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 one 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 one in our BEST1 phase I/II clinical trial, known as BIRD-1, which exceeded our expectations from this first in human cohort. At a high level, we have several key takeaways. Most importantly, OPGX-BEST1 demonstrated a well-tolerated safety profile with no serious adverse events, no dose-limiting toxicities, and no intraocular inflammation at any of the visits.
Our gene therapy has been well-tolerated in this first cohort out to three 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 five patients.
That functional improvement was directly paired with structural improvements at just the three-month time point in four of the five participants. The combined functional and structural improvement on the same location in the retina, which we are defining as co-localization, 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 three-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 a 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 two, the high-dose cohort. Initially, cohort two was planned for five participants. We currently have enrolled eight 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 U.S. 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, general ophthalmologists, and optometrists, and account for evidence that a majority of patients with Best disease stay with their local retina physician, are not genotyped, 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 will 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 a program summary and our next steps.
We have a deep pipeline built on a durable platform that is well-funded into 2029 to advance these clinical programs. LCA5 is our most advanced program. This phase III trial is fully enrolled, and we expect results next year. 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 RHO all entering the clinic in the near future. It is an exciting time here at Opus.
As you look across our pipeline, there is 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 are going to talk about BEST1 disease. As I mentioned earlier, BEST1 is a disease that affects 23,600 U.S. patients, and a majority of these have Best vitelliform macular dystrophy, or BVMD.
BVMD is a type of autosomal dominant Best disease that presents with this vitelliform material in the center of the macula that ophthalmologists refer to as an 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 one 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 is 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 two of our participants today. The BEST1 gene encodes for a protein in the RPE that creates a transmembrane calcium-activated chloride channel. This channel opens and moves chloride ions through the basolateral side of the 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 of the photoreceptors that normally are trafficked out of the eye. But in Best disease, they are 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 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 is 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 one primarily enrolled participants in the later stage of disease where the vitelliform material is fragmented. As you will see in our data, OPGX-BEST1 had a meaningful impact in reduction of the vitelliform material in two of the BVMD participants. With that disease overview, I would 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 one 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 advisors. 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 one, which was dosed at 1.5 e9. Cohort two will be dosed at a higher level, 4.5 E9.
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 five participants per dose level.
In cohort one, we dosed five participants, two with ARB who now have six-month data, and three with BVMD who have three-month data, all of which we are sharing the results from today. We expect to have six months data for the three participants with BVMD in Q2 of 2027. As George mentioned, due to investigator and patient demand, we have already enrolled eight participants into cohort two, with surgery dates already planned for seven of these, exceeding the original target of five.
We expect dosing to be completed in the fourth quarter of this year. As expected, in an early safety study, cohort one 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 vitella form material resides.
A recent natural history study by Bianca et al 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 one 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 five 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 four out of five, had improvements, with possible signs of improvement in the fifth.
Among our BVMD participants, 67%, or two of three, had a decrease in the vitelliform material, and both of our ARB participants treated had a decrease in the intraretinal fluid. One keynote about the structural endpoints is that they are co-localized in each of these participants to where there were improvements in retinal sensitivity observed. In terms of functional improvement, 100% of participants had a clinically meaningful improvement in at least one functional measure.
Specifically, microperimetry improved in 75% of evaluable patients. Participant 101101, the sentinel participant, could not do microperimetry to their low vision at baseline. Of the patients that could do microperimetry, three out of the four had at least five loci with a three-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 five-letter improvement.
Low luminance visual acuity improved in 40% of participants, again, with at least a five-letter improvement. Contrast sensitivity improved in 40% of participants with a 0.2 LogMAR or two-decibel or greater improvement. Of note, participant 101106, our youngest participant, showed the largest functional gains, which was exactly what we were hoping to see. Our next youngest participant, 102102, 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 benefit 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 two 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 five letters of visual improvement as compared to baseline and compared to the fellow eye. This was seen in one ARB and one BVMD participant, 101-101 and 101-106. In participant 102-102, there was quite a large improvement in best-corrected visual acuity at two time points prior to the three-month visit. However, the gain was more modest at three 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 five letters of visual improvement as compared to baseline and compared to the fellow eye. Low luminance visual acuity improved in two out of the five participants.
