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spk01: Thank you for joining us on the call today. 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 for purposes of the Private Securities Litigation Reform Act of 1995. 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 our annual report on Form 10-K for the year ended December 31, 2020, and our other SEC filings available on our 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. On today's call, we have George Lizeski, our Chief Executive Officer, Dr. Thomas Chula, our Chief Medical Officer and Chief Development Officer, and Charlie Dedman, our Chief Financial Officer. After our formal remarks, we will open the call for your questions. I would now like to turn the call over to George.
spk06: Thank you, Jenny. It's our pleasure to join you on the call today to discuss ClearSide's accomplishments in the last two months. Simply put, we've achieved an impressive number of firsts. With the FDA's recent approval, Zypyr is the first commercial product developed by ClearSide and the first product approved for injection into the suprachoroidal space. In addition to being an exciting accomplishment for ClearSide, we believe this approval represents a potential game-changer for as we have developed a truly innovative therapeutic approach in the field of retinal diseases. Our supracoroidal injection platform is a novel, patented approach providing unparalleled access to the back of the eye that precisely administers drug at the site of disease. With our proprietary SES microinjector, we have developed a clinically tested, non-surgical, repeatable microinjection platform designed to unlock the potential clinical benefits of supracoroidal administration. Further, Zypyr is now the first therapy approved for patients suffering from macular edema associated with uveitis, and I am proud of the fact that we are able to make a difference in the lives of these patients battling this potentially blinding condition. With this approval, we are redefining the treatment of macular edema associated with uveitis. Zypyr will be commercialized in the U.S. by our partner, Bausch & Lomb. Bausch is a well-respected leader in our industry and has been a tremendous partner throughout this process. We now expect to receive $15 million in approval and pre-launch milestones from Bausch. We continue to work closely and cooperatively with the Bausch team as they prepare to launch Zypyr and educate retinal specialists on the use of our SCS microinjector. Bausch expects to launch Zypyr in the first quarter of 2022. Also during the quarter, we expanded our Zypyr licensing agreement with Arctic Vision, a Chinese Chinese-based biotechnology company focused on ophthalmic therapies. Based on Arctic's commitment and belief in the product, we agreed to expand their licensed territory from greater China and South Korea to also include Australia, New Zealand, India, and 10 Southeast Asian countries. We received $3 million in upfront payments as consideration for the expanded territory, and we also expect to receive $4 million based on our recent U.S. approval of Zyperin. Arctic Vision is planning to initiate a confirmatory Phase III clinical trial in macular edema associated with uveitis in China by the end of this year with the ultimate goal of commercializing Zypyr, if approved, in their licensed regions. In addition, in the past two months, our clinical development partners reported promising results utilizing our SCS microinjector to deliver their therapeutics into the supercoital space. Regenexx Bio reported initial data from two Phase II clinical trials, which represents the first data ever presented utilizing gene therapy delivered into the supracoroidal space. We look forward to Regenexx Bio reporting additional Phase II data at the upcoming American Academy of Ophthalmology meeting later this week. And our partner, Aura Biosciences, reported the first data ever presented in ocular oncology, with their viral-like drug conjugate administered by suprachoroidal injection to treat choroidal melanoma. We're very excited about the progress to date from our partners, and we look forward to future results from these trials. Finally, our lead clinical development candidate, CLSA-X, continues to progress in our Phase I-IIa OASIS trial in patients with wet AMD. CLS-AX combines our proprietary suspension of the tyrosine kinase inhibitor, Exidinib, for supracoroidal use with our SCS microinjector. We have completed enrollment in Cohort 2 and expect to report safety and tolerability data from this cohort by the end of this year. With the PanVEGF attributes of Exidinib delivered into the supracoroidal space, we have the opportunity to improve the treatment of patients with wet AMD, as we believe CLSA-X may offer improved safety and efficacy, as well as prolonged durability by reducing the frequency of patient injections. With an approved product and four ongoing clinical trials utilizing three distinctly different therapeutic assets, we are revolutionizing the delivery of therapeutics to the back of the eye through the supracoroidal space. I will now turn the call over to Dr. Tom Chula, our Chief Medical Officer and Chief Development Officer, to discuss our clinical development programs and more detail around the data disclosed by our partners. Tom?
