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spk07: Good morning, ladies and gentlemen, and welcome to the ClearSight Biomedical Incorporated third quarter 2022 earnings call. At this time, all participants have been placed on a listen-only mode, and the floor will be open for questions and comments after the presentation. It is now my pleasure to turn the floor over to your host, Jenny Coburn, with Investor Relations. Ma'am, the floor is yours.
spk02: Good morning, and thank you for joining us on the call this morning. On today's call, we will have a brief discussion around Clearside's third quarter financials, followed by the results from the OASIS Phase 1-2A 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 may make during this call about the company's future expectations, plans, and prospects constitute statements 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, 2021, and our other FDC 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 Levesque, our Chief Executive Officer, Dr. Thomas Shula, our Chief Medical Officer and Chief Development Officer, Charlie Dugnan, our Chief Financial Officer, and Dr. Arshad Kanani, who is a Managing Partner at Sierra Eye Associates and a Clinical Associate Professor at the University of Nevada, Reno. The remarks on today's call will be accompanied by a slide presentation, which is available in the Events section of Clearside's Investor Relations website at clearsidebio.com. I would now like to turn the call over to George.
spk08: Thank you, Jenny, and thank you all for joining us this morning. For today's call, I'll make some opening remarks, and then I will turn the call over to Dr. Tom Chula, our Chief Medical Officer and Chief Development Officer, who will walk through our CLSAX Phase 1-2A clinical trial entitled OASIS. We are also joined this morning by Dr. Arshad Kanani, a retinal specialist with extensive experience treating multiple back of the eye diseases. After our formal remarks, we will take your questions. This morning, we issued our press release on the OASIS data, as well as our quarterly earnings announcement, where we reported that our current cash and cash equivalents as of September 30, 2022, totaled $53.4 million. As of now, this gives us a financial runway into 2024. and we will be able to further refine our financial runway once we finalize our plans for a randomized controlled CLS-AX Phase II trial. Today we are going to focus on our CLS-AX data, but our CFO, Charlie Begman, is on the call with us to take any questions as needed. Our OASIS update includes the final data from all four dosing cohorts for the three-month endpoint for the trial. as well as interim data from the extension study with a data cut as of October 27, 2022. The extension study follows patients in cohorts two, three, and four who agreed to be monitored for an additional three months, making it a total of six months after a single dose of CLSAX. Moving now to slide three in the presentation. We are very pleased to report the data today from the OASIS trial, a single-dose escalating trial in anti-VEGF treatment experience sub-responders. The primary endpoint for OASIS was safety and tolerability, and we saw a very favorable safety profile for CLSAX at all doses and time points throughout the study. In addition, we are very encouraged by the durability data that has emerged from the trial to date at higher doses in cohorts three and four. As Tom will elaborate, CLSAX provided at least 73% reduction in treatment burden to the three-month time point in OASIS. From the ongoing extension study, current data shows at least a 90% reduction in treatment burden from the average monthly injections in the six months before CLSAX administration. Further, the OASIS study demonstrated both a stable mean best corrected visual acuity and a stable mean central subfield thickness at both the three-month time point and to date in the extension study. In the extension study, anatomical signs of CLSAX biological effect were also observed on OCT in the subresponder population. While we will continue to follow the remaining eight patients in our extension study, this data gives us very high confidence to move ahead with future CLS-AX clinical trials. We expect to report the final extension study data in the first quarter of 2023. I will now turn the call over to Tom to review our OASIS results. Tom?
spk07: Thank you, George, and good morning, everyone. I'll start with a very quick overview of our program and then review the data. Slide 4 summarizes the benefits of CLSAX by proprietary suspension of excitinib delivered via our SCS microinjector into the supracortical space. In the CLSAX program, we're marrying a very highly potent tyrosine kinase inhibitor that inhibits all VEGF receptors with the potential core retinal tissue targeting benefits of supracortical delivery. And with respect to durability, preclinical studies show that excitinib levels in the retina, choroid, and sclera were maintained at levels well above the IC50s of the DEDRA receptor 2 up to six months after suprachoroidal injection. With a novel delivery system, we're able to specifically target the affected chorioretinal tissues for potential efficacy benefits, and we can compartmentalize our therapy away from unaffected tissues for potential safety benefits. Plus, delivery of small molecules via our SCF microinjector has been commercially accepted by retina physicians following the launch of Zypera. For the sake of time, we've included additional background rationale in the appendix of the slide deck, which is available online. Slide 5 outlines our OASIS Phase 1 to a clinical trial in treatment-experienced patients with ACID with AMD. OASIS is an open-label, single-dose escalating study to evaluate safety and tolerability of CLS-AX administered for a supracordial injection. There were four cohorts of patients treated with escalating doses of CLS-AX. At screening, patients receive a dose of a flibrocept via intravitreal injection. They return one month later, receive a dose of CLSX, and then return for follow-up visits at one, two, and three months. There's an ongoing extension study that facilitates an additional three months of follow-up for a total of six months. I want to take a moment to discuss in more detail the patient population we chose for OASIS. We intentionally chose wet AMD patients who were heavily anti-DIGF treatment experienced. All patients were sub-responders with active disease of screening, which was confirmed by an independent reading center. Consequently, we chose the most difficult-to-treat patients for this study. So why choose this group of patients instead of patients who had people with disease? While our primary objectives of the study were safety and tolerability, we wanted to see if we could observe signs of biologic effect and if we could lower the anti-DIGF treatment burden. By assessing sub-responders, we minimize the risk of false signals of biologic effect, since inactive treated patients may not require further therapy for many months. This anti-digest treatment experience population with active disease represents a significant number of patients in clinical practice, in which more than 30% are sub-responders and have high need for effective therapy with lower treatment burdens. Importantly, we believe that in conducting the OASIS studies in such a patient population, the data is particularly promising since we observe signs of clinically relevant benefits in this first-in-man trial. On slide 7, we break down select baseline demographics and characteristics of the enrolled patients. As you can see, the patients had a history of lead AMD for over four years on average and were very highly treatment experienced. some without their 90 prior anti-VEGF injections, and all had active disease, as confirmed by an independent reading center on screen. It should be noted that, unlike treatment-naive patients, the mean central subfield thickness was essentially normal, thus creating a floor effect, which is unlikely to significantly improve with treatment. Similarly, some of the patients showed best-corrected visual acuity in the 20 over 32 range, which creates a ceiling effect and is unlikely to significantly improve with treatment. Our ongoing hypothesis is that the higher doses of CLSAS in cohorts 3 and 4 may keep both the BCDA and CST stable throughout the study and thereby show potential for the reduction in treatment burden in these patients. We are extremely pleased with the robust safety results that we've seen in the trial across all four cohorts. As you can see on slide 9, there have been no serious adverse events and no treatment-averse events related to a flibrocept, CLSAX, or the supracordial injection procedure. There were no dose-limiting toxicities. There were no adverse eventualities of inflammation, vasculitis, or vascular occlusion. And there were no vitreous floaters or dispersion of CLSAX into the vitreous. Next, I'll review the