Contrast sensitivity, with an improvement defined as at least two 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 five loci within the treated RPE transitional zone, improving by at least three 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 the 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 four of the five participants.
In our two 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 two 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 two 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 three 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 three-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, four out of the five 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 one 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 pre-specified and accompanied by a PGIS improvement. First, I want to spend a moment defining a 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 three 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 three decibel improvement in this treated RPE transitional zone could be acceptable as long as we pre-specify at least five loci in this area.
In cohort one, 75%, or three out of the four 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 three or more decibel improvement in at least five 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 two of three BVMD participants, had a reduction in vitelliform material, and all three BVMD participants had clinically meaningful improvements in at least one 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 four 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 one in their own words.
All were happy they were included in the trial, with four of the five noticing improvement and multiple participants requesting their second eye be treated. It is encouraging to see the functional impact we are able to make for individuals living with this potentially blinding disease. This is the metric that matters most in the end. Now I will hand the program over to Dr. Ash Jayagopal, our Chief Scientific and Development Officer, to review several participant case studies.
Thanks, Sally. I will 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 seven loci improving by at least three 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 three decibel success threshold. The fundus autofluorescence imaging on the far left shows hyperautofluorescent vitelliform material surrounding the lesion. At month three, 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 observe 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 improve by three 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 observe improvement of retinal sensitivity assessed by microperimetry in the RPE transitional zone, with markedly improved centering of fixation from baseline to month three, 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 three, 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 one month, we did not observe any significant change in this material.
However, by three 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 for this case. Functionally, this participant had a significant improvement in contrast sensitivity that peaked at four 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 inter-visit BCVA variability for this disease. On OCT, there is disruption of the retinal architecture in both the inner and outer retina at six 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 two BVMD participants, she had significant clusters of loci, which improved by three or more decibels from baseline.
As with our other two 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 six months, this participant showed a clear reduction in intraretinal fluid, going from 48 µL at baseline to 7 µL at six 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, so it is great to see the opposite effect so far in our participants. In summary, we have cleared four key milestones on the path to a pivotal trial for OPGX-BEST1.
First, across three months of follow-up in the BVMD participants and six months in the ARB participants, the low dose at 1.5 E9 vector genomes per eye was well-tolerated, with no intraocular inflammation observed at any visit. Second, we believe there is evidence of biological activity with initial efficacy observed on both functional and structural endpoints. 100% of participants demonstrated improvement in one or more functional endpoints.
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. Finally, we are excited that three out of four evaluable participants in our low-dose cohort had more than a three-decibel improvement in the treated RPE transitional zone at three months. Now, I am 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 two, which is three times the dose of cohort one at 4.5 E9. Based on investigator and patient interest, cohort two has already enrolled eight participants, most of whom are BVMD participants. The sentinel participant for cohort two at the higher dose is an ARB patient who has already been dosed and is doing well.
We expect a complete dosing of cohort two 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 three-decibel or greater microperimetry improvement across at least five pre-specified 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 have 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 and 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 four 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 five clinical programs through to potential product approvals and priority review voucher opportunities.
I would 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 are 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 researcher's 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 is a pleasure to be here today, and I think as many of the analysts might know, I am a skeptical person, so I am very happy to report that I am quite encouraged by these results for several reasons. I have been involved with probably over 15 different gene therapy studies. First off, I think the safety data is really solid and encouraging. Specifically, we are not seeing any signs of inflammation, which has been one of the biggest barriers for gene therapy in the past. I think partly the reason for that is that we are at a low dose, in fact, probably 10 times lower than the low dose that many other therapies use. The fact that we are 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. 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. I thought that was very impressive. Additionally, I'm really excited by the alignment with the FDA on the change, that three decibel mean change of five points anchored to a patient-reported outcome can be considered to be clinically meaningful.