spk08: Thank you, George, and good afternoon, everyone. Before I discuss our clinical development programs, I would just like to take a moment to recognize the excitement and momentum created by the approval of Zypher. This is a tremendous achievement for our dedicated employees, as they have worked diligently to bring the first drug approval to fruition. As a retina physician, I'm truly thrilled that my physician colleagues and their patients now have a new, innovative treatment option for those suffering from uveitic macular edema, a serious, potentially blinding disease. Retina physicians love adopting new technologies and embracing new therapies to add to their treatment arsenal. And as many of our meeting presentations and publications have shown, there is strong interest in our supracordial delivery platform within the retina community. In fact, our published study Evaluating use of our STS microinjector highlighted that supracordial injection was well accepted by physician investigators with potential for rapid adoption into clinical practice. Importantly, our microinjector has been clinically tested in multiple disorders with over 1,200 supracordial injections and a favorable safety profile in clinical trials. As background on the treatment need for Zypyr, UVI is a set of ocular inflammatory conditions. Approximately one-third of uveitis patients will develop uveitic macular edema, the buildup of fluid in the macula, which causes rapid swelling and distorted vision. Macular edema is a leading cause of vision loss and blindness in uveitis patients, and can occur from uveitis affecting any anatomic location, anterior, intermediate, posterior, or pan uveitis. We are pleased with the FDA-approved label for Zypyr, which includes all of these anatomic locations, to potentially treat a broad patient population, with macular edema associated with uveitis. Approval of ZodCare supports our supracordial delivery platform, as our preclinical work has now translated to proven clinical results. The core advantages of treating via the supracordial space include targeted delivery to affected core retinal tissues for potential efficacy benefits, compartmentalization away from unaffected tissues for potential safety benefits, and bioavailability as the core retinal tissues are essentially bathed with therapy. Furthermore, for small molecule suspensions, there are prolonged pharmacokinetics which facilitate durable therapies. This targeted delivery and compartmentalization was associated with our successful phase three pH-free clinical trial, supporting the efficacy and safety of Xypher. Durability was demonstrated in our Magnolia extension study, and is driven by the relative insolubility in particle size of the formulation in the supracordial space. We have seen similar preclinical durability with other small-molecule suspensions, including a complement inhibitor, a plasmacalocrine inhibitor, and the tyrosine kinase inhibitor, Exitinib, which is the active ingredient in our CLSA-X proprietary formulation. I will next discuss our CLSA-X program in more detail. I'm very excited about combining the potential benefits of panVEGF inhibition with the targeting, compartmentalization, and durability potential benefits of supracordial delivery. Of note, current AMD therapies bind VEGF-A. However, inhibition of VEGF-A has been shown to upregulate other forms of VEGF, which may contribute to limited outcomes. Excentinib, a highly potent tyrosine kinase inhibitor, may improve these outcomes with its broad VEGF blockade. and has already been shown to effectively inhibit corneal, retinal, and choroidal angiogenesis in numerous animal models. In addition, suprachoroidal administration may further leverage these potential benefits of Exitinib by more directly targeting the affected retinal and choroidal tissues. We recently published a preclinical study demonstrating this targeted delivery with suprachoroidal administration, along with favorable ocular distribution and durability compared to intravitreal delivery. These preclinical studies help provide the rationale for our first-in-man supracoroidal CLSAX clinical program and support our belief that supracoroidal CLSAX could represent a very competitive therapy in the future. As we reported last quarter, we are pleased with the promising safety and tolerability results from Cohort 1 of OASIS, our ongoing Phase 1-2A clinical trial with CLSAX. OHS is a multicenter, open-label study to establish the safety and tolerability of escalating doses of CLSAX administered by supracordial injection in patients suffering from wet AMD. The study involves three cohorts of approximately five patients each. The primary endpoint for the trial will assess the safety and tolerability for three months following supracordial administration of CLSAX. To recap our supracordial safety and tolerability data from cohort one, No