do is we take a data-driven approach. We utilize an independent data monitoring committee, and we will present the data to the committee. We're looking for safety. And if the -- there is some efficacy there, but it doesn't represent a maximal approach, then we will dose escalate into higher doses. However, if there is evidence to suggest that a maximal efficacy signal has been reached, we would then progress into a pivotal trial without any further dose escalation. We go to the next slide.

We have 3 programs that we are entering the clinic over the next 12 months. So it's an incredibly exciting time. We're expecting RDH 12 to be initiated later this year, MERTK in Abu Dhabi in the first quarter of 2027 and Row utilizing global locations in the second half of 2027.

As such, if we go to the next slide, we do have a number of strategic partnerships, one of which is with the RDH12 Alliance. This encompasses the fund for site in the U.S. and eyes on the future in the U.K. And I see the RDH12 is a co-developer in our IDH12 program. We have received funding from the alliance to support the progression of this clinical trial. And we have regular calls to discuss the trial design, providing updates to the patient community. And we are actually at the Family Day, the RDH 12 Family Day that's being held in London this weekend where we'll be providing updates of our current RDH12 program. In addition, we have a partnership with the Abu Dhabi Department of Health.

As indicated earlier on, MERTK has a higher prevalence in the UAE and Middle East. and we have received funding to support the execution of the clinical trial there. And we also have other partnerships with Hope and Focus, Foundation Fighting Blindness and other organizations that really help to elevate awareness of the clinical development programs we are running, support our patient enrollments and optimize recruitment to the studies that we run. Moving on to patient recruitment and retention strategies, which are key in the overall success of any clinical development program. It's true that globally, more than 80% of clinical trials fail to enroll in time.

So how can we overcome that? Well, we're developing patient education videos -- we want to increase awareness of the IRDs that we are focusing in on, but also help to provide more education to the patients that are considering participation. So we're interviewing patients that have been involved in prior clinical trials, what were the questions that they had, what was the thought process that they went through, how can we provide more material to the patients in a mentorship capacity to support the decision-making that they might have. Where possible, we'll initiate observational studies before moving to the interventional study, which will help to identify IRD patients in a proactive way. And as I said previously, we optimize patient engagement. So where possible, we'll work with patient alliance groups such as the IDH12 group, be involved in family days -- we also have a newsletter that patients can sign up to through our website. And we also reach out across patient databases, utilizing many of the databases from Foundation Fighting Blindness, SyoGenetics, Invitae and others.

The other thing that we need to consider is that there is an 88% clinical trial dropout rate in long-standing studies. And with our studies, they have a 5-year follow-up. So it's important to collaborate and consult with patient advisory boards, giving their inputs to our protocol design, making sure that we're selecting the right endpoints and also making sure that we're considering the burden on the patients being involved in the study.

And finally, what we are also piloting as part of a way to improve retention in our clinical trials that goes above and beyond the traditional step end that you see in the U.S.-based trials. is that we also want to give something back to the patients. So making sure that we continually educate them throughout the course of the trial, reminding them why they're in the trial and what we're hoping to achieve through the trial, but also providing a coaching initiative to these patients so that they're getting something back in return for their time, which is not insignificant over a 5-year period.

And then lastly, we are all about increasing the patient's voice. So this is one of our patients that was recruited to LCA 5 and was actually featured on -- good Morning America. We're not only wanting to increase awareness amongst the IRD community, but more broad than that. What does it mean to a patient living with blindness, the impact that it has on them and the impact that being in a trial can have on them and the treatment and what it means to them. So we're very proud of this initiative and how we've supported Linzay in increasing awareness of LCA 5 in this way.

I'm now going to hand over to our President, Ben Yerxa.

Thank you, Sally. We've had a few that have come in. Let me sort through these real quick. So for the first question for our guests, we should probably consider this sort of like a lightning round because we've got a number of questions. But I think for Dr. Fan, MacLaren and Vajzovic, let me read this out loud. So for IRDs that affect a relatively small number of patients, such as LCA 5, RDH 12 and MerTK, how difficult is patient identification? Are there ongoing efforts to increase patient genetic testing? And how motivated are patients to undergo such testing when no treatments are available yet?

I can briefly take some of those questions. I would say, obviously, they're very rare diseases, but patient identification for an IRD specialist typically comes naturally. You get a lot of referrals, not just from the retina community, but also the optometric community and fellow ophthalmologists, general ophthalmologists. So typically, if you're in a referral center, they do come. And oftentimes, you can see multiple rare diseases of the same gene mutation in the same day.

I think a lot of a lot of patients are incredibly motivated despite the fact that there may not be an approved therapy just because there's other implications beyond just clinical trial and FDA-approved treatment, including family planning, protecting future generations, genetic counseling, all those things are major factors and perhaps sometimes the primary motivation for genetic testing.

And with efforts from OPI and collaborations with FSB, there's been increased availability, at least in the United States to get low-cost genetic testing universally for all patients. I've had no issues testing these patients and almost 100% of them will do it because they're motivated for sure.

Thank you. Dr. MacLaren?

Yes. I mean in the U.K. and I think in Europe as well, virtually everyone will have genetic testing. It's an essential part of the workup of any patient with an inherited retinal degeneration. And indeed, if anything, the electrophysiology is what's gone out window. We tend not to do that very much anymore because we can tell very well from the imaging how advanced the patient is and monitor progression.

But I think it's important to think about this as a lot more globally, okay? So I agree that there are individual genes, which are very rare, but the strategy is the same. It involves measurements of OCT measures of visual function. It involves an AAV vector. We know now exactly what the dose is. There will be differences in the requirements of different vector. The shipping manufacturing, don't forget, manufacturing is a key part of regulatory approval that should not be underestimated. It might be sometimes manufacturing is more complicated than the actual clinical trial.

And then you've got the administration, the surgery, the subretinal injection, all the technology that's developed quite a lot, followed by the monitoring, the checking for inflammation and all the rest of it. So if you look at all the diseases together, then it becomes quite common. And we're talking about young people as well.

So I always say, since we've been better at managing diabetic retinopathy, the inherited retinal les collectively are now probably in the U.K., the most common cause of untreatable sight loss in people of working age. So if that's not an unmet need, where is it? And I think what we've got quite nicely here is like a platform technology that overlaps on many different genes and therefore, has much more -- many more patients just for one single gene disorder.

Very well. And I agree, CMC here in gene therapy. Dr. Vajzovic?

And just to add to those amazing answers really from Dr. Fan and Dr. MacLaren, I would say, in the U.S., everybody that steps into retinal clinic that has any hint of IRD will get genetically test tested. So I think that has been really the crucial change for all of us in taking care of these patients. And not only will the patient result, but really we're discussing the effects of the entire family.

And I feel like as a result, due to genetic testing, now we're diagnosing siblings and other family members earlier than we might have done before. So that has been really the big change. And lastly, we have amazing technology to image these patients in clinic these days. So I completely agree that we're relying on imaging more than ever to help us understand the disease and in clinical trials to help us understand responses.

Great. Thank you. Next question, I think I'll direct to Dr. Sally Tucker. This one goes, in general, are you planning on testing these next 3 gene therapies in children or adolescents early on in clinical development? Or will data updates in 2027 likely be in adults?

So the clinical trials will be designed to incorporate the inclusion of both adults and adolescent patients. So how they'll be structured. So similar, if you remember the slide that I showed and the platform approach, it will include 2 adults and then a minimum of 3 adolescent patients. So we established the safety first in the adults before moving on to the adolescent patients. So although the adolescents will be recruited to the study later on, the plan is to include younger patients in this first-in-human study.

Great. Thank you. Question, I think I'll direct to Dr. MacLaren. How much do you think the data from the ex-U.S. trial in EMERGE-K will help the eventual development in the U.S., U.K. and Europe?

Well, it wasn't really done as a proper clinical trial in terms of particularly having a natural history beforehand, which you normally have like a just getting baseline data to the tests are. And then the patients were selected with some very, very end stage because they're part of the family. So I think there's limited data we can get across the cohort. But there was one patient who did particularly well with the vision.

And these patients have not had any major side effects and the effects we've seen following the gene therapy with are very, very similar to that seen elsewhere. So I think if I were writing the investigator brochure or preparing the work for the regulators, I'd certainly be citing this trial as a good example of having used the vector before in humans. And I think that would make the process a bit smoother and probably even less requirement for doing NHP work in order to gain regulatory approval.

Great point. Thank you. A question now for Dr. Bennett. For RDH12, could you expand on the similarities and differences from RP65, especially on the preserved current sensitivity. Could you talk about the therapeutic window for RDH12? And is there an optimal treatment age, early childhood versus adolescents? And then finally, one question. On the preclinical RDH12 data, any insights on how much restoration of enzyme expression is required to achieve meaningful functional benefit?