This is just a huge accomplishment not only for this program, but I think for all programs in inherited retinal degenerations. 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. Some of our patients are already meeting that, and I think there's still room for improvement in cohort two. Thank you.
Thank you, Mark. Oh. Sorry.
We will now begin Q&A. For today's session, we will be utilizing the raise hand feature. If you would like to ask a question, simply click on the raise hand button at the bottom of your screen. If you have joined by phone, please press star nine to raise your hand. Once you have been called on, please unmute yourself and begin to ask your question. In the interest of time, and given the number of participants on the call, we ask that you please limit to one question. Thank you. We will now pause a moment to assemble the queue. Your first question comes from the line of Ritu Baral with TD Cowen. Please unmute and ask your question.
Hi. Can you guys hear me?
Yes.
Great. Good morning, and congratulations on this data. I actually 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? Does it change how you view the functionality of the retinal tissue underneath at least the vitelliform deposits, if not under retinal fluid? I have just got a very quick follow-up on the phase III.
Sure. I think that fixational data is really great supportive data. 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. I think there is evidence of that. This is still early. It is only five patients. If we were to see that over additional patients, that certainly does lend evidence to a treatment effect.
Got it. If we could just review that composite responder analysis. George, can you remind us what are the deltas needed on the two individual points, and what is the delta needed on the overall responder rate for success per your alignment with FDA? Is any placebo rate expected given the way that the responder definition was put together?
Yeah, Ritu. I will start with that and then maybe let Dr. Penessi and Sally talk because they were in the meeting as well with the FDA. The alignment right now is that we will pre-specify an area of at least five loci on microperimetry. The data suggests we should try to pick the area of what we described as the treated transitional zone or treated RPE transitional zone. You need to have at least three decibel average improvement in that area.
The second part of the alignment really was interesting, and that is with it being in conjunction with a patient-reported outcome. The suggestion that we have been working through with the FDA is using the PGIS, Patient Global Impression Severity score. It is a single question, well-validated, very well accepted by the FDA. We also had discussions with them about developing a BEST1 specific question.
We have actually done some work in the background with Dr. Penessi already to sort of kick off maybe doing something similar to what we did with LCA5, where we validated an LCA5 specific questionnaire. It is 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 in Best disease. Over a five-year follow-up, none of their patients had an improvement in microperimetry. Quite frankly, the interesting thing is 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 is essentially the same thing or very similar to what we are discussing here.
I think the fact that it is a sham controlled study, where you have to have both an improvement in something that is rather objective with microperimetry and a patient-reported outcome makes the bar for a placebo effect or a sham effect rather high, right? I do not think we will see a big number of false positive responders. Mark, what do you think? Or Sally?
Yeah, I will just echo that I think the change of going from needing a seven decibel change on five pre-specified points to a three decibel change anchored to a PRO is really a huge improvement. I have seen many times over the years patients who clearly have shown an improvement but do not meet that seven decibel measurement. We just knew that that was an unrealistic measurement. We have been saying that for years, to finally get alignment to lower that to a three decibel change really is an accomplishment.
Your next question will come from the line of Kostas Biliouris with Oppenheimer. Please unmute and ask your question.
Good morning, everyone. Congrats on the data and thanks for taking the questions. Maybe two 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? I have a second follow-up. Thank you.
Yeah. Thanks, Kostas. I will start off and then I think we can involve others, too, because a lot of people have been thinking about this. The pathology, the phenotype is really rather different between BVMD and ARB. What we saw in both ARB patients was a reduction in the intraretinal fluid. What we saw in the BVMD patients was reduction of the vitelliform material that is kind of the hallmark of Best vitelliform macular dystrophy. What we did not see was any change in the subretinal fluid. I think that speaks directly to the pathology. In this disease, the vitelliform material typically appears first, and then as you get to later stages of the disease, like stage four or so, and the photoreceptors begin to be very stressed, then the fluid shows up on the scene.
