Clearside Biomedical Inc (CLSD) 2022 Q3 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to the Clearside Biomedical Inc 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 Kobin with Investor Relations. Ma'am, the floor is yours.

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 I/IIa 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 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 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 Lasezkay, our Chief Executive Officer; Dr. Thomas Ciulla, our Chief Medical Officer and Chief Development Officer; Charles Deignan, our Chief Financial Officer; and Dr. Arshad Khanani, 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.

Thank you, Jenny, and thank you all for joining us this morning. For today's call, I will make some opening remarks and then I will turn the call over to Dr. Tom Ciulla, our Chief Medical Officer and Chief Development Officer, who will walk through our CLS-AX Phase I/IIa clinical trial entitled OASIS. We are also joined this morning by Dr. Arshad Khanani, 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, Charles Deignan, is on the call with us to take any questions if 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 2, 3, and 4, who agreed to be monitored for an additional three months, making it a total of six months after a single dose of CLS-AX. Moving now to Slide 3 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 CLS-AX 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 3 and 4. As Tom will elaborate, CLS-AX provided at least 73% reduction in treatment burden to the three-month time point in OASIS. From the ongoing extension study, our interim data shows at least a 90% reduction in treatment burden from the average monthly injections in the six months before CLS-AX 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 CLS-AX biological effect were also observed on OCT in the sub-responder 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?

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 CLS-AX our proprietary suspension of axitinib delivered via our SCS Microinjector into the suprachoroidal space. In the CLS-AX program, we're marrying a very highly potent tyrosine kinase inhibitor that inhibits all VEGF receptors with a potential chorioretinal tissue targeting benefit of suprachoroidal delivery and with respect to durability, preclinical studies show that axitinib levels in the retina, choroid, and sclera were maintained at levels well above the IC50 for the VEGF receptor 2 up to six months after suprachoroidal injection.

With our novel delivery system, we're able to specifically target the affected choroid-retinal 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 SCS Microinjector has been commercially accepted by retina physicians following the launch of XIPERE. 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 I/IIa clinical trial in treatment-experienced patients with active wet AMD. OASIS is an open-label, single-dose escalating study to evaluate safety and tolerability of CLS-AX administered through a suprachoroidal injection. There were four cohorts of patients treated with escalating doses of CLS-AX. At screening, patients received a dose of aflibercept, for intravitreal injections. They returned 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 are heavily anti-VEGF treatment experience. All patients were sub-responders with active disease at 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 have controlled disease? While our primary objective for the study was safety and tolerability, we wanted to see if we could observe signs of biologic effect, and if we can lower the anti-VEGF treatment burden. By assessing sub-responders, we minimize the risk of false signals of biologic effect since inactive treatment -- treated patients may not require further therapy for many months.

This anti-VEGF treatment experienced population with active disease represents a significant number of patients in clinical practice in which more than 30% are sub-responders and have a high need for effective therapy with lower treatment burden. Importantly, we believe that when conducting the OASIS study in such a patient population, the data is particularly promising since we observed signs of clinically relevant benefits in the 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 wet AMD for over four years on average, and we're very highly treatment-experienced [somewhat after 90] prior anti-VEGF injections and all had active disease as confirmed by an independent reading center on screening.

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 CLS-AX in cohorts 3 and 4 may keep both the BCVA 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 adverse events related to aflibercept, CLS-AX or the suprachoroidal injection procedure. There were no dose-limiting toxicities. There were no adverse events related to inflammation, vasculitis, or vascular occlusion, and there were no vitreous floaters or dispersion of CLS-AX into the vitreous. Next, I'll review the promising durability results in the trial. Slide 11 shows the prior anti-VEGF therapy and the treatments administered during the study for all patients treated to the three-month OASIS endpoint. In the middle of the [swimlane] the column of red dots represents the aflibercept administered screening. Everything to the left of that column represents the patient's prior six-month anti-VEGF treatment regimen.

As you can see, most of the patients were being treated monthly. The green column of dots shows the CLS-AX injection at baseline, and then the patients were followed at 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 on to the data. Going forward, I'll focus the discussion on Cohorts 3 and 4 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 3 and 4, 11 of 16 or 69% of patients did not receive additional therapy to three months. On Slide 12, this swim lane plot shows only the patients treated per protocol criteria. Here in cohorts 3 and 4, 11 of 12 or 92% of patients treated per protocol did not receive additional therapy to three months. We're extremely encouraged with these results. We're also pleased to report that CLS-AX reduced the treatment burden across all cohorts to month three as seen on Slide 13. Again, we showed treatment across all therapies on the left and per protocol treatment on the right.

Importantly, in cohorts 3 and 4, there is 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 Cohort 4, 1 mg dose. Moving now to the interim results of the extension study. On Slide 14, we saw the prior anti-VEGF 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 3 and 4. Eight patients are still being monitored in the study.