promising durability results from the trial. Slide 11 shows the prior anti-digestive therapy and the treatment administered during the study for all patients treated for the three-month OASIS endpoint. In the middle of the swim lane, the column of red dots represents the flip-receptive administered screening. Everything to the left of that column represents the patient's prior six-month anti-digestive treatment regimen. As you can see, most of the patients were being treated monthly. The green column of dots shows the CLSAX injection at baseline, and then the patients were followed up one, two, and three months. The blue dots represent additional therapies administered per protocol criteria. The olive-colored dots represent therapy administered not in accordance with the defined protocol criteria for additional treatment. Importantly, in the vast majority of these cases, the independent reading center did not verify the rationale for additional treatment. We've detailed the reasons the investigator did not treat per protocol defined criteria in the appendix. which is also available online. Now onto the data. Going forward, I'll focus on the discussion, I'll focus the discussion on cohorts three and four, as these higher doses are the most meaningful, and one or both will be utilized in our future clinical trials. As you can see, the results show that in cohorts three and four, 11 of 16, or 69% of patients, did not receive additional therapy the three months. On slide 12, this swim lane plot shows only the patients treated per protocol criteria. Here, in cohorts three and four, 11 or 12 or 92% of patients treated per protocol did not receive additional therapy for three months. We're extremely encouraged with these results. We're also pleased to report that CLSAX reduced the treatment burden across all cohorts to month three as seen in slide 13. Again, we show treatment across all therapies on the left and per protocol treatment on the right. Importantly, in cohort 3 and 4, there was at least a 73% reduction in treatment burden from the average monthly injections in the three months before CLS-AX injection. This reduction reached 100% at the cohort 4 1mg dose. Moving now to the interim results of the extension study. On July 14, we showed the prior anti-bacterial therapy and the treatments administered for all 14 patients who agreed to participate in the extension study. from our data cut as of October 27, 2022. For today's discussion, I'll focus on the 12 patients enrolled at the higher doses in cohort three and four. Eight patients are still being monitored in the study. As you can see, from month four, eight of 10 patients have not received additional therapy. From month five, seven of eight patients have not received additional therapy, and from month six, three of four patients have not received additional therapy. Once again, on slide 15, the swim lane slide shows only the patients treated per protocol criteria. This slide is important as you can see that to date, only one patient in cohort three has received additional therapy prior to the six-month time point, and one patient was dosed at month six. In cohort four, no patients in the extension study have received additional therapy per protocol criteria to date. This breakdown is followed. To month four, eight of nine patients have not received additional therapy. To month five, seven of eight patients have not received additional therapy. And to month six, three of four patients have not received additional therapy. To illustrate this data further, the graph on slide 16 shows the supplemental anti-digest injection free rate up to each visit. We're pleased to note that so far, 88% of the patients have not required any additional therapy to month five, and 75% of the patients have not required any additional therapies in month six. As you can see on slide 17, cohorts three and four also showed a meaningful reduction in treatment burden to date. This data compares treatment received during the six months before CLS-AX administration to treatment in the six months after CLS-AX. Again, we show anti-by-death treatment burden across all therapies on the left and per protocol criteria on the right. In cohort 3 and 4, there was at least a 90% reduction in treatment burden. Next, I'll briefly review the biological effect we observed in cohort 3 and 4. Slide 19 shows the mean change in best corrected visual acuity results from screening for cohort 3 and 4. In the graph, cohort 3 is shown in green, cohort 4 is shown in blue, and the mean change by ETDRS letters is shown with the thick black lines. Importantly, what we note is that over the three-month course of the OASIS study, post-CLS-AX dosing, the visual acuity remained stable. The same data is plotted on the right, but we excluded the data post-retreatment to be sure that the patients who received additional therapy weren't driving these results. Interestingly, we see that the end result was essentially the same. The key takeaway is that the BCVA data demonstrates that patients were stable during the three months post-CLS-AX. Slide 20 shows the results related to the main change in central sub-tool thickness from screening for cohort 3 and 4. On the left, we include all data, and you can see that the CFT remains stable. On the right, we exclude post-retreatment data, and again, it looks similar. Notably, the CFT data demonstrates that patients were stable over the course of the three months post-CLSAX. Similarly, slides 21 and 22 show that the main BCDA ZFT also remains stable for a total of six months in the extension study in cohorts three and four. On slide 21, on the left, we observed that over the six months post-CLSAS dosing, the visual acuity remained stable on average. Here you can see that there are some variability in the visual acuity at the six-month time point with error bars that cross the zero, no change line, as the sample size decreases over time in this interim analysis. On the right, with the same data post-retreatment excluded, we can see that the end result was very similar. This interim BCDA data indicates that so far, the visual acuity of patients in the extension study has remained stable over six months post-CLS-AX. On slide 22, again, all the data is graphed on the left over six months post-CLS-AX dose. Here you can see that there is some variability with the CST, all within approximately 50 microns, as the sample size decreases over time in this interim analysis. However, as shown by the overall mean in black, the CST remains stable. On the right, with the post-retreatment data excluded, the results actually look similar. Notably, this interim data indicates that so far, CST measurements of patients in the extension study have remained stable over the course of the six months post-CLSAX. Now I'm going to walk through four case studies that visually support the durability and biologic effect we've observed from the OASIS extension study. As a reminder, for all of these examples, the patient enters the trial of screening and receives a Flibercept individually. This is followed one month later at baseline with a single dose of CLS-AX administered supercoordinately. Slide 24 is a case study that supports the biologic effect in an anti-digest sub-responder. we can see that the patient entered the study with a relatively good BCDA of 75 letters, or 20 over 32, which tends to create a steering effect in these treatment-experienced patients. The CFT measures 265 microns. The fovea, subfoveal fluid, and the fibrovascular pigment epithelial detachment, or PED, are all marked. The patient receives a flibrocept at the screening visit and returns one month later, and you'll note that the subretinal fluid has improved, but does persist to some extent. The patient receives CLSAX at the baseline visit, and then we note over time at months 1, 2, and 3 where the subphobial fluid improved, and finally at month 4, the subphobial fluid is essentially resolved. The BCBA has remained stable throughout. The CFT has improved from 218 microns one month after a flipper set to 182 microns four months after CLSAX. Importantly, the CFT is actually better four months after CLSAX. versus one month after a sliver set. Subsequent to month four, the exudation recurs, and at month six, the patient receives additional therapy. Slide 25 represents another case study that shows that after CLSA-X, there's durable stability in both BCDA and CFT. Once again, the anatomy is noted in the upper left. We can see at screening that the patient entered the study with a BCDA of 37 letters, and a CST of 228 microns. There's mild interretinal fluid, there's mild subpulmonary fluid, as well as a shallow fibrovascular PED. The patient received CLSAS at baseline, and over five months of follow-up, the BCDA, CFT, and macular anatomy range stable. This patient has yet to return for the month six visit. Slide 26 is another example of the potential durability to the six-month time frame. In the upper