study suspension of stopping rules were met, and there were no serious adverse events. Importantly, there were no signs of inflammation, vitreous haze, intraocular pressure safety signals, vasculitis, or intravitreal dispersion of CLSAX. There were two treatment emergent adverse events that were assessed as unrelated to CLSAX. Durability is an important component of our treatment plan, and we are encouraged by the preliminary signs of potential durability that we saw in cohort one. especially given the very low initial dose of 0.03 milligrams of CLSAX in these highly anti-VEGF treatment-experienced patients that were enrolled. With these results from Cohort 1, we've advanced to Cohort 2 at a dose of 0.1 milligram. While this is still a low dose of CLSAX, it's a 3.3-fold increase compared to the Cohort 1 dose. In September, we reported that we completed enrollment in Cohort 2 whereby all patients have received a Flibberstep at their first visit and a single dose of CLSAX at their second visit one month later. Patients are monitored monthly by their physicians for the next three months of their treatment, and we expect to report safety and tolerability results from Cohort 2 by the end of this year. For Cohort 2, we're also adding a three-month extension study to follow patients over a longer period of time. We believe that by combining the pan-VEGF attributes of excitinib with our proprietary CLSAX formulation and delivery via our SDS microinjector, we may facilitate an effective treatment option for patients suffering from wet AMD. Furthermore, a well-characterized small molecule like excitinib may have less potential for immune response compared to a biologic agent. With the recent well-documented safety challenges associated with other approved and investigational wet AMD therapies, We cannot emphasize enough the importance and prime focus of the safety component in our OASIS trial. If our Cohort 2 data readout continues to demonstrate supportive safety results, we will both escalate in Cohort 3 and have potential to escalate even further if we believe it's appropriate. With respect to our partner programs, the last few weeks have been a very exciting time for ClearSight in our supercoital delivery platform as our development partners have reported promising results from several trials using our SCS microinjector to deliver their product candidates into the suprachoroidal space. I will start with Regenexx Bio as they are running two multicenter, open-label, randomized control dose escalating studies evaluating the efficacy, safety, and tolerability of suprachoroidal delivery of RGX314. Excitingly, data presented by Regenexx Bio is the first data ever presented utilizing gene therapy delivered in the supracortical space. The first trial, entitled Aviate, is targeting the treatment of patients with severe wet AMD who are responsive to anti-VEGF treatment. Importantly, patients in this trial do not receive prophylactic immune-suppressive corticosteroid therapy. In September, Regenexx Bio reported the following. In cohorts 1, 2, and 3, supracoital delivery of RGX314 was well-tolerated in 50 patients with no drug-related serious adverse events. In cohort 1, positive initial efficacy data at six months after one-time treatment of RGX314 showed a treatment effect observed with stable visual acuity and retinal thickness, and RGX314 demonstrated meaningful reduction in anti-VEGF treatment burdens. For cohort two, Regenexx Bio plans to report interim results at six months of follow-up at the upcoming AAO meeting later this week. Cohort three has completed dosing in patients positive for neutralizing antibodies. And Regenexx Bio is expanding the trial to enroll cohorts four and five at a higher dose. The second RGX314 clinical trial is a phase two trial for the treatment of diabetic retinopathy entitled altitude. Similar to AV8, patients in this trial do not receive prophylactic immune-suppressive corticosteroid therapy before or after administration of RGX314. In October, Regenexx Bio reported the following. Cohort 1 had positive initial data that demonstrated supracoital delivery of RGX314 was well-tolerated in 15 patients with no drug-related serious adverse events. No interocular inflammation was observed. And 33% of patients demonstrated a two or more step improvement from baseline on a standardized diabetic retinopathy severity scale, compared to 0% of patients in the observational control. Cohort two is currently enrolling. And cohort three is currently enrolling patients positive for neutralizing antibodies. In addition, our partner, Oro Bioscience, has presented the first set of data utilizing supracoital delivery to treat coital melanoma. the most common primary ocular cancer in adults. Ora reported that suprachoral administration VRISCS microinjector may improve the therapeutic index and optimize treatment parameters for