Great questions. The bottom line is we don't know because we haven't run the trial yet, but what -- but this disease is more severe than R65 deficiency. It -- the symptoms are manifest earlier and the degeneration is a little bit faster. But there is a great natural history study that is being carried out and has been carried out by Dr. Smasloman and colleagues, which is giving us a lot of information about the optimal time points and of treatment in terms of the rates of progression. Likely, we will be able to rescue -- I would predict we'd be able to rescue vision at least through adolescents, but probably the best outcomes are going to be in younger children. The other question was, can we predict -- can you repeat the second part of the question in terms of enzyme levels?

So how much restoration of enzyme function like percent restoration of function do you think will be relevant for improving...

Right. Well, knowing that heterozygotes are -- have fairly normal vision, we don't -- we believe that if we restore up to 50% of the level of enzyme activity, that should be sufficient. But even a small amount of enzyme activity should be helpful. And similarly to what we have found with RP65 deficiency, there may be just a rate-limiting step, which we need to overcome to be able to deliver some vision.

Got it. Thank you. So the next question came in. we'll think about who wants to jump in to answer it is how should we think about ranking potential pivotal endpoints for each program? Among the programs in development, do you see clusters of programs for which you expect the clinical development path or pivotal study designs to be the same in terms of like endpoints, number of patients, length of trial, et cetera. So I don't know who wants to jump in on that. Maybe, Sally, do you want to start? So...

I think that it's a little early to determine what our pivotal trial endpoints, primary endpoints would be at this moment in time. I think that all of our assets are rare or ultra-rare. And therefore, we're in this unique position to be able to get regulatory recognition such as RMAT, orphan designation, RDE, which really allows close collaboration and discussions with the agency. And that's certainly something that we I think that with these IRDs as well, there also needs to be consideration of novel endpoints and utilizing novel endpoints and also statistical methodology as well to be able to determine mean net benefit. And these are all things that we can consider when talking to the agency. I think that microperimetry is an endpoint that we're very interested in from determining central macular sensitivity. But I think it's a little early to say whether that would be uniformly utilized as our primary endpoint for all our pivotal trials.

Thank you. Last question in the first part here. Across these defined IRDs, are certain mutations considered higher priority in terms of progression? And does this impact Opus' gene therapy development prioritization? -- might be back to you, Sally, unless one of the KOLs want to jump on that as well.

Can you repeat that, Ben? Sorry.

Yes. So across all these IRDs that we're looking at, are certain mutations considered higher priority in terms of progression, like LCA versus RTE? And does this impact our prioritization of the pipeline?

So I think the prioritization of our pipeline is much led by our manufacturing efforts and when we're ready to take the various assets into the clinic. rather than the prevalence or the severity of the disease. So at the moment, as I said, we're expecting IDH12 to be in the clinic at the end of this year, with MerTK the beginning of next year and at the end of next year. And we'll be bringing these as quickly to the clinic as we can, dependent upon when we have availability of the drug and can push these forward.

Great. Makes sense. Dr. Bennett, anything you want to add to that?

I would agree with what Sally said. We plan to move forward with both -- with all of these candidates in a regimented time line and move as quickly as possible. But of course, there may be some factors which which would make one set of mutations, one disease target move faster than another. At this point, we can't predict.

Great. Thank you. All right. Great session for Part 1. Thanks to everyone for your participation. Thank you to all the speakers and all the great questions that came in. We're now going to move to Part 2 of our agenda. So I would now like to turn the call over to Dr. Bart Leroy to begin our clinical program discussion with LCA5.

Thank you, Ben, and thank you everyone -- to everyone for inviting me to be part of this beautiful series of presentations. So my brief is to talk on the LCA5 update. And can I have the next slide, please? So what is LCA5? It's actually an early onset severe inherited retinal disease with early onset visual loss as so many we've discussed previously in the first part of the meeting.

Now the LCA5 is a particularly severe disease with very early onset loss of vision. It supposedly represents about 2% of all LCA cases. That would be globally 3,200-plus patients within the U.S., about 170 approximately thought to be there. a pigmentary retinopathy, which is typified by macular atrophy quite early, but preservation of photoreceptors in the pericentral area of the macula. The vision loss typically starts in infancy and patients often have just vision of hand movements or light perception. Thestagnus and hyperopia are things that are not only seen in this condition, but certainly also here or people with congenital bad disease or very early onset bad disease have nostatnus and hyperopia.

But the photoreceptor cell loss also leads to the fact that it's very hard to obtain any visual fields in such patients, although there is potential because there's preservation of the pericenteral photoreceptors. Can I have the next slide, please? So the Opus Genetics LCA5 gene therapy, which is currently being used and tested is designed to restore a key protein of the visual cycle. And so basically, that protein is called liocillin.

It's actually a ciliary protein that is critical for the function of photoreceptor outer segments mostly because it works in the connect in sum. All of the proteins that are involved in what is translation of light into electrical signals, the photo transduction are being produced around the nucleus and then have to travel all the way to the outer segment to do the phototransduction. Levoillin is very important in getting them there.

The photoreceptors, as we said before, can actually survive quite long until the third decade of life, and that is suggestive again of as so many of the diseases we've been talking about of having a window of time during which treatment can happen. So on Opus genetics CCF5 is designed to address the mutations in this gene, and it's clinically a derisked AAV8 vector that delivers a functional copy of the LCA5 gene directly to the photoreceptor cells using similar promoter technology as it was used in Luxturna. It's a single subretinal injection.

Next slide, please. So what is remarkable is that adults have been treated. And so what we're showing here is that the mean change from baseline in visual acuity in the adult cohort with 3 patients involved is continuing to be significant, as you can see on the left-hand side with the orange line, an improvement is upwards in this slide. On the right-hand side, you see for the first time until month 6, the results coming from the pediatric cohort, equally 3 patients. And you can certainly see that there's an improvement, a significant improvement of best corrected visual acuity.

Next slide, please. So you can also continue to measure function. And in this slide, for example, we talk about cone function as measured using the FSD or full field stimulus test, actually full field sensitivity testing that is showing on the left-hand side, what we do with red light and with blue light in the adult cohort. And on the right-hand side, you see the pediatric cohort. And you can see a significant improvement again for both colors used in the cohorts, both adult and pediatric, the pediatric up to 6 months and 24 months for the adult cohort.

Next slide. So you can also test sensitivity, if possible, that is if fixation is sufficient, using microperimetry. Microperimetry used separate protocols are available. And so here, for example, it's a 10-2 protocol that was used. This is a photopic test. And as you can tell, the sensitivity in one patient, adult participant 104 and pediatric participant 106, the 2 only patients who are capable of doing this test shows an absolutely significant increase in sensitivity in the central area of the macula and actually a little bit of a movement of the fixation of the patient towards the foveal area. So both patients show significant increase in function of the central area of the macula that is consistent with the treatment effect.

Next slide, please. So one last thing that I just wanted to mention is what do people say -- and patients actually report changes in their daily life, activities of daily living are significantly improved. And for example, in the adult participants, 0101 reported being able to identify her children within a larger group of children 1 month after the surgery, which she couldn't do before, navigating urban environments independently and no longer requiring continuous use of a cane was reported by 0104. That's the patient -- the adult patient who was able to do the microperimetry.

If we go to the pediatric patients, -- for example, the 0106 patient, also the one with a better fixation so that she could do the microperimetry reported a noticeable difference in the visual brightness between the treated and the untreated eyes. I said it was a girl, it's actually a boy, I'm sorry, and able to watch basketball, important for children, I think, and can see the players and follow the ball instead of watching the score ticker and listening to the commentary. So I think with that, I've shown that there is a real treatment effect of the Opus Genetics LCA5 program.

And with this, I'd love to pass on to Ash again.

Thank you, Dr. Leroy. There are over 300 mutations associated with Best disease, which we'll talk about now. And there are several distinct phenotypes with both dominant and recessive modes of inheritance. The dominant forms include AVverC, which is autosomal dominant vitreoretinal choroidopathy. And then there is a highly prevalent phenotype, which is called BBMD or Best vitlloform macular dystrophy. It's named for the hallmark EggYoke or vitllaorm macular lesion in this disease.

And then there's the recessive form, autosomal recessive bestrophinopathy. And disease onset and severity of BEST can vary. BEST1 is a calcium-activated chloride channel or CAC, and it is expressed in the retinal pigment epithelial cells, and it's responsible primarily for retinal ion and fluid homeostasis. So it follows that dysfunction in the BEST1 channel and its activity can result in a number of vision-threatening complications that you see here. As we discussed, there are several variants of BEST1 looking a little bit closer.