left, the anatomy shows here's a fibrovascular PED and mild subphobial fluid. The patient entered the study with a BCVA of 42 letters and CST of 194 microns. After receiving treatment with CLSX, the month three visit in the lower left and the month six visit in the lower right show that the patient has stable BCVA and stable CST as well as stable macular anatomy. Slide 27 shows our final case study demonstrating durable stability for the six-month time point. The patient entered the study with BCBA of 72 letters and CFT of 262 microns. In the top left corner, we note that this cross-section is superior to the fovea in the central subfield. And in that cut, we can see the fibrobacteria of PDD as well as subretinal fluid. At baseline, they returned with stable BCBA, and the subretinal fluid has essentially resolved. The month 3 and month 6 visits show that the patient has stable BCDA and stable CST, as well as stable macular anatomy. In conclusion, I would like to briefly summarize our discussion and next steps for our CLS-AX program. Y29 is a very detailed summary of our results, alongside the competitive advantages for our program. Importantly, CLS-AX is delivered into the supracordial space via our proprietary SCS microjector, demonstrated an excellent safety profile at all doses and all time points, including no adverse events related to inflammation. The data suggests that our FGS microinjector potentially allows for in-office studies with no risk of implant migration and very low risk of vitreous floaters or haze, as well as very low risk of ocular hypertension or glaucoma. Plus, the FGS microinjector has been commercially accepted by retina physicians, following the launch of the design here, but the treatment of macular edema associated with UV items. We feel that our CLSS program may have strong competitive advantages in treating retinal diseases. Exitinib is a well-characterized small molecule with the potential of a lower risk of inflammation than a novel biologic agent. Exitinib is the most potent tyrosine kinase inhibitor currently in development for retinal diseases, and it's pan-VEGF-inhibited differentiated from those agents which focus on VEGF-A blockade. These potential benefits of excitinib are further leveraged with suprachordal delivery that targets high levels of the drug to the affected choroid retina. Our OASIS trial data and the interim extension study data showed very encouraging signs of durability and biologic effect in a difficult-to-treat patient population of anti-VEGF treatment experience sub-responders. This durability may compare favorably to other current TKI formulations and investigational intravitreal injective biologic agents. Moving now to slide 30, we lay out our current status and future plans for COSAX. We will continue to follow the eight patients remaining in the extension study until they all reach the six-month time point, and we expect to report this data in the first quarter of 2023. We are actively planning for the initiation of a randomized controlled phase two clinical trial in the first quarter of 2023 in wet AMD and or diabetic retinopathy. We're very pleased to have Dr. Arshad Kanani with us today. Dr. Kanani is a managing partner, director of clinical research, and director of fellowship at Sierra Eye Associates, and one of the leading research centers in the country. And he's a clinical associate professor at the University of Nevada at Reno School of Medicine. He's been a top enroller for multiple phase one to three trials. He's a member of numerous clinical trial steering committees and scientific advisory boards. His full bio is available in the appendix. Dr. Kanani will make some summary remarks and then we'll open the call for questions. Dr. Kanani, thank you again for joining us on this call. Can you provide our listeners with a brief background of your practice?
spk01: Thank you, Tom, and congratulations on this data. I'm Arshad Kanani. I'm a surgical and medical retina specialist. I'm in private practice in Reno, Nevada. My practice is, as you mentioned, heavily focused on clinical trials from early stage and late stage of clinical trials, new mechanism of action, and new delivery methods. And I'm excited to be here, especially talking about TKIs. I'm very interested in TKIs for multiple reasons, and we'll discuss that. And we also recently published an article about TKIs, really reviewing the landscape, so excited to be here.
spk07: Well, thanks again. I enjoyed your article. I thought it was really terrific. So, speaking of TKIs, what's your rationale on TKIs, and particularly CLSX administered supracordial retreat wet EMV?
spk01: I think, as a field, we're always looking to do better than what we currently do with anti-VEGF agents and, you know, recently with bispecific antibodies. And I think TKIs are interesting because of the fact that they can lead to 10 VEGF in addition, you know, with the routine. trap or antibodies, we are trapping the extracellular VEGF. Here, we are actually targeting intracellularly, and we are able to do a pan-VEGF blockade. We actually have seen better efficacy than we target VEGF C and D with other programs. So I think this idea of having one injection, you know, doing a pan-VEGF inhibition is very exciting. Exciting about CLS-AX because, as you mentioned, the validated delivery system. So, when you look at new molecules, you need to look at what are the variables in those molecules. You know, we have hydrogels, we have polymers, and on top of the drug, the delivery system matters. So, here you have supracoidal delivery, which is FDA approved. Me and many of the retina physicians who are involved in the trial or now not involved in the trial are using commercially approved out there for uveic macular edema. So, So the delivery is very exciting. It's easy. It's predictable. And then the next thing about Excedinib is that it is the most potent TKI because it has the highest affinity. So I think leveraging the delivery that's validated using a molecule that is most potent in the class of TKIs, I think it's exciting because of the fact that, you know, when you look at new MOAs, your delivery system, you need to get the best in terms of delivery, in terms of needle size, in terms of molecule, and I think that's what we are doing here.
spk07: Well, thanks for your insights. What are your impressions of the data, particularly with respect to safety, durability, and biologic effect?
spk01: I think for any new MRA, new molecule, safety is paramount. So it is super exciting to see that at this stage we have not seen any safety signals, you know, with other TKI programs. We have had particles. We have had particle migration in the front. We have been involved with all TKI trials. So I think having a good and favorable safety profile is crucial to take the program forward. And then the other thing here is the fact that we have seen biological effect, which is very hard to see in many other programs. So this patient population is very different than what we enrolled in other TKI programs. So we are enrolling in other TKI programs currently. So I think when you look at the data, you know, it's very easy. People want to cross-trial compare the durability. People want to cross-trial compare the top-line results. I think that's something to keep in mind that here your bar is much, much higher because you are taking this patient population that's difficult to treat. So having that patient population and the OCTs you have shown, it clearly shows a biological effect because I think it's important for companies to see the signal early. Otherwise, you feel like you see a signal, but there's no signal and programs fail. So I think de-risking your program was a really good idea. And then in terms of efficacy, you are maintaining BCDA and CSP. Of course, in previously treated patients, we don't expect improvement, but I think having a stable BCDA, having stable CSP is very meaningful, and, you know, that has been a primary endpoint for some durability trials for new agents or new delivery systems that FDA has approved. And then the last thing is durability. So, you know, tough-to-treat population, it's very hard to get durability. These are heavily treated patients needing frequent injections, and if you can take a patient on a clipper shaft that is not well-controlled with every four to six weeks of injections, and you give them steel like this, and you are able to extend them to three months or longer, I think that is very meaningful as a clinician, because you're targeting two things. You're targeting this high need patient population, that is a third of your practice, and then you're extending patients further out. So what it shows to me that if you took stable patients and you give them this treatment, they will go much further than they would with current patients. So really, overall, safety, efficacy, durability, and biological effect is positive, in my opinion, to take the program forward.