In our patients at least, the fluid tends to pool in the center area of atrophy where there is a pretty deep scotoma on microperimetry. 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 the vitelliform material going away there. It will be interesting to see over time what happens with the fluid. It is only three months so far, so the fluid may change over time. I think at this point, in my mind, honestly, it is just a scientific curiosity because the fact that we were able to modify vitelliform material in two out of the three patients was really pretty cool. I think that is my thought on it right now. I would be interested in, Ash, what do you think from a biology standpoint? Then maybe Dr. Penessi.
Sure. There are passive and active transport mechanisms for the RPE to remove fluid from the subretinal space that they are designed to do. One thing we need to look for is whether the RPE are metabolically stressed by the vitelliform material and aging and late-stage time course of the disease, and whether there is resolution of that fluid resorption capability once the vitelliform material is removed. Like George said, it will be interesting to see how the time course evolves with respect to fluid, and it is at a very early stage right now, and we will be watching closely to see if we can prove out that hypothesis.
Yeah, I would also add.
Thank you.
Had 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. The fact that we are seeing improvement in microperimetry is actually a more important metric.
Great. Thank you. 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 two? Is it a way to quantify the reduction of the vitelliform material? Because the qualitative correlation seems very impressive. Thank you.
Yeah, Kostas, it is a great question. It is something 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 is not anything that I am aware that anybody has really done before, so our team is working on that. I think it is going to be important for the program. My presentation in October will be a little bit some of the early work we have done in conjunction with Retina Foundation of the Southwest with Dr. Penessi, Dr. Birch, and others on trying to mathematically correlate measurements on the OCTs with the changes in microperimetry. Thank you, Kostas. Yeah, it is a good question.
As a reminder, please limit to one single question in the interest of time. Your next question will come from the line of Biren Amin with Piper Sandler. Please unmute and ask your question.
Yeah. Hi, guys. Thanks for taking my questions. Maybe for cohort two, can you talk about with the higher dose, are you doing anything that is 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 eight patients as it relates to their disease profile and how they compare to cohort one specifically? Would you exclude the one patient that you had in cohort one that had foveal sub RPE scar in cohort two? Thanks.
Yeah, great question, Biren. So a couple of things. So with the higher dose, we are hoping potentially maybe 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. So I think that the targeting of the blebs is being informed by the results that we have had to date. 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 is going to be a lot more targeting towards the transitional area where we are seeing changes and towards the vitelliform material in this cohort two.
The second question, it has been a lot of fun because it has enrolled so fast in cohort two. We opened the thing up, I think the IDMC met early August. And we have already got eight patients in a five-patient cohort. And Dr. Penessi and the Retina Foundation have already treated the first patient. Of the eight patients, seven are BVMD, one is ARB. There are a number in that cohort that are earlier stage patients compared to what we have shown to date. There are some that are still advanced stage. We are still learning about the product. So, for example, the ARB patient that Dr. Penessi treated is still a pretty advanced patient, but a majority of the BVMD patients that we have 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 is used in geographic atrophy studies. I think it does help those patients, but it may not be the best for trying to get a homogeneous population for phase III. Thanks for that, Biren.
Your next question will come from the line of Lily Nsongo with Leerink Partners. Please unmute and ask your question.
Hi, good morning and congratulations on the data. Maybe following up on kind of getting more or additional color on cohort two. Given that going into pivotal design, you will be excluding patient with subfoveal scarring or fibrosis. Can you give us a sense of, among the eight 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? Then, thinking about the patient population as a whole, how should we think about the person or patient that are diagnosed prior to reaching that stage of subfoveal scarring and fibrosis?
Yeah, it is a good question. I do not have the exact numbers off the top of my head for that. I would say that a vast majority, if not all of the BVMD patients do not have subfoveal scarring in cohort two. I think that as we get more and more experience with the drug, we are going to move earlier and earlier in the stage of disease.
It is a process as we get more and more comfortable that the risk-benefit profile is advantageous for patients. I think we will probably do something similar to what we did for this cohort, where we publish the demographics of the patients and once the cohort is fully enrolled. More to come on that, Lily. Again, that will obviously inform our phase III design too, which will be likely extreme, very. The data right now is suggesting we should skew that to earlier stage patients.