The recessive form, BEST-ARB, lacks functional copies of BEST1 expression in the RPE. Now the more common dominant form of BEST, which is associated with BBMD, for example, has 2 different forms. It's a loss of function and gain of function variant type. And that's a critical distinction that we're making there because -- it's thought that gain of function dominant mutations are unlikely to be treatable with conventional AAV gene augmentation, which is the focus of the OPUS clinical trial with our candidate OPGXBest1. However, we and others have demonstrated that loss of function mutations in contrast are treatable with AAV gene therapy.

And those happen to account for the majority of best 1 mutations, perhaps over 98% However, the genetic test in the clinic used to diagnose BEST1 IRDs may not report this detailed loss of function gain of function information. So OPUS has developed a paradigm to help predict treatment responses to BEST1 gene therapy and help ensure that the patient carries indeed a loss of function mutation, which is going to be amenable to gene therapy.

So we're in the process now of testing every known BEST1 mutation for treatment response using tools such as iPSC-derived RPE cells and other engineered mammalian cell models. And in this case, we use technologies such as patch clamp electrophysiology and fluorescence reporter assays, which allow us to directly or indirectly measure the chloride conductance function of the TAC channel. And we've developed these in-house to understand, first, if the mutation is a loss of function or gain of function mutation and also whether or not it is amenable to VestT1 gene correction.

So when we receive the genetic test, we can then look this mutation up in our test battery to see if this mutation has been tested for personalized responder, nonresponder type analysis by OPUS. And so we will be using this information in collaboration with our community of specialists to help select patients for clinical investigations of our candidate OPGXVest1. This is a single AAV2 vector for onetime subretinal administration and also features an RPE-specific promoter.

And with that overview, I'm happy to hand the call over to George for a brief clinical review of VestT1.

Thank you, Ash. I'll provide a brief clinical update on BEST1 program. For reference, the data we have presented to date at Macula Society and ARVO are available on our website on the BEST1 page. We've completed enrollment in Cohort 1 of the Phase I/II study with 5 participants, including 2 autosomal recessive and 3 BDMD participants. You'll see that the BDMD participants are significantly better at baseline with participant 102, 102 being the least advanced participant from a visual acuity standpoint.

What I'd like to really show you today is some of the phenotypes on the OCT that we're selecting for. Now this is being selected with a number of our colleagues in the field and has really been a a great process for ensuring that we get the right subjects into the trial. This participant is 101, 106, and this is a representative BBMD patient. You can see that the participant has a pretty intact foveal depression along with the retinal layers being intact in the periphery, both on the nasal and temporal side. Under the fovea and extending particularly to the temporal periphery of the retina, you can see the subretinal fluid that is part of the vllorm lesion. This fluid is low in diffuse and it's on the backside of the neurosensory retina, which is detached.

Now importantly, for these patients, you can see the small areas of hyperreflective material, which are so-called shiny photoreceptors, which indicate the photoreceptor all segments may still be present. This is an important differentiation from the so-called faced backside of the neurosensory retina. So we do expect that the product, if it works, should be able to decrease the amount of fluid under the retina, under the fovea. And as that fluid decreases and the retina is repposed to the RPE and Brooke's membrane complex, there is a potential that there might be a functional benefit for this patient. We also may potentially see that the ellipsoid zone line, which is present in the periphery of this image, began to expand back out into the center of the macula, which would be fantastic for this patient. That would be expected to result in an increase in visual function.

When we test visual function, we're testing really 4 different parameters. One of the most interesting to our team is the microperimetry. And what I'd like to see here is the overlay of microperimetry on the infrared image of the OCT that we've already shown on the prior slide. Essentially, the OCT and the infrared image on the prior slide can be directly overlaid onto a map similar to what you see here. So what you notice is that the areas of subretinal fluid that were present on the last slide on OCT are highly correlated with depression on sensitivity map on this slide.

Therefore, in the areas where you see a 0 decibel sensitivity or a sensitivity of, say, less than 20 or so decibels on the heat map, you would expect the sensitivity of the retina to improve as the subretinal fluid in those areas goes away. That would be the hypothesis we're trying to prove in this study. The ability to overlay the pathology and the modification of the pathology with this functional endpoint is a very unique thing for this program, and it allows us to test functional improvement of the retina at a very high spatial resolution. This is an approval endpoint with the FDA, so the improvement in these phosal microperimetry treatment would be acceptable as a potential pivotal endpoint.

Obviously, we're still collecting all the other functional data, but this is a very unique thing for this program that we're excited about. So this is why we're looking for patients with fluid that correlates with visual functional improvement. If we're successful in decreasing the fluid and there are photoreceptors present, then they should function better if they're in their native configuration. This should -- this we hypothesize should lead to an improvement in multiple functional endpoints. And most notably, as I've shown here today, potentially microperimetry.

At this point, I'd like to turn the call over to Dr. -- I'm sorry, to Joe Schachle, our Chief Operating Officer, to discuss the patient journey and epidemiology of these IRDs.

Thank you, George. Good morning, everyone, and good afternoon to those in Europe and elsewhere. Two topics I'd like to touch base with you on. First is the IRD patient journey. I'll give you a brief overview of the patient journey. You heard a little bit of that this morning earlier.

And then also talk about disease prevalence, global disease prevalence, which you've seen in each of the individual presentations, but we'd like to show you all together as well. So looking at the patient flow, as you heard, patients will often see an optometrist or a general ophthalmologist and then be referred to a retinal specialist. And that retinal specialist may make the diagnosis, may refer to a specialist that specializes in IRDs or a genetic counselor for genetic testing. And this is a very key step and something that we all need to support is the genetic testing aspect.

If you look at the green bar, if you move to the left side of that, that's a patient that has a gene that we have a potential to treat and has been identified. Currently, RPE65 is the only one we have to treat and look forward to being able to add to that in the future. So that's kind of a general view of how patients may move from symptoms to diagnosis to ultimately treatment. So thinking about global estimates on prevalence.

Originally, we look -- we use 2 primary sources for global incidence and prevalence. The first was the Stone paper, which is an excellent study. It's 1,000 I&D families being treated at one site from across 40 states. It's very helpful. The HA study is also very helpful. It's a global study looking at 6 markets outside of the U.S. and that was initial data that helped us estimate prevalence. Since then, we actually have asked Trimal Insights group to prepare analysis, a meta-analysis of studies and they completed that in the first quarter of this year, and that's what you're seeing data here in a moment. That meta-analysis originally looked at over 1,200 studies.

And of those 1,200 studies, greater than 90 qualified for use in this study. They need to have genetic testing as a backbone to the actual study itself. And we looked at 5 geographies: the U.S., EU4 plus U.K., China, Japan and Middle East and North Africa. So just taking a look across the globe here, let's focus on the U.S. first. We kind of generalize that we have small, medium and large prevalence diseases we're focused on.

If you look at LCA5 and MAT1, those are our smaller prevalence diseases at 170 and 1,200 -- if you think about the midsized disease, we're looking at RDH 12, MERTK and CNGB1, -- those are on the 2,000 range for prevalence. And then finally, we look at BEST1 and Re as the larger prevalence diseases at 8,400 and 8,800. And as you heard in some of the previous presentations, looking Middle East and North Africa, you can see RDH12 with a prevalence of 17,500, so a fairly large population and MERTK over 14,000 patients.

Moving to China, you see Re has almost 15,000 patients and RDH12 has almost 10,000 patients. So you can see across the globe, there is substantial medical need for treatments for these diseases. One final slide here, and this is just -- this tags into some of the things you heard earlier is there may be underestimation of the actual prevalence of some of these diseases. If you look at our current best 1 prevalence, we're estimating about 8,400 patients with Bestung in the U.S. And that's based on studies that have confirmed genetic testing in the diagnosis.

If you look at the right portion of this slide, we may be underreporting best disease, and there's 2 factors for that. First is, while most patients do get genetic testing, because of the vllongoest1, some patients may not get tested because they may be assumed to be best 1 and currently no treatment available. The flip side of that is actually the misdiagnosis of best 1. We're in the midst of a market research study right now, a large market research study, and we're hearing quite frequently about the misdiagnosis. And I'm going to read quickly this quote to you. Quite a few of my best patients have been seen by other physicians in my practice and did not get the diagnosis of Best disease.

I think there are a lot of patients who are not diagnosed correctly, I would say, about 50%. So we are hearing this consistently across the study that there's a misdiagnosis and lack of diagnosis for best. So we may actually have some higher rates of prevalence that we have estimated currently. So thank you for your time.

With that, I'll turn it back over to Ben.

Thanks, Joe. So now in addition to Dr. Bennett and Dr. Leroy, we are pleased to have joining us today Dr. Todd Durham, Senior Vice President of Clinical and Outcomes Research at the Foundation Planning Blindness. Todd is responsible for overseeing the Foundation's patient registry, natural history studies and other clinical programs. So let's go ahead and kick off this session. And I'll start with a question for Jean. Since Jean, you have such a unique perspective given your history in the field and the LUXTURNA development days. But if you could just kind of give us a perspective, what was the state of play with respect to genetic testing then versus now? And what were some of the biggest hurdles and unknowns?