spk07: Thanks for your insights. I want to briefly touch upon the not per protocol retreatments that we observe. And I just want to share my thoughts and hear your perspective. You know, as I mentioned earlier, we intentionally chose wet A and D patients who were heavily anti-VEGF treatment experienced, as you just alluded to. And all these patients are sub-responders. They all had acid disease at screening, and that was confirmed by an independent reading center. And these patients had received frequent anti-VEGF injections prior to the study's enrollment. One of my colleagues refers to this group of patients as anti-VEGF addicts. And consequently, we chose these most difficult-to-treat patients for this first in-man study, which, as we alluded to, involved a new therapy delivered to the supracordial space for the first time. So naturally, during the course of the study, if the investigators who had previously treated these patients frequently did not note prompt improvement with this novel treatment, some would err on the side of constant intrigue. given their prior experience with these particular patients. And I think this behavior is somewhat understandable in these early-phase trials, and some of our peer companies have noted this behavior in their trials as well. So, Dr. Kanani, do you agree? What do you think? What's your perspective on that?
spk01: No, I agree with what you said, Tom. I think these are super high-need patients, and we know their treatment history, and we know that they require frequent treatment, injections and even with frequent injections, they're not well controlled. So I think, you know, as a clinician and a physician, you know, and as a company, I mean, all of us are doing this to help our patients. And if you have, you know, early stage trial and you're seeing some fluid, I think it's a knee jerk reaction to treat these patients. We have seen that with the gene therapy trials, we have seen that other trials. But I think Phase 1s are obviously a learning opportunity, and I think what we have seen here is that biological activity will happen with this molecule delivered to the supraclital space. So I think, you know, treating patients in this fluid is our standard of care, but I think with new MOA and the sustained delivery, I think that behavior is changing. We actually saw that with the forward delivery system. and other modalities where we're doing sustained delivery, including gene therapy, as I mentioned. So I think it's a learning opportunity. So going forward, I think having discussions about the retreatment criteria with investigators and convincing them that this is a very durable molecule based on the data we have seen, I think that will help physicians understand and not, you know, treat our protocol acutely. Great.
spk07: Thank you for your perspective. So, Dr. Kanani, you have a lot of experience treating wedding and deep patients in your busy practice and numerous clinical trials, and you've advised a variety of companies. You know, many of our listeners are not retina specialists, don't normally look at OCTs in the course of their work, and I thought it might be valuable for our listeners if you might expand a little bit on the OCT case studies that we reviewed and and maybe further discuss some of your impressions and insights.
spk01: I think, John, showing cases, I think it's super important to understand the value of a molecule. Many presentations we see where you don't see the details, so thank you to you and the team for actually being very transparent and showing us cases to actually see the biological effect. As I said, this patient population is not the patient population that was enrolled in other TKI trials. And sometimes when patients are enrolled in the trial, they have to have a history of neuroplasticity, but most trials, the TKIs, don't require any fluid. And this idea that maybe the disease was burned out and these patients never needed injections kind of gives this question mark about durability. We actually saw that in the Harvard study where there were a subset of patients after, you know, three injections, never required injections, they were treated PRN. So I think this patient population that you have really enrolled in this trial shows that they have active disease. So number one, that is, you know, convincing to me just seeing that these are high-need patients with active disease. Now comes the fact that how can we help them with, with this, you know, new MRA and supracoidal delivery, and seeing that effect after the Flipper step is screening, and then seeing the effect after CLS-AX, it's clearly convincing to me as a physician that we are seeing biological activity, and, you know, there's no question that this molecule is helping patients. Now, of course, the learning is, you know, how fast it's helping and how long it's helping. And, you know, that is going to really help us design the next stage. But at this stage, it is very convincing to me as a clinician that TKI is actually, especially this one, is helping our patients control disease. So disease control and durability, both are being shown by these case studies.
spk07: No, thanks for your insights, and thanks for your comments on transparency. So in the appendix of the deck, which is available for download, we actually include, in particular for cohort three and four, you know, all their prior treatment history going back three years, as well as all the subject-level data. So we have every visit, every CFT, and every BCBA plotted out in the appendix of the deck. And so finally, one last question. What is your opinion of the future of CLSAX?
spk01: I think based on the data you have shown, you know, safety, efficacy, and durability, Tom, obviously, we need to take this program forward. You know, being involved in all the TKI trials and written extensively about TKIs, I personally always thought that TKIs were just for well-controlled patients, but I think here I'm seeing a signal that we can actually benefit our high-need patients with CLS-AS delivered supra-coitally. So it's exciting to see that this is not just for a subset of patients. It can actually benefit majority of our patients. And, you know, going forward, obviously, now you have seen biological activity. If you do a controlled trial, with a comparator in stable patients, I think you're going to see durability that's going to be even better than what you have already shown. So I think looking at stable patient population, not just the hiney population, and then designing a trial with an active control with non-inferiority in BCVH primary endpoint, I think that's the way to go forward. But it's exciting that I actually, looking at this data, learn, and I'm thinking that TKIs are not just for stable patients, but actually all patients can benefit from it.
spk07: Once again, thanks for your insight. And now I'm going to turn the call over to George.
spk08: Thanks, Tom. Thanks to you and Dr. Kanani for that discussion. And I want to thank everyone on this call for your attention during our presentation. I'd now like to ask the operator to open the call off for questions.
spk05: Thank you.
spk07: Ladies and gentlemen, the door is now open for questions. And if you have any questions or comments, please press star 1 on your phone at this time. We ask that while posing your question, you please pick up your handset and listen on speakerphone to provide optimum sound quality. Please hold while we pose for questions. Thank you.
spk03: Our first question is coming from Andres Aguirrez with Wentbush. Please go ahead.
spk04: Good morning, and thanks for taking our question. Congrats on the updated results. Tom, you did a great job of asking a lot of our questions, so forgive us if we repeat them in some form. Can you just give us a sense of how these results inform planning and expectations for the Phase II, specifically around dose and patient selection? And can you also give us more color on how stabilizing DCVA and CST would translate to achieving a primary endpoint against an axis comparator? And then for Dr. Kanani, based on the results with durability around five months or so, where do you see CLS-AX sitting in the treatment paradigm? And is stabilizing DCVA and CST the goal for CLS-AX? Thanks.
spk08: All right, Tom, I thank you. And Dr. Kanani, I have a couple of questions that you need to answer. So please proceed.