AU011. Ora is currently running a phase two trial comprised of an open label dose escalating phase and a randomized mass dose expansion phase that is assessing the safety and efficacy of ascending single and repeat doses of AU011 via SCS microinjector administration. In October, ORRA reported the following. Interim safety data showed no treatments related serious adverse events, dose-limiting toxicities, or grade 3 adverse events. Cohorts 1 through 5 are fully enrolled with a total of 13 patients. And cohort 6 is enrolling. The randomized phase of the trial is planned to begin the second half of 2022 in patients with documented growth, to establish the safety and efficacy of AU011 and serve as the first pivotal trial for the treatment of indeterminate lesions and chordal melanoma. The continued progress by Regenexx Bio and Ora Biosciences is very encouraging, and we look forward to their ongoing clinical trial results. Before I conclude my discussion, I would like to touch on our integrin and gene therapy programs. We're working on integrin formulation studies that will continue into 2022, as our research team is currently running preclinical studies, including pharmacokinetic work assessing ocular distribution. In our gene therapy program, this year we presented and published data including preclinical studies and supercoitally delivered non-viral DNA nanoparticles containing the MYO7 gene, which causes Usher syndrome and is too large to fit in AAV vectors. Outside of our existing gene therapy licensing relationship with the genic spinal, we have the opportunity to partner with other companies working on gene therapy using non-viral vectors or viral vectors targeting diseases that are not primarily treated with current standard of care anti-VEGF therapies, such as geographic atrophy and inherited retinal diseases, including Usher syndrome or Starbuck disease. In closing, we continue to remain active within the retina physician community with 10 presentations recently given at the Retina Society and American Society of Retina Specialists medical meetings. We will also have three Zypair presentations at the American Academy of Ophthalmology meeting this weekend. These presentations and other ongoing interactions with leaders in the field continue to generate interest in the suprachordal space and the potential to adopt this procedure in their practices. I will now turn the call over to our CFO, Charlie Degnan, to review our financial results. Charlie?
spk07: Thanks, Tom. Our financial results for the third quarter were published this afternoon in our press release, and are available on our website. Therefore, I will summarize our current financial status. Our cash and cash equivalents as of September 30th, 2021, totaled approximately $25.2 million, which included the $3 million in payments from our division for the expansion of their licensed territories for Zipure. Our quarterly cash burn is primarily due to the activities related to our CLSAX program and obtaining approval for Zipure. Investments in our broader research pipeline are also incorporated into their operating areas. With the approval of Zypere, we anticipate receiving a total of $19 million in non-dilutive funding for approval and pre-launch milestones from our commercialization partners. We expect these funds, along with the $5 million of deferred revenue from the BAUSH upfront payment, will be recorded in the fourth quarter of 2021 as licensed revenue on the income statement. This additional capital will be utilized to advance our clinical development pipeline led by CLSAX. Based on our current funding and planned spend, we now expect to have sufficient resources to fund our operations into 2023. We appreciate the interest and support from our shareholders and the broader investment community, and we look forward to participating at several virtual investor events over the next few weeks. The Stiefel Healthcare Conference, the Piper Sandler Healthcare Conference, and the UBS Ophthalmology Day. I will now turn the call back over to George for his closing remarks.
spk06: Thank you, Charlie. In closing, I'd like to take a moment to recognize the accomplishments of our team here at ClearSide. Their hard work and dedication for the past several years has taken Zypure through discovery, research, clinical development, and ultimately to FDA approval. I'm extremely proud of their efforts to get Zypure to the finish line. I'd also like to thank our shareholders, clinical investigators, and board of directors who have supported us through this multi-year process. Our recent success only inspires us to continue to move forward as we focus on advancing CLS-AX through its clinical program and exploring future opportunities to make a difference in the lives of patients suffering from sight-threatening diseases. I would now like to ask the operator to open the call up for questions.