When we first started getting ready to recruit patients in 2007, we had gotten everything all together and gotten all of the approvals, the institutional approvals, the FDA approvals. And then we looked out to try to find patients -- where were the patients? Nobody or very few patients in the United States had had genotyping because there was no reason to get genotype. There was no treatment, no clinical trial available. And it was thanks to our colleagues in the European Union that we were able to start.

Our first 4 patients came from Italy, where they had made great progress in genotype phenotype correlations. And several of the next patients came from Bart Lois site in Belgium because he had also been genotyping patients. And so now the situation has changed dramatically. There are now numerous sites, physicians genotyping patients because there are treatments -- there is the LUXTURNA treatment available, and there are clinical trials available for many of the other forms of IRDs. And plus people are anticipating the clinical trials that are being developed by Opus Genetics.

Got it. Got it. Yes, it sounds like kind of a night and day difference. Well, that's great. Thanks, Jean. Todd, a question for you since the foundation offers free genetic testing program. Could you walk us through the history of the program, how it might differ from others? And what are some other resources available for doctors and patients?

Yes, sure. Thanks, Ben. Foundation Fighting Blindness has had a registry study, my Retina tracker registry since 2013. In 2017, we received a grant to try a pilot study to provide genetic testing and counseling to a small number of sites, really the centers of excellence at that time to see how -- what the uptake would be as a pilot study. And it turned into an amazing success.

We now are able to offer at no cost genetic testing and counseling to patients with inherited retinal disease in the U.S. We have hundreds of eye care professionals, including optometrists, both vision specialists all over the country who are ordering through the program now. And at this point, we have tested over 32,000 individuals as of the end of March. And it's very -- it's a huge program, I would say, wildly successful. And I think from the foundation's perspective, we're opening access to patients all over the country, not just those who have access to a specialist center.

And that makes a huge difference when it comes to recruiting for clinical trials. This program is just one of many that exists today. It has always been -- well, most recently has been an option in the clinical setting to access a test for those individuals who have insurance coverage or able to afford a cash pay. But there have been other programs over the years offered by commercial labs, the National Eye Institute had their own program for many years. I would say -- I would say -- I would estimate that at least half of the individuals in the U.S. with inherited retinal disease have had access to a genetic test by now. And I think this is going to be a program we will continue to need because not everyone will have access to a test at no cost or free.

That's great. I'm always astounded at how fast that registry is growing and how many tests you guys have provided. It's really remarkable and really moved the field forward. So great work. Bart, Dr. Leroy, since you sit in a different geography in Europe and Belgium, what's been your experience with genetic testing? How does that work in your part of the world? And what percentage of your IRD patients have confirmed genetic diagnosis...

Well, thanks, Ben. It is the culture of how to organize society is indeed very different from one side of the Atlantic to the other. Taxation is far less in the U.S. So more money is given for grants and so on and so on. That is certainly less in the EU where taxation is higher, but the tax is used, for example, for national health services. And so for example, in Belgium, but not only in Belgium, in many other countries, we have a fairly free or nearly free or if you're a clinical geneticist, which I also am, I can offer free genetic testing to our patients.

Basically, everyone who walks into the door through the door with a genetic diagnosis gets genotyped. And so obviously, because of the constraints of what testing currently is, we don't do yet whole genome sequencing on everyone. But I would say we say about 70% of the patients get their genotype, but everyone gets the opportunity, and they generally don't pay a euro for it.

Got it. That's great. So it sounds like basically everyone in your practice with an IRD has at least had access to a test.

It's true. And I'd love to actually add to what Joe is saying because if you look at, for example, the bigger European countries, I mean, don't forget if you take the U.K. plus the EU currently because the U.K. left us, Together, it's 550 million people. I think that in the U.S., there are 335 million people. So I think if you look at the whole of the EU and certainly the Western part of the EU, they have really good molecular programs. So for example, for bestophinopathies, I would certainly say that there are many more patients in the EU than there are in the U.S. And as he was rightfully saying, there are many underdiagnosed.

Yes. Yes, great point. All right. Let's transition over to natural history studies and thinking about how it affects clinical trials because as we know, every IRD has its own clinical natural history and there's even genotype, phenotype correlations or noncorrelations that can complicate the picture here. So Maybe, Jean, starting with you, how do you see how an understanding of clinical natural history affects clinical development plans and for example, how that helped in the development of LUXTURNA?

Well, when we started planning towards a clinical trial for LUXTURNA, we started doing a retrospective natural history study for RPE65 because there was no information and it would have taken too long to do a forward planned study. And that natural history study was run by Dan Chung, who went to numerous centers, including Dr. Luz and and other centers around the world to collect this data. And the data was extraordinarily helpful.

It demonstrated that contrary to some people's hypotheses, this disease is not stable, that it does progress in the photoreceptors degenerate and retinal pigment epithelium degenerates over time and it's relentless. And it confirmed that the various outcome measures that are used to monitor retinal degeneration, standard clinical measures such as visual acuity, visual fields, et cetera, light sensitivity decrease over time.

And that data has been really important, not just in the early stages of the trial, but also in following the durability of the treatment. We're now looking at long-term durability and comparing that to what one would normally see in an untreated patient and seeing big differences.

Right. Great. So like deviation from natural history is a clear sign of efficacy, I guess. Yes.

Todd, at the foundation, you guys have been running these really large multicenter longitudinal studies. I mean some would say these are the gold standard in the field now. And can you talk about the clinical consortium that you guys are running, your approach and some of the benefits of like a multicenter versus single center study?

Sure. Yes, the Foundation Fighting Blindness clinical Consortium is a collaborative network of inherited retinal disease specialists, reading centers and geneticists to help us better understand inherited retinal disease.

And I would say from the foundation's perspective, the primary purpose there is to better inform better clinical trial design, selection of outcome measures, length of follow-up that's required. finding the best opportunity for therapeutic intervention for various modalities.

The largest of these that we've completed to date is the RUSH 2A study in non-syndromic and syndromic SS2A retinal degeneration, and we've had numerous papers about that. I think what makes it unique is the investigators, this is intended to be collaborative. And I think the benefit here is we share the learnings across the centers. And I think from a data perspective, A single center offers one advantage when it comes to clinical development, especially for subretinal injections, things like that.

But many of the larger IRD trials and programs will require multiple centers to recruit sufficient participants for rare disease. And so we need to know how to run those studies so they can be generalizable and maintain the quality. So that's a big focus of ours is to use standard protocols, same images and equipment, reading center methodologies and to develop and to publish those results. We have lessons to learn to share with the whole community.

Super helpful for any sponsor in the space wanting to run a trial, that's really, really helpful. Real quick, could you also just talk a little bit about the UNyARE study? I know OPUS is sponsoring a couple of arms of that study for RDH12 and BEST1. Any updates there?

Yes. Just briefly, the UnyE study was our answer to trying to streamline the start-up process for natural history studies, where we already launched a study in EYS-associated RP that essentially using same protocol and procedures as did the RUSH2A study. So Dr. Shell from UPMC said, why do we keep doing the same start-up process? Let's develop a protocol that -- where we can do a plug and play, so bring in gene-specific cohorts and run with those rather than having to put the sites and all of us through all the pain and hassle of having to do all the protocol review and IRB submissions. So UnyRE was intended to target the most rare of the IRDs because it got relatively little attention in other studies.

And as you mentioned, Ben, we are partnering with Opus Genetics on a BEST one cohort of UNyRARE and one for RDH12. And these 2 cohorts illustrate the unique design of UNyRARE, which is a very large cross-sectional study. We're calling the registry component of the study, where we have planned enrollment of 1,500 individuals. And this is really just an opportunity to get a good phenotypic characterization and cross-sectional look, including images that we can then send to the reading center. So that's in the case of OPUS, the BEST1 cohort.

And then as we receive funding interest and prioritization for cohorts to follow longitudinally, we can then plug those into the longitudinal protocol and follow people annually up to 4 years. In the case of OPUS, that's the RDH12 cohort. And the latest update on those is we have 65 enrolled in the BEST 1 cohort with OPUS and 19 enrolled in RDH 12, and we're beginning to bring in the RDH 12 participants to year 2.

Great. Great. Thank you, Todd, for the update. We're really excited about that work. We are real quick lightning round, one last sort of question for each of you, starting with Jean. What's one actionable step you think sponsors and sites can take together tomorrow to improve recruitment and retention in IRD trials?

I think one possibility would be to make genetic testing available on commercial platforms or patient-oriented platforms such as 23andMe and not just patients, but people who are interested in looking at their own genetics might make it more available.