spk07: Well, thanks, Andreas, and thanks for this list of questions. So I think the first question was, you know, next steps. And I think, you know, the important point here is that this is interim data with regard to the extension study. So we want to follow the patients to the end of the extension study and, you know, validate and confirm these initial results. But I do want to point out that, as I mentioned, eight of the patients in the extension study have made it to – that's eight of 12 patients in the extension study – have made it since the month five, and only one was treated prior to month five. So I think we have a fairly good sampling of all the patients in the extensive study, but we still want to follow these patients out to the completion of the trial. And so obviously we'll be analyzing the data at the next cut when these patients finish, and that will inform our future plans. And I think you know, your next question is, I think, around just generally clinical trials done. I think Dr. Kanani alluded to this, and I'll let him respond on it as well, but so the point I think you're making is that if you have treatment-experienced patients and you provide a sustained belief therapy that's meant to really stabilize them and reduce treatment burden, you know, the question is, what is the end point? And thankfully, we have a model for that with the port delivery system. So that was a, you know, that was studied in phase three trials. It's now commercially approved and available. And in that trial, you know, they had patients with what I would call, you know, much more lightly treatment experience. They had a diagnosis of neovascular A&D within nine months. They had two prior treatments. They enrolled in the trial. And then the goal of the trial was to stabilize. And so really, if you look at the visual community curve, even in the label, the prescribing information, you can see that what they've achieved with stability, and they compare it to an acid computer that's dosed for its label. And ultimately, you know, they show non-inferiority, as Dr. Kanani alluded to, and that led to approval. So we have a model for a therapy that is approved for essentially maintenance of stability. And Again, we're still analyzing this interim data, and we still need to decide on the best patient population going forward. As Dr. Kanani mentioned, in less treatment-experienced patients, we might expect even better signs of biologic effect and durability. So I'll now turn this over to Dr. Kanani, because I think you had some questions specifically for him as well.
spk01: Thanks, Tom. I think I agree with you that we haven't. we have a model to go after, and I think in that trial, as you remember, patients were allowed to get supplemental injection at month four or five after the surgery or after the last refill if they met pre-specified disease activity criteria, and those were very strict criteria. So I think the bottom line for me is the fact that the differences we have here, right, we have suprachoroidal delivery, which is inclinic, which is validated, FEF-proof, you know, and then they have a molecule that has good safety. So I think whenever there's a new treatment, not only do you have to look at durability, I think we have great anti-VEGF agents currently, as I said, so the safety bar is very high. So in terms of the question from Andreas about patient population where this will be utilized, I think, as Tom, you said, we are still learning about the durability and gathering data, but I think looking at it, clearly the stable patients on current treatment can go longer with, you know, this molecule. So that's one patient population, and that's actually the majority of our patients who are stuck at between four to eight weeks, and maybe that's going to be eight or 12 weeks with Pristamab or Bobycinib. So I think taking these patients to longer treatment intervals. Tom, you've done a lot of work about real-world data and published extensively that even if patients are getting injections, you know, every two months or so, they don't come to our clinic and their vision is worse over time. So I think as a clinician, I'm just not looking at a percent durability. I want to make sure these patients actually maintain their visual acuity long-term. I want to make sure that any knee treatment I give does not have adverse events or irreversible vision loss like we have seen with Polacizumab. So I think the fact is that if we can take those current patients and give them less frequent treatment, I think we will be able to stabilize their visual acuity longer. I think it's all about having patients keep their independence, you know, able to drive, able to function. I think those are important parameters, and we see there's a loss over time. So under a stable population, obviously, It's a no-brainer. And then I said earlier about higher need population that comes in frequently every four to six weeks and still have persistent fluid. So I think we are still learning if we can add on this therapy or use this therapy primarily for that patient population. And then the last question obviously always is naive patient population. I think after controlling the disease acutely, this will also fit in nicely. So, I think broad patient population may benefit from this molecule if obviously, you know, we continue to see the efficacy safety as regularly.
spk04: Okay, great. Thanks for the insight and congrats on the results.
spk07: Thank you. Our next question is coming from Annabelle Samini with Cypher. Please go ahead.
spk02: Hi, thanks for taking my question, and congratulations on some strong data. I'll just reiterate the point. You guys are doing a great job of explaining everything. So I'm just going to ask for a couple clarification questions. So just when you think about, you know, defining a sub-responder, is it just about fluid or is it about non-optimal visual acuity or CSP? The CFP you said reached sort of a floor, so therefore you're not really seeing improvement, but would you have seen improvement in visual acuity as well? So is it only fluid that makes them a non-responder? So I guess that's one of the points that I want to understand better.
spk07: That's a great question, Annabelle. So the question, I think, is, you know, what is a non-responder? And I don't think You know, it's a binary determination. They're either a non-responder or responder. And that's why, you know, I call them sub-responders. Yeah, and a couple of items here. So, you know, as clinicians, as investigators, as sponsors of trials, we like CST because it's convenient. It's a convenient measurement. you're measuring the central one millimeter that includes the fovea, and it includes the thickness of the retina, and that would encompass often subretinal fluid and interretinal fluid. So it's an easy, convenient measurement. The machine in clinic automatically prints it out for you within a minute. And so, you know, it's numerical. It's easy to grasp. It loans itself well to statistical analysis. But CST doesn't correlate perfectly with vision. And I think it's an important point that there's other aspects here that affect vision. You can have atrophy, which often occurs in wet A&G. They have dry A&G as well, so they have atrophy. You can have scarring from uncontrolled... you can have fluid under the RPE layer, which we call a pigment epithelial detachment. And all of this isn't captured by the CFT. But again, we like CFT because it's convenient. It loans itself well to analysis and graphing. And so when we think of subresponders, CFT doesn't capture all of it. So yes, I mentioned there's a floor effect, but you can see, for example, in the second case that I showed, and again, this will be available online, You know, the CST was essentially normal, but yet when you look at the actual anatomy of the images, you can see that there is mild subfolder fluid, there is mild inter-retinal fluid. And so I think it is important to look at these cases. And I think, you know, when I think of sub-responders, I think of patients that have persistent fluid on the OCT. And again, the images that we see in OCT are printed out almost immediately. So it's convenient. And I think most clinicians would consider, you know, persistent fluid on an OCT image after an antidepressant injection as a sub-respirator. So I don't think there's a clear-cut definition, but I do think that having patients with persistent fluid after antidepressant therapy is quite common. It's at least 30% of our patients. And persistent fluid has been shown, you know, over time. to be bad. There's a paper from the CAT study that showed that patients who have persistent intraretinal fluid over two years have a worse prognosis visually. So I guess to summarize, you know, there aren't these clear-cut correlations that we all like. CFT is really something that we conveniently plot. The images as retina specials is really what we like to see. And we have papers suggesting that at least 30% of patients, some papers suggest more, at least 30% of patients have persistent fluid on the OCT image. Most retina specialists would agree that those are sub-responders. Dr. Kanani, any more thoughts? Do you agree?
spk01: No, I agree. I think those are great thoughts. One thing I would add is that, you know, in a busy clinical practice, I'm seeing patients 80 to 90 patients, and the visual acuity in clinical practice actually could be variable because of dry eye, because of poor effort. You know, CSP and OCT images are not subjective. They're objective tests, and they give us the data right away. We call it a digest meter. So having, you know, fluids or having, you know, disease activity and OCT is what we treat patients for as And, of course, that's not a regulatory endpoint. Vision is. But I think we know from multiple trials, as you mentioned, Hawken-Harrier, Katz, Ivan, that fluctuations in CST actually are bad for the retina and can end up with long-term vision decline. So all these patients that are in our clinic getting monthly injections, we may have even in a week or two after the injection, and they may not have fluid, and then they come back in a month, and that fluid, those are suboptimal responders because they're having fluctuations in their fluid status. They're very high need patients, and that's the patient population you enrolled in the trial. So the hope is that with this molecule, if we can stabilize CSC or improve fluid than what it was with the standard, you know, frequent injection, I think that's going to be meaningful, for our patients in the future.