spk04: As a reminder, to ask a question, you will need to press star 1 on your telephone keypad. Again, that is star 1 on your telephone keypad. You have your first question coming from the line of Annabel Samini from STCell. Your line is now open.
spk03: Hi. Thanks for taking my question. I have a few. So first for CLS-AX and Cohort 2. I just want to verify whether this would be the same heavily pretreated population that you saw in cohort one. And, you know, you added on the three-month extension. That was not part of cohort one as well, right? I think that was just a one month. So just can you go through those details one more time? And for cohort three, you're going to be adding – or sorry, you're going to be increasing dose again to 10 times of what it was cohort one. Are you also adding extension studies to that one? I think I missed that. And then, you know, also again on CLS-AX, obviously the treatment landscape is evolving to go longer and longer. Some are already pushing out to six months, aiming for a year. I know that you're also aiming for that six to 12 months. If you don't reach that durability, where is it that you have room to modify? Is it primarily in the dose, or is there something in a formulation that you can adjust for SCS delivery? And I've got a couple more follow-ups. Thanks.
spk06: Tom, you want to take the first several of those questions?
spk03: Several of the 20 questions I asked? Sorry.
spk08: So let me take, I think the first one was about the extension study. So if you recall, cohort one was a very low dose, 0.03 milligrams, and we did not include an extension study for that. For cohorts two and beyond, we are adding a three-month extension study. The primary study includes three months of follow-up, in all cases, including cohort one, And then the extension study includes another three months of follow-up after the initial dose. So it'll be six months of follow-up. So I think that was your first question. The second question was, I think you were asking what the cohort three dose is. We've already announced that we intend to use the 0.3 milligram dose. And yes, it is a tenfold increase in the dosing versus cohort one. You know, and I should add that, you know, the primary dose focus of the study is safety, because it has to be. This is a first-in-man study using a tyrosine kinase inhibitor in the supracordial space. So we're purposely starting low, and we're purposely escalating gradually, because safety is our primary concern. As I mentioned in my prepared remarks, there's been some well-publicized safety issues with other companies in the space using biologics. And although we're confident in our safety profile, we feel that a small molecule may have less intrinsic risk of an inflammatory response, we're still very much focused on safety. So we are escalating gradually. I think your third question was about durability. And this is a conversation we have a lot with other KOLs and investors. And, you know, everybody talks about prolonged durability, six months, one year, one and done. But the truth of the matter is that we don't have anything right now that's beyond three or four months. And even if you look at some of the therapies that are about to be approved, when they talk about three- and four-month durability, it's only a fraction of the patients that go that long. So I think there's an aspirational bar of durability that's quite high, but the reality is far less. So we think that... you know, durability is somewhere in the sweet spot of three months. Retina physicians are going to evaluate their patients at least once a quarter, regardless of the durability of the therapy. And anything beyond that, obviously, is great. But I think the reality is that it's set much lower. And then I think your fourth question was, you know, what else does this approach offer besides durability? And as I mentioned in my prepared remarks, Exitinib is a very, very highly potent tyrosine kinase inhibitor. It's a pan-VEGF inhibitor. There's potential for it to not only be durable because of its formulation in the supracordial space, but there's also potential for it to have better efficacy. And we've seen that with another company using blockade of VEGF-C and D in conjunction with VEGF-A inhibition. And in their phase two trial, they showed superior results over VEGF-A only blockage. Of course, there were two injections every month, but nevertheless, conceptually, it suggests that blocking multiple forms of VEGF could lead to better efficacy outcomes. So we think our approach has proven multiple potential benefits, including durability and pan-VEGF blockade, which has potential for better efficacy.
spk03: And you're going to be enrolling the same treatment experience population, correct?