Got it. All right.

Yes. I think certainly, there's a difference. I think having genetic testing, like Jean was saying in the U.S., a little bit more accessible despite the unbelievable actions of FFB. I'm a real big fan of FFB, and you can see that initiative from large organizations like this help enormously. I think patient retention is not as bad as I think the numbers that were shown in the sense that it's not my experience across 13 different gene therapy trials that we're currently running in GE that we lose many patients.

It's actually by all means, just here and there, maybe one individual. So I basically think that getting them in will be better, as Jean was saying with what she mentioned. Maybe if you want to do even better is really helping sponsor the activities of what FFB is doing because I think the Unilever study is the way to go for the future.

Thank you. Todd bring us up.

Yes. I think the -- in addition to those comments, I would say, hyper focus on the needs of patients and their families regarding trial participation, communication about what clinical trials are, making sure they have assistance with any translation or interpretation that they may need when they visit the site. And I think this is all pretty standard in the IRD field now, but really focus on that experience for them. It's a tough decision for people to decide to participate in the clinical trial.

Yes. Great. Perfect. Thank you very much to all of our panels for sharing your thoughts on this important topic.

Now we will transition to our final Q&A session, where we will be joined by the rest of our speakers. So the we will get ready for our first question. That is -- I think I'll send this to you, Jean, actually. So can you comment on the expected duration of effect of a single treatment?

The best information I have goes to LUXTURNA, where we started out studying dogs and the longest -- we followed was the life of a dog, which was 10 years. We showed that, that rescued the photoreceptors in the treated area of the retina only. We're now following patients in long-term studies. In fact, the LUXTURNA studies go for 15 years of follow-up. That's a long time, and we are at the 10-year mark. That data will be -- has been submitted for publication and so should be out shortly. But it looks very promising in that the durability data is excellent.

Got it. A quick follow-up to this for Ash. It's a question about the MerTK animal model slide, where it looks like the effect is waning at the latest time point at 71 days. Is there something you could comment there?

This was a preliminary proof-of-concept study and further dose optimization, further readouts are necessary to confirm kind of the true window of treatment and durability. So that's an effort that's ongoing right now.

All right. So are the other IRDs beside BEST1 also likely to be underreported? How are the general dynamics in genetic testing and diagnosis for IRDs? I'll take a volunteer for this one.

And I'm happy to talk about the best one or the question on IRD frequency. I think we -- others may be underreported. So that may be the case with some of the IRDs because there are so few treatments. However, we really have the most data on BET one because of our quantitative market research. So I really can't speak to as much as the other ones, maybe some of our key opinion leaders have an opinion on that.

Got it. Anyone want to chime in on that?

I can do so if you want to. So I think Joe is right. So bestrophinopathies are probably highly underreported -- some of them have been seen from clinics that treat uveitis patients, et cetera, et cetera, even patients who are just not aware that they have anything. I think that other ILDs are underreported, but probably at lower numbers. I'm pretty certain there are patients even in developed countries like the EU countries and the U.S., where still patients even with night blindness and some visual field issues roam around without understanding that their disease is actually a retinal degeneration. So there's an underreporting certainly ongoing. I think many people will still not get to a specialist, but I think the numbers are particularly high for bestrophinopathies.

Question for Ash. For best for BE1 gain-of-function mutations, would it be possible in the future to test a silence and replace strategy similar to R.

Sure. So why that's not in scope for OPUS now, silence and replace and editing could be possible for gain-of-function mutations in the future.

All right. So regarding the 24-month update for LCA 5, did improvements in BCVA translate to benefit observed in the virtual reality mobility test at month 24? Probably a question for Sally.

Yes, it did. So with all 3 patients, they all had a meaningful improvement in the virtual object recognition.

Great.

All right. What is the proportion of LCA 5 patients would be candidates for treatment? And how long is the treatment window for most patients? Do you want to take that one also, Sally, or maybe one of the KOLs...

It's down to the O&L preservation. So a lot of these patients have preserved ONL quite late on in the disease. I mean up to in their 40s and 50s. So I would say that it's a large amount of the population. Bart might be better to comment. However, that's -- those are the patients that we'd be targeting. We'd be targeting those that have preserved ONL.

And Sally, I can just comment what you just said. In the interest of briefness, you're absolutely right. I think a large chunk of the patients would be treatable because they have preservation of some meaningful cells that can be targeted until fairly late in life.

This one is probably good for George. In BEST1, how do you think about treating patients whose lesions do not yet involve the fovea? How can benefit be assessed in these patients?

This is one of the beautiful things about the microperimetry. It's kind of the key point of the microperimetry is that the grid overlay can identify the retinal sensitivity directly over where the lesion is present. And so for patients with extrafoveal or paraphoveal, the tellform lesions, you can look at the microperimetry grid points that are overlying the area of the teleform material and our natural history studies and our initial patients enrolled in this trial -- inform us that those should be depressed compared to retina without nurositry detachment.

A question for ASH. Will the disease and the dish be part of the clinical workup -- and how much time cost does that add? How can you determine that the expression of wild-type BES will be sufficiently high for any given mutation?

Sure. We're currently testing all mutations now. So we don't wait for the patient information or genetic testing to come in. We are testing all annotated mutations in this disease in a dish model to understand which mutations are loss of function and which are likely candidates for gene therapy.

And in those tests, we're able to directly interrogate using in vitro cell models that resemble B1 disease pathology, whether we can restore BS1 channel activity to that of wild-type best expression. So that is a proxy for expression, but also directly measures function. And we think that's a decent predictor of what could happen clinically and then which patients are going to likely be responders.

Great. Thank yo. Next one is, given the recessive ARB subtype is mechanistically cleaner than the dominant BVMD subtype, would you consider splitting the 2 into separate time lines, so the ARB program can keep moving even if BVMD optimization takes longer. Someone from the OPUS team, George or Sally.

Sally, why don't you take that one?

So I think that it will be down to -- like I said earlier on, we take a data-driven approach. So we'll be looking at the data, seeing how the patients respond following treatment. And then that will scope our strategy as to whether we continue with BBMD and ALD together or if we split out into 2 separate studies. So it's something that we might consider. But again, it will be down to the data and what we're seeing.

All right. I think we're here at our last question, just about our last question. So based on manufacturing, how many patients can you treat once approved in initial 3 indications? First question on manufacturing. Who wants to take that?

So I can take that. So the manufacturing has been a really productive discussion with the FDA. So just like we've been having the clinical discussions on trial size and endpoints for ultrarare, we're also having the same type of discussion on the manufacturing processes. For some of -- for the smaller programs, certainly for LC5, a single 50-liter batch will treat a majority of the world's population, right? So we're delivering 300 microliters through the subretinal injection LCA5, the manufacturing is quite modest. For RDH12,erckyK R, those programs are a little bit bigger, but still should be well covered by 50-liter batches.

As will best disease, if the upside of best disease that Joe talked about, it turns out to be true, then certainly, we will start to get up to a -- to needing more than batch and having to make multiple batches, which in our experience with best one should be very doable. It's important to remember -- a big part of the thesis of OPUS is not just clinical efficiency, but it's also on the manufacturing side.

And I think Dr. MacLaren mentioned this earlier. This is one of the reasons why we're using pretty well-known vectors well-known gene augmentation techniques is because these things can be readily manufactured. And now the world has now a couple of decades of experience, thanks to some of the pioneering work by Dr. Bennett and the University of Pennsylvania team years ago.

Great. Thanks, George. So I'll do one more quick question and then George will make some closing remarks. So this is to Todd Durham. Can you just talk a little bit about how Foundation Play and Blindness as a patient advocacy group works with the FDA to help move the field forward.

Yes, sure. Happy to, Ben. So I guess the best example is from our RUSH 2A study. We had several meetings involving the FDA and the European Medicines Authority to share our learnings from that. One of those things, I would say, resulted in a Duke Margolis meeting in September 2025, primarily about our findings and recommendations about the FST.

I think where we ended up with that is the FDA currently is not ready to accept that as a primary outcome measure for inherited retinal disease trials. That has, I think, informed our decision to develop a strategic plan to provide the missing evidence around clinically meaningfulness for that outcome measure and others for inherited retinal disease, and that's work we're undertaking now, having gotten a lot of input from our key opinion leaders and experts on that.

So we intend to continue our dialogue with the FDA and EMA and other regulators as we learn about novel endpoints. And we are also advocating for patients through patient-focused drug development meetings as we go through time. So it's an active engagement, and we're pleased to collaborate with them.

Great. Thanks, Todd. Appreciate that. Thanks, everyone, for that Q&A session. I'll now like to turn the call over to George for some closing remarks.