spk02: Okay, but there's no expectation that you would be improving visual acuity on that? Just you don't want worsening of it, so you want to maintain stability? I mean, I guess I'm trying to understand the visual acuity side of it, not the visual acuity.
spk01: Yeah, I think that's a really good question. Tom, can I take that?
spk07: Sure, yeah, sure.
spk01: Sure. Yes, perfect. You know, these are super high need patients. It's all about maintaining where they are. Otherwise, you know, or the CSP fluctuations, they're going to get worse over time. So I think, yes, we don't expect visual acuity improvement even in patients who don't have long-term disease like in the poor delivery system. We saw that patients, you know, as Tom said, had very recent disease and they got stabilized with with minimum of two anti-red-deaf injections, we didn't see visual acuity improvement, but rather maintenance. So, I think the acute improvements have been quickly, but there is long-term visual acuity loss because of non-compliance, because of CSD fluctuations. So, those are my comments to your question, Tom.
spk07: Yeah, so let me, I sometimes, you know, as retrospectives, we're too close to it to really, let me broaden the focus. So, so, With treatment-naive patients, you know, we have approved agents that are treated with, you know, what I call induction dosing. They're given monthly therapies initially. And if you look actually on their prescribing information, you know, you can see the visual acuity curves. And what you'll notice is that the visual acuity improves rapidly in treatment-naive patients who undergo this initial induction phase. And the visual acuity improvement, somewhere in the order of, you know, depending on the trial and the therapy, but somewhere in the order of, you know, eight to ten letters on average. So they improve within the first three or four months by eight to ten letters. Then the curve plateaus. And so these patients come in every four to six weeks, and their visual acuity is what it is. And these are the, you know, what one of my colleagues calls, these are the dead-death addicts that they have to keep coming in because if they don't come in for their treatment, they have persistent fluid which tends to progress. You know, persistent fluid leads to a visual decline from that plateau. And as Dr. Kanani mentioned, published extensively on real-world outcomes, and we know that in the real world, patients can't keep up. And so ultimately, they lose vision from that plateau. So in this treatment-experienced patient, they've already undergone that induction phase. You know, it's inherent in their prior treatment, and they're on the plateau. So you can see from the swim lane plots we show both, you know, six months prior and up to three years prior, these are patients receiving frequent injections. So they've already plateaued, and we don't expect them to improve. Now, in other patient populations, as Dr. Kanani mentioned, in treatment-naive patients, there's potential to see improved vision. So I think we've answered your question. Any follow-up? Is that clear?
spk02: Yes. No, that actually hit it exactly. And just, I guess, following on to the treatment experience, treatment-naive population. So as you move into phase two, you have a pretty good model, as you said, where you want to do it in BCVA as well as OCT. Is there any other endpoints that you're I mean, obviously you're looking at the, you know, reduction of any further treatment or reduction of treatment burden. Is it strictly about stability and BCVA and OCC, or you also need that reduction in treatment burden? Is that going to be like a key endpoint that people look at outside the durability? And then the treatment, do you have any intention of moving into OCC treatment-naive patients. I was always under the impression that anti-VEGF is the most rapid-acting, I guess, agent that you can use for stabilizing these patients. Do TKIs have that rapid effect as well, or do you just not know at this stage because it hasn't been studied in that treatment-naive population?
spk07: Annabelle, that's a great question. So let me start with the first one. So the question is, you know, the end point. And as Dr. Kanani mentioned, the primary endpoint for trials is generally, you know, visual function, in this case, visual acuity. So that has to be the endpoint. And so, you know, generally in these trials, we keep using the report delivery system as a model, but it's a good model, is, you know, can we maintain, after patients undergo induction, after they've risen, you know, their visual acuity has risen to the plateau, Can we maintain their visual acuity often in a non-steriority file with standards of care, you know, fixed frequent injections? And so visual acuity almost always sits at the primary endpoint. These other endpoints are interesting because they support the primary endpoint. You know, they suggest a biologic mechanism. And then, you know, a little bit more about your first question on visual improvement. Patients who... have chronic myodasco-AMD or chronic myodasco-AMD with elements of geographic geography, those patients often can't improve because they've had scarring. So I just wanted to follow that up. And then your second question, would we enroll treatment IE patients in the next trial? I think you answered your own question. We just don't know yet. We want to follow the patients in the extension trial up to the completion. But the beauty of this patient population is that We found a biological factor in a very difficult to treat patients and this opens up potential for, you know, a variety of patient populations that Dr. Kanani alluded to. Dr. Kanani, any other follow-up comments?
spk01: No, I think you answered the question very well, Tom. So, I think we'll learn as we generate more data and then this really helps. If you have biological activity in high-need patients, then you know that you're going to have activity in every other patient population. We are still learning about how fast TTIs, you know, help control disease. Of course, your technology is different because it's not a hydrogel or a polymer or microparticle, you know, injected in the vitreous, so I think With your program, I think you may see biological effect quicker than others, but we are still learning how quick that effect is so that we can help design the next study.
spk02: Okay. Thanks a lot.
spk07: Thank you. Our next question is coming from John Wallopin with JMP Securities. Please go ahead.
spk09: Thanks for taking the questions and congrats on the data, and thanks for the thorough release. One for Dr. Kanani, if I may, and then I'll follow up for management. Just wondering, you know, how frequently do you want to see your patients today? And when we have this longer durability agents becoming available, what do you need to see from a clinical program to, you know, lengthen that frequency? Or are you set that you want to see your patients on a set schedule? How are you thinking about, I guess, durability affecting your practice and patients?
spk01: Thanks. That's a really, really good question. So, I think there is a difference in following these patients in clinical trials versus following these patients in clinical practice. So, obviously, in clinical trial, you want to follow these patients monthly in most trials to look for any safety issues, any adverse events, and then, of course, look at the disease control. Patients are very heterogeneous. They're different in all aspects once you dive into So I think once we have controlled data about how long we can take majority of patients, then you'll have to individualize treatment to a patient. So for example, somebody who is very high need, let's say like this patient population needing monthly injection and you give them, you know, this molecule, you may want to see them monthly initially to see how fast you get to disease control. And then once you figure out what's called a sweet spot, you know, we do treat and extend in our clinic. Currently, the dentists are just trying to find a sweet spot where a patient is stable. Then you only see that patient that often, given that you are not looking for intraocular inflammation, given you are not looking for, like we did before delivery, you know, conjunctival erosions and retraction and endosomitis. So I think we have to balance the efficacy, safety, durability. But if I have a patient that can go four or five months on this molecule or six months that was on once every month or every other month treatment, then after that first cycle, I'll be comfortable seeing that patient at that time interval. And then lastly, we have, you know, home monitoring and OCT, home OCT and other things that are coming in pipeline where we'll be able to monitor these patients remotely. So, So overall, I think using technology and new mechanism of action will be able to significantly decrease treatment burden for our patients, and that's my hope.