spk08: Yes. So all patients have to have had prior treatment in this study. And, you know, it's a great question because, in a way, we're choosing the most difficult patients to treat initially. These are patients who have been very treatment experienced and are In cohort one, they had an average of 26 prior injections, and they had to have persistent activity confirmed by a mask reading center assessment of imaging. But these are patients who are highly VEGF or anti-VEGF treatment dependent with persistent disease. So, you know, it's a very high bar, and, you know, we simply are keying our initial studies on safety. But, yes, very highly treatment experience, and it sets a high bar.
spk03: Okay, and if I could just squeeze in one more question about partnership programs. Notice that Abby signed an agreement with Regenexx Bio, I think, for their subretinal formulation for 314. To what extent could this involve SCS delivery in the future? Do you know if there are any options for them to sort of expand into the SCS delivery of it? I'm just curious if there are any behind-the-scenes discussions there. Thanks.
spk06: Let me take that one. We have not seen the details of the FV Regenexx deal. I guess it closed today. It was signed some time ago, but then it obviously closed today. But our understanding is that the deal is not limited to subretinal. It has any form of administration of RGX 314.
spk03: Okay.
spk06: That's our understanding.
spk03: Thank you.
spk04: Your next question comes from the line of Yi Chen from HCL Wainwright. Please go ahead.
spk02: Hi. Thank you for taking my question. Can you remind us which drugs are the major competitors on the market today for Zypere?
spk06: Tom, do you want to take that? Sure.
spk08: You know, I think the obvious competitor is Ozerdex. You know, it's also a steroid. It's delivered individually. Ours is a steroid delivered super quarterly. So I think that's probably the most analogous. Of course, there's others. There's Utique and Red Assert. And then there's a whole host of other therapies, you know, given systemically, anti-metabolites. But, you know, physicians like to use local therapy. And so the field of competition for local therapy, you know, is still somewhat limited. And we think our approach to supracoital delivery is very much a differentiating feature. As I mentioned in my prepared remarks, we target the affected cortiretinal tissues, but we're essentially injecting the therapy directly in the affected tissues. the therapy is compartmentalized away from the front of the eye, which is potentially very important for a corticosteroid. As you know, corticosteroids can increase the risk of ocular hypertension, glaucoma, and cataract. We have pharmacokinetic data showing that we do indeed compartmentalize the steroid away from the front of the eye. And we have a really robust safety profile in our various uveitic macular edema studies, especially the peach tree azalea studies. We've also shown durability in our Magnolia studies. So, you know, there is competition, but we think that our approach is very differentiated and has, you know, potential benefits over other therapies.
spk02: Got it. And second question, do you believe CLS-AX has to show superiority over Aflibicept to be commercially successful in the future?
spk08: You know, that's a really great question. It's an important question. But it's, you know, we're just at the very beginning innings of this ballgame. This is just, you know, a very simple, straightforward, single-dose escalating study. And it would have to be, you know, everything is data-dependent as we go along. So, you know, we have potential to show better durability than existing therapies. We have potential to show better efficacy than existing therapies. And, you know, because we compartmentalize the drug in the space and we use a small molecule instead of a biologic, we have potential to show maybe better safety. But again, all this is all speculative. I think everything is data dependent.
spk02: Got it. Thank you.
spk04: Next question is from Andrea's argue rides from a red Bush. Please go ahead.
spk10: Thank you and good evening. Congrats all the progress during the quarter. So just some thoughts. I guess this question is for Tom on the Regenexx bio data that was recently presented and to get your thoughts on. provide, well, one, give your thoughts on the data, but also how you see them either as a read-through to the CLS-AX program. Yeah, just your thoughts on those. That would be great. Thanks.