Thanks, Ben. And so let me just summarize what's special about Opus. Number one is it's proven science. Number two is that we're uniquely well capitalized to execute against multiple programs. Number three is that we do have multiple shots on goal. And number four is that there are real near-term significant value inflection points, multiple within our current runway.

And I'd like to thank everyone for your time and attention this morning, especially a big thank you to our guest speakers. What an amazing panel, I mean, really honored to be a part of for adding -- thank you for adding your insights and your expertise. We look forward to updating everyone on our progress as we continue to advance our gene therapy pipeline and continue to hopefully bring these innovative therapies to patients. Have a great day.

Good morning, everyone. My name is Susmita Roy, and I'm an associate on the JPMorgan Healthcare Investment Banking team. On behalf of JPMorgan, I would like to thank everyone for attending the Healthcare Conference this year. And I'm pleased and honored to introduce Opus Genetics for the company presentation today.

A bit about Opus Genetics. It is a clinical stage biopharmaceutical company developing gene therapies for inherited retinal diseases, trading under the ticker symbol IRD. They have a multi-asset pipeline with near-term data readouts with many milestones in 2026.

It's my pleasure to introduce the CEO, George Magrath, for the company presentation. I'll hand it off to him, and we'll take Q&A right after. Thank you.

So thank you, and thank you to the JPMorgan team for inviting us, and it's great to see a full room here. That's wonderful.

So I'd like to take a minute to talk to you about Opus Genetics and what we're up to. So this year is going to be a pivotal year for us. We have a readout in our biggest indication, which is BEST1 disease, which will happen in the midyear. We've got the ongoing pivotal trial in the LCA5 program. That was the program that was featured on Good Morning America a few months ago, and that's going to have additional data coming in the not distant future as well. And then we're looking forward to multiple additional assets hitting the clinic. So it really is a good year.

The Opus Genetics story is really interesting. It's very unique. It is a story that's based on Dr. Jean Bennett from University of Pennsylvania, along with a number of other collaborators of hers. And we're looking at what we consider sort of low-hanging fruits. So we're looking for diseases where the structure of the eye is normal, but the function is not, and it's not because a single gene is missing. And that lends itself very well to straightforward gene augmentation, very similar to what Luxturna did as the first approved genetic medicine in 2017, also invented by Dr. Jean Bennett.

So in these AAVs, you're delivering a small dose directly under the retina, very localized, very precise and looking at diseases where we're not trying to do long studies where you bend curves. These are studies where you should see an improvement of function, a reversal of the pathology pretty quickly, 3 to 6 months. So it lends itself to efficient development. There are a number of these in our pipeline. You can see we refer to as a string of pearls. The seven of them are at the bottom of this slide. And each of these is a very efficient, quick program that's been hand-selected for these reasons.

When you think about this delivery system, it is, I think, the most precise drug delivery in all of medicine. We're delivering a 300-microliter bleb under the retina, really like in our BEST1 program, we're really only trying to transfect 5,000 or 10,000 cells in the retina. The exposure outside of the eye is negligible. The side effects are -- the systemic side effects are negligible and the ocular AEs are very well characterized. These are all AAV2s, AAV8s, AAV9s. These things have been used in the eye before our company is really more of a development company, not a discovery company. We pick things that we think are going to have high probability of success and are reasonable to show efficacy in efficient, quick trials.

Now the important key underlying factor to what we're doing is the concept of structure function dissociation. So in these patients, in these diseases, we're looking for patients that have almost normal anatomy, right? So the photoreceptors are there, the bipolar cells are there, the Muller cells are there, the ganglion cells are there, the RPE cells are present, the retina structure is there and the machinery is turned off for some reason. And so that is the structure function dissociation, lends itself very well to gene augmentation. It's almost like you're baking a cake and you're missing one ingredient. You put that ingredient in and all of a sudden, you're off to the races.

So the structure function dissociation is important because it gives you a high probability of making a biologic impact. It also gives you a quick readout. And so when you reverse pathology, when you take these profoundly blind people and give them vision back, you see it pretty quickly. So in these studies, we know whether or not we have a drug pretty quickly.

Now the pipeline is broad with these. So there are 7 of them. The key thing to focus in on is the fact that we typically use equity dollars to concentrate on clinical programs. Right now, those are LCA5 and BEST1. This year, it's going to be multiple others that are in this pipeline. The preclinical assets all have additional support to get them through the clinical -- preclinical pipeline. So the team led by Ash and others has been incredibly efficient at getting grant funding, getting partnerships with different patient alliances such as the RDH12 group that are bringing these things forward. So it really is an interesting business model that is taking these things from the lab into the clinic.

We have another unique aspect to the company is which we have a commercial asset that's partnered with Viatris for sales. So this asset is a topical eye drop called Phentolamine Ophthalmic Solution. The brand name is Ryzumvi. It's on the market for the first indication, which is that it reverses dilation after an eye exam. And then it's -- we just submitted the sNDA for presbyopia, which is the need for reading glasses.

So if you put this eye drop in once at night, if you look at our Phase III studies, people can then read without glasses for about 24 hours. So a very, very interesting value proposition for people. So this has been partnered with Viatris. We have a double-digit royalty that tiers into the 20s, and we have around $120 million in milestones on it. Viatris is a great partner. They have a large sales force, and we're very excited for presbyopia to potentially be approved this year.

So we're going to have a readout in BEST1, which is our biggest wholly owned indication. We're going to have a potential approval for presbyopia, and we're going to have an ongoing pivotal trial for LCA5, and we're going to have multiple of these preclinical assets entering the clinic this year. So the team is busy. It's a lot of fun.

Let's talk about 2 of the lead programs here and the upcoming milestones that we have for these. So BEST1 is a disease I'll talk about in some detail in a minute, but it's a large indication in the rare space. It's 9,000 patients in the United States. When you think about that epidemiology, there are around 5 or so epidemiological studies. The bookends of that are somewhere between 5,000 and 19,000. Using our methodologies, we're honing in on around 9,000 patients in the United States.

This disease is a loss of a calcium chloride channel where you get a blister of fluid under the retina. If you replace that calcium chloride channel, then the fluid should go away and the vision improves. This trial -- the Phase I/II trial is ongoing. And in the midyear, we'll report data. And the things to look at in the data are an improvement in the electrophysiology, so the ability to have a calcium chloride gradient, a voltage gradient across the RPE, you can actually measure that. So that will tell you about cellular target engagement. If the fluid on OCT goes away, then that will tell you about the macro structure. And then if vision improves, that will tell you about the function. So it's a really nice logical walk of endpoints that we'll be able to read out in the midyear.

LCA5 is a program where we have already treated 6 patients. All 6 of those patients have had clinically meaningful improvements in vision. One of those patients was featured on Good Morning America because of how profound her vision restoration was. And after an RMAT meeting in October, we have begun enrolling into the pivotal trial. And so the first 2 patients have been enrolled in a pivotal trial, and we're going to continue that this year, looking for data readout -- not this year, but probably in 2027.

These are actually big indications. And the reason I say that is because a first principle is that you get reimbursed for the improvement in patients' lives that you create. And when you have a dramatic improvement like taking a blind child and restoring vision, you can command reasonable pricing to make it worth your while. So you can see here that the market opportunity is actually really good as long as the string of pearls stays intact. And these are -- this is a very important slide because a lot of the preconceptions that gene therapy development is long, expensive and with limited return is just fundamentally not true for Opus Genetics. We're going after very well-characterized AAVs, very well-characterized diseases, quick endpoints, small trials, meaningful impact that should be reimbursed in a reasonable manner.

So let's talk a little bit about -- more about BEST1. So BEST1 disease is one of the most common IRDs that's out there. There are about 350 of these inherited retinal degenerations. 3.5% of those have BEST disease. It's typically seen in regular retina clinics. So the way the patient's journey goes with this is that they -- it's in the first -- in the midlife years, second to fourth decade of life or so, the patient will have mildly distorted vision, and they'll typically go to their optometrist. The optometrists will see the clinical exam, which is almost pathognomonic for BEST disease. They'll send them to a retina specialist to confirm that diagnosis.

A lot of times, in my practice, I didn't even genotype these patients. because you could tell -- you can make a clinical diagnosis of BEST disease and there was nothing you could do for these patients. So you would tell them to follow up once a year. Eventually, those photoreceptors will atrophy and they will end up with a large area of geographic atrophy. It looks exactly like the geographic atrophy associated with macular degeneration. That's profound vision loss. So you end up with this multiyear window of potentially intervening for these patients where they're mildly symptomatic, the photoreceptors are still present, but they're detached from the retina, so they're kind of floating in this fluid. If you can resolve that fluid, the photoreceptors won't atrophy, they'll be back in their native place and they can potentially see again. It's a really nice pathology to be able to intervene with, large therapeutic window, not much of the channel is needed to impact the disease, and it's a very precisely delivered directly to the lesion.