spk09: That's very helpful. And then maybe one for Tom. When you're thinking about going to subsequent studies and dose selection, we see pretty good durability in both COVID-3 and 4, 4 a little bit better, smaller number of patients, shorter follow-up. But then when you factor in DST, it looks like it's worsening a bit, and cohort four, well, cohort three seems stable, improving, but then visual acuity dropping off, and cohort three is a longer follow-up. How do you factor in all these things? Safety, we don't have it by dose, but you say everything looks good so far. So what's the most important metric for you guys when you're thinking about a preferred dose moving forward?
spk07: Well, I think the most important thing is that we follow the patients in the extension study to see, you know, what happens in a broader patient population. And, you know, your point about the BCDA and CST, as I mentioned in my prepared comments, you know, as since the different interim analysis, the sample size really drops quite significantly as you hit month six. In fact, for the BCDA curve, when we exclude data after additional therapy, that month six time point really only consists of three patients. And I think, you know, you can look at the subject level curves yourself, but I think it's driven by one patient. So I don't really agree that the vision drops off at month six because it's driven by one patient. And the error bars cross the zero-no change line. So I would say that overall the visual acuity is stable, particularly since these patients weren't six months And same with CST. You know, again, the sample size drops immediately as you get to that final six-month visit. It's only three patients if we exclude patients after additional therapy. And then, you know, that's why I always worry when we want to be transparent and we want to provide the results, but with such small sample sizes, one can conclude that on the CST curves, the cohort three looks like it improves and cohort It looks like it worsened slightly. But the sample size is really small. And I think, if anything, you need to look at the mean of the two groups in order to increase the sample size a little bit. And the mean looks quite stable. And, if anything, you know, one could conclude that the CST gets better at six months. But, again, small sample sizes, we don't want to make much of it. I think, overall, we'd say that the CST and DCDA is stable over six months. And then the second part of your question.
spk09: Yeah, you touched on it, Tom. I guess maybe just a follow-up. Are you guys planning on bringing one or two doses forward into a Phase II program?
spk07: Yeah, so I think at this point we need to see more data and wait for that final analysis. But I think the good thing is that we saw really pristine safety. We saw really no safety signals at all at both doses. And I think you know, the biologic effect. In fact, all the cases I showed were from cohort three because we had just slightly longer follow-up. So I think the biologic effect is there in cohort three, and we're going to analyze cohort four more extensively once we have more follow-up. So I think it's premature to comment on the dose that we take forward. If we take one or both doses, you know, we're still deciding.
spk09: Got it. Thanks for taking the questions, and congrats on the data.
spk07: Thank you. Our next question is coming from Yi Chen with HC Wainwrights. Please go ahead.
spk05: Thank you for taking my questions.
spk07: You mentioned that at the screening, the patients had the active disease. Does that mean all the patients had excess fluid at the time of screening? Well, that's a great question. So, as I mentioned, at screenings, the patients were all assessed by the Independent Reading Center, and the Independent Reading Center defined active subflovial corneal vascular membrane as having subflovial corneal vascular membrane on angiography, which leaks, and having either subflovial subretinal fluid or interretinal fluid in the central subfield of the OCT. So, yes, they had to have fluid on the OTT and central subfield. So, is there a reason that you, you know, the clinical study would exclude patients who do not have access fluid? So, we excluded patients who don't have acid disease, who don't have fluid, but we included patients who had fluid, who had subretinal and interretinal fluid in the central sub fluid. And the degree of that fluid, you know, we did not expect that. They just had to have an active chordal miogastric membrane. Because these patients were heavily treated, you know, most of them did not have very thick CFTs. But these were patients who had, you know, high need patients who came back frequently. So they had fluid on their OCT as well as an actively leaking subphobial coronary vascular membrane on the angiogram, as defined by the reason. Does that suggest DRS-AX is not as good a drug for those patients who do not have excess fluid? You know, I'm not sure what you mean by excess fluid. We didn't exclude patients who had, you know, lots of fluid. But because these patients are all treatment experience, you know, they're not going to have lots of fluid unless they're treatment naive. And it goes back to my comments earlier with Annabelle, where, you know, patients, when they're first diagnosed, oftentimes will have very thick OCTs. The visual acuity will have dropped. They undergo induction dosing, which is often monthly. And then the OCTs improve. The vision improves. and then they're on the plateau of that visual acuity curve. And they often have, you know, some patients respond and become inactive, and some patients have smoldering leakage or leakage that comes back if they go too long between treatments. Okay. And would you expect the upcoming Phase II trial to have the same involvement criteria? Well, we're still evaluating all the, you know, we have a lot of potential with this agent, and we're still evaluating, still waiting for the results. for the final analysis from the extension study.
spk05: Okay, got it.
spk08: And so regarding the rescue-free rate versus the rate per particle criteria, would you say the former one would be more similar to a real-world practice scenario?
spk07: I'm not sure if I understand the question. Can you? For example, for the three-month time frame, you reported 69% of patients did not receive additional therapy versus 92% who did not receive additional therapy per protocol criteria.
spk06: I'm asking whether the former situation would be more similar to a real-world practice scenario in terms of rescue-free rates.
spk07: Again, I'm not sure if I understand the question, but, you know, in the real world, some patients, I think the most common treatment regimen is a treat and extend regimen. So patients, you know, like, for example, a naive patient will undergo monthly induction dosing. The visual acuity improves. The OCT improves. They go to the plateau of that visual acuity improvement curve, and then oftentimes patients The interval is extended. I think most retina specials will extend by two weeks at a time. And then, you know, in subsequent visits, if the fluid starts to recur or the vision starts to drop, they'll then contract by two weeks. And there are patients who have, you know, kind of almost a personalized interval where they can go. And it's very hard to get patients beyond, you know, beyond two months with current easing. So I think that's probably what we see in the real world. Dr. Tanani, do you want to expand since you have a busy practice and are most familiar with real-world treatment regimens?
spk01: Yeah, of course. I think, you know, the question is how does real-world practice differ from clinical trials and, you know, this off-protocol treatment versus protocol treatment. So I think When I'm participating in a trial, obviously I want to make sure that, you know, it's designed well and it has, you know, safety net for my patients. And some trials, you know, have criteria that are unrealistic and they do OCT, hand vision, and this and that, and then you end up having patients who actually get worse in the trial. Here, that's not the case. I think these are high-need patients, as we discussed, And what happens is if you are in an early stage study and you give the treatment and the patient still has fluid, your expectation was, well, maybe the treatment is not working. And then you try to give them an off-protocol treatment, just nervous that it's going to get worse. But here we actually saw that the fluid gets better over time. So this learning about following the protocol will be helpful when we go to to the next stage so we can convince our colleagues that, hey, you know, this treatment is working. It is going to improve. You just have to be patient. And I think I just want to comment to the earlier question about the patient population. So this patient population, as I said, is very different than other TKI studies, whether you look at, you know, other TKIs. The reason is the criticism TKI studies get is that, well, you're enrolling these patients. You have not shown fluid for the last five years. What if the disease is burned out and you're just treating them because you're scared about disease coming back or patients getting active? This is the only TKI study that we have participated in actually is requiring active fluids. So this actually shows the biological activity and is convincing for the community and the clinicians that, TKI slowly can benefit our patients.