spk08: Let me take your second question first. I think there's very little read-through to our CLS-AX program. You know, they're utilizing a gene therapy. It's a viral vector. We're using a small molecule. It's not a biologic. If I didn't know any of their data, I would predict that a small molecule has some potential safety benefits because it doesn't have potential for an immune response like a viral vector does. But to the second half of your question, the first half, to your first question now, I'm very excited about their data. I actually think their data is very, very compelling so far. It's early. Their diabetic retinopathy data in particular, you know, had a really clean safety profile. I think this paved the way for supracoital gene therapy delivery, which of course is an in-office procedure as opposed to subretinal surgery. I was at SPARC previously and helped launch Luxturna, helped train the ocular gene therapy treatment centers, and as you know, administration of Luxterna and most other gene therapies involve subretinal delivery, which is a trip to the operating room with a tracheotomy, a hole in the retina that we call retinotomy, and you inject the therapy under the retina, you create a limited retinal detachment, all of which, you know, has potential to cause problems. So an in-office gene therapy delivery would be really fantastic, not just for Regenexx Bio and ClearSight, but really for the entire field. So I think that Regenexx Bio is doing some really important work in advancing the entire field. And I think their diabetic retinopathy study data is very exciting.
spk10: Just a quick follow-up. Again, your thoughts as a retinal specialist. Any possible explanations for for the difference in the inflammation rates in those studies, you know, from, as you mentioned, clean and diabetic retinopathy, but there were some instances in the wet AMD study?
spk08: You know, it's hard for me to comment on another company's trial, although we are partners with them and work with them closely. I don't have access to all the data they do, but, you know, from afar, I can say that, just reflect what they've said, is that the inflammation they've seen is, you know, in their AMD patients was in a minority of patients. It was subclinical. It was treated with topical therapy. It was limited. It really didn't have any meaningful safety effect. And also, you know, again, it's very early, and I think time will tell. But I do think, you know, their actions speak to their confidence in the approach because, their dose escalating in additional cohorts to a meaningfully higher dose. They're assessing this in patients who are neutralizing antibody positive for their vector, and they're not using corticosteroid immune suppressive regimen. So I think, to me, that shows that they have very meaningful confidence in their approach and in the safety of their approach.
spk10: Okay, great. Thanks. I'll jump back in the queue. Appreciate the comments.
spk04: Your next question is from John Walden from JMP Securities. Your line is now open.
spk09: Hey, congrats on all the progress, and thanks for taking the questions. A couple quick ones from me. I know you're targeting five patients in each cohort. You had six in cohort one. I don't think I've seen you say how many patients have been dosed in cohort two, so I was hoping you could let us know that. And then also, if you started dosing in cohort three, and if not, when that might kick off.
spk08: We've announced publicly that we've completed dosing in cohort two, and as you might recall from the study design, patients are followed three months after they receive COSAX. We have a safety monitoring committee meeting, review all the data, and then, you know, decide on dose escalation. We have not started cohort three yet.
spk09: Okay. And how many patients did you dose in cohort two?
spk06: I think, Tom, all we've really talked about is the total number of patients, the approximate number of total patients in the three cohorts.
spk08: That's right. So we've come out and said that we're targeting five patients per cohort, and I think that's all we've disclosed publicly.
spk09: Okay, and back to an earlier question, you mentioned that these patients are pretreated. So my guess is we're not going to see much wiggle in retinal thickness, but you did see nice improvements in BCVA in cohort one. Is the expectation to see dose-dependent increases in BCVA in these patients, or is there a ceiling perhaps given the stage of the disease, or is it more of the durability that we want to see in terms of retreatment? Just wondering what you're expecting when we get to these higher doses.
spk08: Oh, that's a great question. You know, with small numbers of patients, you know, it's hard to, a small number of very treatment-experienced patients, it's hard to speculate what we're going to see. I think what we saw was a pleasant surprise because we weren't expecting these patients to improve. And again, with small numbers of treatment-experienced patients, there could be, you know, ceiling effects with visual acuity improvement and floor effects with CST improvement. We did see some floor effects in CST improvement in cohort one. So it's hard to predict. And really, this study is a safety study. And, you know, what we really want to do is continue the dose escalation until we find a dose that is both safe and shows, you know, meaningful signs of biologic activity.