So the cellular biology is really interesting with this. So the bestrophin channel is a pentamer that creates a calcium chloride channel. The purpose is to put calcium on one side of the cell, chloride on the other side; doing that creates a gradient, which pulls fluid from the photoreceptors into the choroid, into the systemic circulation for disposal. So as those photoreceptors, which are incredibly metabolically active, are continually to produce byproducts, that osmotic gradient causes those byproducts to be pulled out of the retina into the circulation.

In BEST disease, you lose that channel. That gradient goes away and the fluid just accumulates under the retina. And that's exactly what you see on these scans. So on the right of this slide, where you see OCT, that is a cross-sectional view through the retina. And at the top, on a Stage I, that is essentially normal looking. And what you see is as the fluid accumulates, as the patients go from Stage II to III to IV, you get more and more fluid. So the photoreceptors now are on the backside of that fluid detached from the wall of the eye. So if you look at the bleb of fluid, you've got photoreceptors, you've got RPE, you've got fluid in between them.

That fundamentally takes the photoreceptors away from their support system, from their nourishment. So they are kind of hanging out in the wind there. And if they do that for long enough, they will atrophy. As they atrophy, they stop producing metabolic byproduct. The fluid goes away and you start to see that in Stage IV, and you see the conclusion of that in Stage V, where you have atrophy where the photoreceptors are gone and you have total vision loss in that image where the black circle is in the middle of the autofluorescence image.

There are 2 types of BEST disease that are important for us to talk about. The first is BVMD, the second is Autosomal Recessive. So Autosomal Recessive is a very clear-cut gene augmentation target. There's no bestrophin channel that's being made. Gene augmentation can restore that. In autosomal dominant disease, this is still a good augmentation target without the need to silence the mutant protein because this is -- the stoichiometry allows you to outcompete the mutant, which is nontoxic in most cases. and formed that pentamer.

So we've actually done a lot of in vivo disease in the dish type models at a patient level basis where we can show restoration of the function of that channel with dominant mutations. So the one part of this disease, one genotype of this disease where we will not work is gain of function. In a recent publication by GeneScape, that accounts for around 2% of the BEST population.

The AAV is very straightforward. So it is a construct in an AAV2 that has the normal BEST promoter. So not only are we delivering it directly to the RPE cells in a very targeted fashion, the promoter won't even be turned on unless it is in an RPE cell. So it's like a second line of safety for off-target effects.

In a dog model, which is the data is shown here on this slide, what you can see, this is a naturally occurring dog model that was done at the University of Pennsylvania published in PNAS on the citation that's listed. You can see that, that blister of fluid on the cross-sectional image, which is the image right below the picture, you see the pocket of fluid in a control animal, that pocket just gets bigger. In a treated animal, that pocket literally goes away. So you're looking at reversal of pathology in this disease. It's a wonderful endpoint. It's a wonderful view of target engagement.

The retina specialists in the United States, every one of them does this scan on every patient that comes through their door. This is going to be very important to us as we try to show target engagement and modification of biology.

On the histopathology right underneath that, you can see that the photoreceptors not only lay back down on the RPE, but they restore normal interdigitation with the RPE. It's almost like a handshake. So it goes literally back to a normal configuration.

So right now, we're doing a Phase I/II trial. We've -- we're enrolling these patients in 2 cohorts, 1.5E9, 4.5E9, 5 per cohort, and we're going to be reporting the data in midyear. We do think that the -- that even at the lowest dose, we should see target engagement. And that target engagement, we would know through electrophysiology at the cellular level, OCT at the macro structural level and microperimetry and visual acuity at the functional level. BEST disease is incredibly exciting.

I'll talk a little bit about LCA5. It's a much smaller indication, but we have amazing data in this. So this is a really, really impactful medicine. This disease is a type of childhood blindness where the typical patient journey is that these children are born with the mutation. They usually -- mom or dad notices that the kid at age 1 or 2 can't really pick up a toy, can't see to pick up their cheerios to eat, things like that, take them into the doctor's office. The fundus looks pretty nondescript.

And so these patients all get genotyped. They all end up at tertiary care centers. Honestly, most of them end up at the University of Pennsylvania. So of the 200 patients, I think 50 or so are seen at the University of Pennsylvania by [ Dr. Tomas Solomon ], who's the world's expert in this. So this is a profound blinding disease from early in childhood.

However, for the first few decades of life, the structure remains normal. So as in the nondescript fundus findings, when you look at these patients, typically, the fundus looks pretty normal, the OCT has all the structure there. Everything looks good, patient can't see. They have a defect in a protein called lebercilin, which is a structural protein in the photoreceptors that causes them to be in their normal configuration. So the loss of lebercilin causes the photoreceptors to still be present, but not to be able to sense light.

So the rest of -- so what we're doing is very simple. We're using an AAV8 with the same promoter technology as Luxturna to replace lebercilin in photoreceptors. The reason this is AAV8, BEST1 is AAV2 is because of the target cells. BEST1 is targeted to RPE. This one is targeted to photoreceptors.

So we've -- at this point, we've treated 6 patients. All 6 have had clinically meaningful endpoints and profoundly blind patients, you need to look at the endpoints across different types of modalities to be able to evaluate them. The first and actually, honestly, the most unexpected was that 5 out of 6 had a clinically meaningful improvement in actual visual acuity.

The first patient that I'll show you in a minute, went from -- this is an example, went from being able to just see shadows like a hand maybe in front of their face to being able to see the biggy on the eye chart. So very profound type improvements. And these gains were seen as early as 1 month. And so it's pretty fast to turn on the machinery.

The durability that we've seen in the adults that we've treated so far is out to 18 months. And really, you sort of see a peak in efficacy at 3 to 6 months with a duration at least out to 18 months at this point.

FST is an incredibly important endpoint. This was the first statistically significant endpoint in the Luxturna trials in the 2010s. FST is a way to measure the overall sensitivity of the retina to light. It's a very good test. What we've seen here is a logarithmic scale improvement in FST and an improvement to what the investigators and the FDA consider to be sort of a theoretical maximum for this disease. The improvements in FST in these patients is the reason why we worked with the FDA to -- even at the lowest dose to stop dose escalation and go immediately into a pivotal trial. It's really remarkable on FST.

MLoMT, this is a virtual reality maze. So this is a test where the patient puts on a headset like a meta headset, and they have the 2 little joysticks or whether the controllers, whatever you call them. And they are presented a course that they follow in virtual reality world through the headset with objects that they tag. And so it's a very simple elegant test, mostly of their peripheral vision. So if visual acuity measures sort of your central vision, then MLoMT is more of a peripheral vision test.

And so what you'll see reported here is the number of objects that they could identify. And you do it at multiple luminances, which are all clinically significant. You kind of start at like a starry night lumens and you go to like a full moon to a normal conference room to a bright conference room type lighting. And you'll see that this was pretty meaningful. Safety was as expected. So there were no ocular treatment-related serious adverse events.

So the 6 patients we've treated, you can see here. The main things to see on this, we started with adult patients, right? So these are adults literally like the 34-year-old patient, 0101 is the one that was on Good Morning America. She's 34. She's been blind since she was a little child. And what you can see is with the logMAR visual acuity, it's pretty severe. Now we are going into pediatric patients because we believe as you treat younger and younger patients, you have more of an ability to intervene and restore vision. And so we think that the results are probably going to be amplified in the pediatric population, and that's exactly what I'm going to show you in the coming data slides.

The first is visual acuity. We measure visual acuity in logMAR because these patients are off of typical eye charts. And actually, they jump between charts, and it's a little bit more nuanced to measure this low of vision. But you measure in logMAR and a kind of rule of thumb for the people in the audience that are familiar with ophthalmic trials is that for every 0.1 logMAR improvement is about the equivalent, approximately the equivalent of 5 letters on an eye chart or 1 line on an eye chart. So what you can see here in the adults is the orange line is the treated eye. The untreated eye is the more teal line, and you see a nice separation there that is seen pretty early in disease and is maintained out to 18 months.

In the children, on the right of the slide, we have much less follow-up. We only have 3 months of follow-up, but you see a more profound separation from the fellow eye, and you see a really remarkable 0.4 improvement in logMAR visual acuity. It's really great vision. Patient level data is available on our website, if anybody is interested in seeing actually all 6 patients.

FST is really interesting. So FST, again, this is a logarithmic scale. So when you look at the separation, you have to put this into a logarithmic type framework, not a linear framework. And red and blue is both -- is different wavelengths of light, obviously, measuring different types of photoreceptors. Again, you see a separation that is clear, consistent and durable.