spk03: Thank you. Our next question is coming from Serge Ballinger with Needham & Company. Please go ahead.
spk06: Hi, good morning. Thanks for taking my questions. I'll just pick the two. First one for Tom. Can you just talk about... In your plans for the phase 2 for all of you mentioned, also evaluating CLSAX in diabetic retinopathy patients, just curious if that would be a separate study or it would be part of the phase 2 for all. And then secondly, for Dr. Kamani, given your expertise with sarcinokinase inhibitors, the drug class that's been around for a long time, but I think it's had mixed results in retinal diseases so far, And some of it has been due to the delivery mechanism. But just curious, why do you think it's been difficult for this drug class? Is it a question of finding the right molecule and the right delivery mechanism? Or the treatment burden provides a high hurdle for success? Thanks.
spk07: So, I'll take that first question and turn the second question over to Dr. Kanani, as you requested. So I think you asked about diabetic retinopathy and, you know, potential study design. And, again, we're considering all options. We think we have a lot of potential with this therapy. And so, you know, we mentioned it in our remarks, you know, as a potential. It's an obvious potential. And how we design that trial, again, we're still considering all options. And I'll turn the second question over to Dr. Knotney.
spk01: Thanks, Tom. By the way, I agree with that about eclectopathy. The VEGF levels are low, and, you know, we have standard treatments of anti-VEGF, but the majority of the patients are not getting those treatments because of the frequency of visits. So I think that's some indication, obviously, to look into. The second question about, as a field, what do you think about PKI? Because we have had some some not so promising results in some trials. And I think as you alluded to, those were because of the safety concerns. Those were because of not picking the right patient population. And adverse events, you know, pressure issues, corneal toxicity, particles going to the front of the eye. But I think we have, you know, evolved from the version one of TKIs like GB102 to now in a situation that you have a delivery, you know, super current delivery, which is validated and FDA approved, and then you have a space where you are avoiding exposure to the front of the eye or to the vitreous cavity. So, you know, as I said, you know, I always am conservative in terms of looking at things, and I always thought that TTIs are probably best fit for very stable patients receiving injections every two or three months, and maybe if we can go to six months, that would be meaningful. But here, for the first time, I'm seeing this activity in these patients that actually were very, very high needs. So I think we still need to generate evidence, and the reason for that is that we have really good treatment. We have multiple FDA-approved treatment, and we have, you know, provides for now that we take patients but it's incremental benefit. It's not a six-month benefit. It's not a five-month benefit. It's close to, you know, anywhere from three to four months. And we are moving that needle forward. We are getting these patients, you know, stretched out a little bit longer than what they did in the past. So I think we are still open to new options, but the bar, again, is very high in terms of safety, efficacy, and durability. And, you know, the trials continue to generate data on multiple TKI programs So we'll see where it takes us. But at least for this program, I'm pleased to see that we are seeing biological activity in a very safety-favorable safety profile that really points to taking this program forward.
spk05: Thank you. Our next question is coming from Mayank Mamchami with BeWriting.
spk07: Please go ahead.
spk03: Good morning, team. Thanks for taking our questions and congrats on the data. So maybe just speaking with the prior sort of thematic conversation with Dr. Kanani. So induction therapy has also been very different across these PKI studies. Doctor, so could you just comment on, you know, as you think of going forward with this agent, what have been the learnings here and, you know, especially if you think about active disease, making sure that you're getting that induction is important. So could you maybe comment on that? And also at AO, as you know, the high-dose ILEA, obviously discussion was very relevant. So maybe if you could also put that in context would be very helpful. And then I have a follow-up for Tom about the data today.
spk01: Sure, I think those are all excellent questions. And you're right, you know, depending on the TKI trial, whether you get in a flipper step or anti-vegetarian screening, or you get it, you know, four to six weeks prior, and then you get it a month after you dose with TKI. So it is variable between trials. So I think this phase one is a learning opportunity for us. Once we get full data set, we'll be able to see where we want to, you know, load these patients, whether it's screening, whether a month after, things like that will be relevant as we take the program forward. Because I agree with you, I think we need to control these patients and give TKI some time to kick in so that they don't get worse over time. But here, you know, unlike other studies, there was no slivers that give in a month after TKI. So we are actually... seeing an effect post-dosing at two or three or four months, which is actually directly a result of the TKI, not a result of antiret just given a month after TKI. So that's why it's important to look at the data in detail and not just cross-trial compare top-line durability percentages, as I said, because the patient population is very different among the trials as well as the treatment regimen. And then the question about You know, a high-dose idea, obviously, that's a very detailed conversation for a later time. But I think, again, as I said, you know, with anti-VEGF injections, putting a little bit more may give you a little bit longer half-life, but you are seeing incremental benefits a week or two weeks at a time. You're not seeing a benefit that's lasting six months. So I think it's always good to have new agents, but I think a new mechanism of action designed for sustained delivery It's really exciting.
spk03: Thank you. That's very helpful. And maybe for you, Tom, in terms of follow-up as part of the trial protocol, maybe I missed that. Were there any patients lost in follow-up, or did you catch all of them? And if there was any of those, you know, protocol observations, what could have been the reasons for that? Can you just clarify that?
spk07: Sure. In terms of follow-up, we have data on all the patients who enrolled in the parent study, in the three-month parent study. And then those patients, as George mentioned initially, were offered the opportunity to participate in the extension study. And we haven't had any of those patients who actually showed up to participate in the extension study and showed up for their month four visit so far not show up for their subsequent visits to or tell us that they're not going to show up for their subsequent visits. I believe if you look at the swim lane box, you'll see that there are still patients who have showed up for month four and we're still following them. But so far, we haven't had any patients show up for their first extension study visit and then indicate that they're dropping out. Yeah, thanks for taking our questions and coming out again. Thanks. Thank you. As there appear to be no further questions in queue, I will hand it back to Mr. Lozeski for any final comments.
spk08: Thanks. Thank you for your time and attention this morning. I'd especially like to thank Dr. Kanani for joining us on the call today. I think we had a great discussion. I want to note that Flushside has an active investment conference schedule coming up starting with the Steeple Healthcare Conference next week. We also look forward to participating in the BTIG Ophthalmology Day, the Piper Sandler Healthcare Conference, and Cantor's Medical and Aesthetic Dermatology, Ophthalmology, and MedTech Conference. We appreciate your continued interest in ClearSight, and we look forward to updating you on our progress in the future. Operator, you may now disconnect.
spk03: Thank you, ladies and gentlemen. This does conclude today's conference call.
spk07: You may disconnect your lines at this time and have a wonderful day. And we thank you for your participation.
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