Your next question will come from the line of Steven Seedhouse with Cantor Fitzgerald. Please unmute and ask your question.
Hi, good morning. Congrats on the data. This is Nick on for Steve. For the pivotal study, is there a maximum number of loci that can be pre-specified along the transitional zone? 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?
Yeah. So thanks. Great question. Yes. So, there's no maximum for the number of loci you can pick. It just has to be at least five. You could theoretically pick all 68, but we're going to be much more targeted than that. The second aspect of your question is, yeah, absolutely. Dr. Penessi's always really good at this, but all the investigators do it. We sit down before every patient's dosed, and we sort of go through the surgical planning. 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. With that being said, surgery is surgery, so it can be unpredictable. Sometimes the blebs don't go exactly where you pre-plan them.
We are being very careful to enroll at sites that have a lot of experience, like the Retina Foundation of the Southwest, and control that as best as possible.
Your next question will come from the line of Francois Brisebois with LifeSci Capital. Please unmute and ask your question.
Hi, can you guys hear me okay?
Yeah. We got you, Franc.
Okay, great. Congrats on the data. Thanks for the question here. I am just wondering, we touched a little bit on this in the prior questions here with the higher dose cohort two. I was just wondering, 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? 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 have seen?
Yeah. 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. I am 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 is really exciting to see signals of efficacy at such a low dose. BEST1 is a heterogeneous disease, over 500 different mutations. Every patient may present differently in some way or the other, and it is nice to explore dosing flexibility to cover every situation, phenotype we might encounter. 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 JonesTrading. Please unmute and ask your question. Debanjana, if you could please unmute and ask your question.
Hi. Do you hear me?
Yes, we have you, Deb.
Hi. Congratulations on the encouraging data, and thanks for taking my questions. Just to clarify, the microperimetry endpoint, is this going to be a responder analysis where a responder being defined as at least, like, that they show three decibels of improvement at each of the pre-specified loci, or is this going to be an average across the five plus loci cluster? Just curious on for the cohort two, since you have already enrolled, have you pre-specified these points already?
Good questions. It's an average at the patient level, right? You take an average of the spots that you pre-specify for each patient. But at a study level, it's a responder analysis. For a patient to be a responder, they have to have an average of three decibel or more improvement over a pre-specified area of five loci in conjunction with the PRO. Then that patient would be classified as a responder. Then you would just obviously compare between your sham arm. For the cohort two, yes. Sally, do you want to talk a little bit about some of the changes you've made for cohort two and the learnings from this?
Sure. Okay. So in cohort two, as George has already indicated, I think the learnings from cohort one will be utilizing to discuss with the investigators to help planning of where the bleb is placed and where we think that we will see the optimum response to placement of the drug. We are not pre-specifying the loci formally in our analysis in the cohort two. That is 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 two. 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 Onzi Goditzel with Guggenheim Securities. Please unmute your line and ask your question.
Hello. Good morning. So I just want to go back maybe to the endpoint for the phase III. Specifically, how is this three decibel threshold determined since it is quite significantly lower to seven, that was the previous bar. And kind of related to that, what is the chance of observing that just by chance? I guess that goes to, that relates to kind of specificity of test, retest, reliability of microperimetry, if you have any information, any thought on that.
Yeah. I would definitely point to the natural history of microperimetry and BEST disease study that was published in IOVS this year that showed that there were no three decibel improvers that I could see in that study. So, I think that three decibels is still a pretty high bar, with a fairly low chance of a false positive. Dr. Penessi, you have a lot of experience. Would you like to talk about test, retest and sort of how you think about microperimetry?
Yeah. No, I would agree with what you said. The reality was that the previous requirements were just completely unrealistic. 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 has been well-tolerated with no inflammation seen in the patients. There is potential to really modify the actual core of the disease on OCT, fundus autofluorescence, and also on function with microperimetry and BCVA. 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 are a lot more than we originally thought. So thank you all for joining us today, and this concludes the webcast.