MLoMT, this is the virtual reality mobility test. Again, this is the number of objects a patient could identify through the meta headset. On the Y-axis, you see the number of objects. On the X-axis, you see time. And again, you see the adult cohort on slide left and the pediatric cohort on slide right. And what we think is noise in this based on some work done at Penn on the validation of this test is that approximately a difference of about 2 or 3 objects is going to be the standard error.

Microperimetry is really interesting. Microperimetry is a test where you can actually do a point-wise testing of the -- it's almost like probing the retina to see the light sensitivity. So on this image that you see here on this slide, you see a grid overlaid on the patient's retina. And then in every one of those black points, you test the sensitivity of light at that point. And so only this requires fixation at baseline. Only 2 of our patients could actually complete the test, but these patients had a remarkable improvement in the area of the retina that could sense light.

So the thing to concentrate on this is really sort of the heat map. So if you look, for example, in the second column, that's the study eye, if you look under sensitivity, you see baseline is the first image with maybe 3 little red marks at 1 month and then at 12 months, you see something that looks like the continent of Australia, I think, something like that, much, much better. You see this also in one of our pediatric patients who could do this. Really remarkable test that shows not only target engagement, but also shows functional improvement in these patients.

So at this point, we have excellent safety data. We have robust biological activity across every endpoint that we've tested. We've received Rare Pediatric Orphan Regenerative RMAT, all the things. And we have talked to the FDA, and we flipped this trial into an adaptive Phase III trial that we're currently enrolling.

We do have that partnership with phentolamine. I'll go very quickly through this. We're very excited about the sNDA for presbyopia. I'll tell you the differentiation here is that currently, the approved version of phentolamine, Ryzumvi does not carry a warning label for retinal detachment or for issues with dim light vision. And so we think that this will be very well received for patients and a great product. So we're looking forward to potentially having this approved this year.

At this point, I'll go through a little bit of just the expected catalyst one more time, and then we'll open it up for questions. So again, the main thing to concentrate on is the BEST1 readout in the second half of -- or I'm sorry, in the midyear of '26. Initial data will be at a medical conference in Q1, but that will be very limited data.

LCA5, we're going to continue dose in the Phase III, and we'll provide updates on that. We think that at least 2 additional gene therapy programs will enter the clinic this year, and we're very excited about both of those. And then Phentolamine, the second indication of presbyopia, we hope for an approval sometime this year.

With that, we'll open it up for questions. And I'll also ask the President of the company and Co-Founder of the company, Ben Yerxa, to come up along with Ash Jayagopal, the Chief Regulatory Development Scientific Officer.

I'll kick off questions that we have here. You slightly touched on it during the presentation, but if we could just double-click on what you think is the differentiation on Opus' approach to gene therapy, in particular, in the diseases that you mentioned.

Yes. Ben, I'll let you take that since you founded the company.

I mean in terms of the differentiation of approach, I think it's a really unique opportunity to take assets that have a very straightforward material set. So known capsids, known promoters, very well-understood method of delivery. So it kind of derisks our approach as we go into the clinic. I think that we rely on Jean Bennett for her expertise so that we really know the right starting doses to go into. So that translational moment from animals to man is a really important moment. And I think just kind of nailing that program after program is a pretty big differentiator for us. Did that answer your question?

Yes. I appreciate it. As a quick follow-up to that, I think a lot of the presentation focused on the mechanism of action and the delivery to the back of the eye. Could you just double-click a bit more on not only the -- I guess, more on the safety benefits of that, kind of just double-clicking on that would be appreciated.

Ash, do you want to take that? Talk a little bit about safety of the product.

Sure. To date, the drug products in both BEST1 and LCA5 trials has been well tolerated with no serious adverse effects. And we're not surprised that's based on a very well-established subretinal delivery technique. We use very low doses of vector compared to approved gene therapies on the market. And we have -- these clinical programs are backed by an extensive nonclinical safety package. So this helps to derisk our approach.

Awesome. That's great to hear. Kind of going along the lines of that with the upcoming milestones that you mentioned and the data readout expected later this year, what readouts are you expecting to be able to talk about with the voice later on?

Yes. Well, the one that we would index most people to the biggest value inflection for the company will be the BEST1 readout in the midyear. And our goal for that readout will be to show in the first cohort, a full cohort of data, obviously focused on safety first. And then on target engagement. We think we should be able to show meaningful target engagement.

And again, to reiterate, the things to look at are, it's really beautiful because we can study this disease at a cellular level in humans using electrophysiology that should translate to a macro imaging endpoint with OCT, which then should cross over into multiple different types of functional improvement, either with different types of visual acuity or with microperimetry. So I'd index to that, I think that's going to be the most important thing for the company this year.

Awesome. That's very exciting, and we look forward to it. Briefly moving on to the LCA5 program, not knowing much about it myself. I would love to hear a bit more about what does the therapeutic window look like for a patient with this. Could you talk a bit more about the rate of degeneration and exactly how OPGx, the program, how does it fit into the window that the patients are provided and the options that they have?

Yes, totally. Ash, do you want to talk about that one?

Sure. In LCA5 inherited retinal degenerations. -- this program was selected as the first in the Opus portfolio really because of our conviction and confidence in the treatment potential for gene augmentation. In LCA5, although the visual function declines severely, in the first decade of life. Most patients are diagnosed as legally blind within those first few years of life.

There persists a viable photoreceptor structure that we observed in natural history studies going into the third and fourth decade of life. So these patients have poorly functioning photoreceptors, but they are viable, and we believe that they can be restored by a low-dose restoration of a ciliary structural protein that they're missing. And early results indicate that it is indeed possible even in patients in their 30s to restore what we believe to be clinically meaningful real-world visual function. So hopefully proving out Dr. Bennett's hypothesis.

Awesome. Thank you. I appreciate that. Last question before I turn it over to audience or any closing remarks. I think this is a question all biotech and pharmaceutical companies have with so many great programs and all the diseases that the team is studying. What are -- how is the team thinking about prioritization? Obviously, with the data releases that makes it a bit easy to do, but would love to hear given the extensive pipeline the team has.

It's a great question. And it's something that is unique to us, but we think a whole lot about, and we think it actually is very interesting for patients and for stakeholders in the company. We pick programs that fundamentally have high probability of success with efficient development pathways. So what you're going to see here is manufacturing costs and time lines are reasonable because we're not trying to invent new manufacturing techniques or anything like that. We're doing straightforward AAV augmentation.

We're picking diseases where the pathology can be reversed, which allows you to see an improvement and as we saw in LCA5 as early as a month. And so we're picking diseases. We're picking manufacturing techniques. We're picking science that really -- I think the first principle way to think about it is this is more of a development company, less of a discovery company. Our goal is just to get approved products. I mean that we're going as fast and as quickly as we can towards that.

Truly cool. But thank you so much. I'll leave it. Any other questions from the audience or any closing remarks?

I have a quick question about the presbyopia asset. Is it expected to be a long duration treatment option like last more than 8 hours, a day or?

Yes. So it's -- one of the unique aspects about this presbyopia asset is that you dose it at night and it lasts for up to 24 hours. The reason that we can do that is because you don't -- you fundamentally don't have the issue with dimming that you get with some of the other presbyopia assets out there. The reason for that is fundamental biology. Our target pupil diameter is 2.5 millimeters. The target pupil diameter for the pilocarpine or pilocarpine-like products that are available in the market is more like 1 millimeter. And so if you don't dim the patient's vision, then you can dose at night and you can dose with longer durability. It's a great question. Yes.

So I was just curious about whether you intend to commercialize the approved products when approved or your focus on being a development company. So just how to think about that.

So this is a really great question. So a couple of sort of first principle considerations here. Number one is that in the United States, these are small populations. The call point for a sales team for BEST1, the biggest indication would be around 2,000 doctors. So it's very reasonable. You could do this as opposed to phentolamine, which we partnered with Viatris on because that is a mass -- like the presbyopia market is 140 million Americans or so. So they're very different profiles in the United States. So you certainly could commercialize this in the United States.

One critical -- the second critical sort of first principle thought here is that these inherited retinal degenerations have different founder effects in different regions of the world. So some of these, for example, LCA5 is very common in Germany. MERTK, very common in the Middle East; CNGB1, very common in Asia. So I do think that there's a need for a global type commercialization, which is going to be tricky, but it's something that Luxturna has been succeeding with and that we're looking at different avenues for how to do.

But we see this as -- we see these gene therapies, not just as U.S. products, but as global products. And we think that you will get reimbursed globally. If fundamentally back to what I said earlier, if truly these results kind of hold and are replicated in the other programs, then I think that people will want these for their children.

Any other questions? All right. If there's no further questions, we'll wrap up the presentation. Thank you so much all for attending, and thank you all for presenting. Appreciate it. Any closing remarks, please go ahead.

No. Just thank you for everybody that came. This is great to see the room, and thank you to JPMorgan for the invitation and for all the support.