spk09: Got it. Fair enough. Thanks again for taking the questions.
spk04: Your last question is from Zeg Benjala from Ross Capital Partners. Please go ahead.
spk05: Hi, guys. Thanks for taking my question and congrats on the update. Looking forward to the CLSAX data. I just have three quick questions. The first one is just about your thoughts on the competitive landscape in Wedding Deeds. I know you can't really say if we're going to, you know, do late-stage studies in pre-treated or treatment-naive patients, but I was just wondering if, Tom, perhaps you can talk about how you see the hurdle in the pre-treated versus the naive setting and, you know, the timeline perhaps to approval, which could be faster. And then the second one is just because this came up a little bit from the Regenix data in terms of viscosity of what's being injected into the supracorotyl space. Can you talk a little bit about the proprietary suspension that Zypera is in, and is that the same suspension for CLSAX, and what kind of viscosity you guys look for, and what are you trying to optimize for with that viscosity? And then the last bit here is a comment on inherited retinal diseases. Tom, I think you mentioned it, and I know the focus still remains on CLSAX, but I was just wondering if you guys can comment on how you're thinking about that opportunity. and if that could be a partnership or you could do it independently.
spk08: Sure. So you asked about competitive landscape initially. You know, as I mentioned earlier, I think there's a little bit of a disconnect between the sort of aspirational durability and what we see in reality. You know, right now patients are dependent on very frequent fixed dosing. We know if most patients... in the United States are undertreated because they simply can't come in often enough to receive their therapy. And ultimately, their real-world outcomes are pretty poor. And I've published on this extensively in the past. And then, you know, so if you use on-label, they can do okay. And, you know, we'll soon have therapies approved that, you know, in a meaningful fraction of patients, they can potentially go three to four months. I also think most of the therapies out there are anti-VEGF-A. So I think CLSAX is well positioned potentially with respect to durability and the fact that it's a pan-VEGF inhibitor, that we leverage that further by targeting the affected tissues to really get high levels where we want them and keeping it away from unaffected tissues. As I mentioned earlier, I also think we have potential safety benefits with a well-characterized small molecule like exitinib over a complex biologic. So I think COSAX could fit very well into the competitive landscape. And I also think that, you know, again, it's data dependent, but, you know, we don't know if it'll be used for maintenance of efficacy because of its potential durability. or be used as potentially the primary monotherapy or used even in refractory cases. So I think it will fit well into the competitive landscape. For your second question about formulations, I'm not sure how much of this we've disclosed publicly. I don't know, George, if you want to take that one. Formulations of Zypyr and Exitinib. Anyway, I can just say that I don't think we've discussed the formulation in detail. But basically, you know, these are small molecule suspensions. I mentioned that the durability is driven by the relative insolubility of the suspension. as well as the particle size. And so that's what drives the durability. And we've seen this with a multitude of small molecule suspensions preclinically. We've seen it with triazomone or Zypyr. We've seen it with Exitinib. We've seen it with a complement inhibitor as well as a plasma calc inhibitor. And what's really encouraging now with respect to Zypyr is that it's been approved And so we're seeing read-through of what we saw preclinically now into the clinic, especially with respect to our Magnolia study, which suggested durability. And then finally, Zegba, you asked about inherited retinal diseases. You know, we think that Regenexx Bio is paving the way for supracordial delivery of gene therapies. And obviously, that would include gene therapies for inherited retinal disease. We also believe that supercoital delivery covers a large surface area potentially of the posterior pole. It covers it peripherally and posteriorly and circumferentially. And so in theory, supercoital delivery could provide an in-office means to expose a large surface area peripherally of the retina, which may loan itself really well to the treatment of inherited retinal diseases, which start in the retinal periphery. So as I mentioned earlier, You know, that field is still open for collaboration. We've also looked at that preclinically with DNA nanoparticles and have published and presented that at ARVO this year.
spk04: Thanks, Tom. That concludes today's conference call. Thank you all for participating. You may now disconnect.
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