As you can see, to month four, eight of 10 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. Once again, on slide 15, the swim lane plot shows only the patients treated per protocol criteria. This slide is important as you can see that to date, only one patient in cohort 3 has received additional therapy prior to the six-month time point and one patient was dosed at month six. In Cohort 4, no patients in the extension study have received [additional] therapy per protocol criteria to date. This breaks down as follows; 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 patients have not required any additional therapy to month five, and 75% of the patients have not required any additional therapy to month six. As you can see on Slide 17, Cohorts 3 and 4 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-VEGF 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 biologic effect we observed in cohorts 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 a thick black line. Importantly, what we note is that over the three-month course of the OASIS study post CLS-AX dosing, the visual acuity remains 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 mean change in central subfield thickness from screening for cohorts 3 and 4. On the left, we include all data, and you can see that the CST remains stable. On the right, we exclude post retreatment data, and again, it looks similar. Notably, the CST data demonstrates that patients were stable over the course of the three months post CLS-AX. Similarly, Slides 21 and 22 show that the mean BCVA and CST also remained stable through a total of six months in the extension study in cohorts 3 and 4. On Slide 21, on the left, we observed that over the six months post CLS-AX dosing, the visual acuity remains 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 BCVA 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 are some variability with the CST all within approximately [50 mg] 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 CLS-AX. 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 these examples, the patient enters the trial at screening and receives aflibercept intravitreally. This is followed one month later at baseline with a single dose of CLS-AX administered suprachoroidally.

Slide 24 is a case study that supports the biologic effect and anti-VEGF sub-responder. We can see that the patient enters the study with a relatively good BCVA of 75 letters or 20 over 32, which tends to create a ceiling effect in these treatment-experienced patients. The CST measures 265 microns. The Fovea, subfoveal fluid, and the fibrovascular pigment epithelial detachment or PED are all marked. The patient received aflibercept 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 CLS-AX at this baseline visit, and then we note over time at month one, two, and three with subfoveal fluid improves and finally, at month four, the subfoveal fluid is essentially resolved.

The BCVA has remained stable throughout. The CST has improved from 218 microns one month after aflibercept to 182 microns four months after CLS-AX. Importantly, the CST is actually better four months after CLS-AX versus one month after aflibercept. Subsequent to month four, the [expedation] occurs and at month six, the patient received additional therapy. Slide 25 represents another case study that shows that after CLS-AX, there's durable stability in both BCVA and CST. Once again, the anatomy is noted in the upper left. We can see a screening that the patient entered the study with a BCVA of 37 letters and a CST of 228 microns. There is mild intraretinal fluid, there is mild subfoveal fluid as well as a shallow fibrovascular PED.

The patient receives CLS-AX at baseline and over five months of follow-up, the BCVA, CST and macular anatomy remained stable. This patient is yet to return for the month six visit. Slide 26 is another example of the potential durability to the six-month time point. In the upper left, the anatomy shows there's a Fibrovascular PED and mild subfoveal fluid. The patient entered the study with a BCVA of 42-letters and CST of 194 microns. After receiving treatment with CLS-AX, the month three visit in the lower left and month six visit in the lower right show that the patient had stable BCVA and stable CST as well as stable macular anatomy.

Slide 27 shows our final case study, demonstrating durable stability to the six-month time point. The patient enters the study with BCVA of 72 letters and CST 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 Fibrovascular PED as well as subretinal fluid. At baseline, they returned with stable BCVA and the subretinal fluid has essentially resolved. The month three and month six visits show that the patient has stable BCVA 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. Slide 29 is a very detailed summary of our results alongside the competitive advantages for our program. Importantly, CLS-AX delivered into the suprachoroidal space via our proprietary SCS microinjector demonstrated an excellent safety profile at all doses and all time points, including low adverse events related to inflammation. The data suggests that our SCS microinjector potentially allows for in-office setting with no risk of implant migration and very low risk of vitreous floaters or haze as well as very low risk with ocular hypertension or glaucoma. Plus the SCS microinjector has been commercially accepted by retina physicians following the launch of XIPERE for the treatment of macular edema associated with uveitis.

We feel that our CLS-AX program may have strong competitive advantages in treating retinal diseases. Axitinib is a well-characterized, small molecule with the potential of a lower risk of inflammation than a novel biologic agent. Axitinib is the most potent tyrosine kinase inhibitor currently in development for retinal diseases and its pan-VEGF inhibition is differentiated from those agents which focus on VEGF-A blockade. These potential benefits of axitinib are further leveraged with suprachoroidal delivery that targets high levels of the drug to the affected chorioretina. 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 injected biologic agents. Moving now to Slide 30. We lay out our current status and future plans for CLS-AX. We will continue to follow the eight patients remaining in the extension study until they all reach a six month (inaudible) 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 II clinical trial in the first quarter of 2023 in wet AMD and/or diabetic retinopathy. We're very pleased to have Dr. Arshad Khanani with us today. Dr. Khanani 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, Reno School of Medicine. He's been a top enroller for multiple Phase I to III trials. He's a member of numerous clinical trial steering committees and scientific advisory board. His full bio is available in the appendix.

Dr. Khanani will make some summary remarks, and then we'll open the call for questions. Dr. Khanani, thank you again for joining us on this call. Can you provide our listeners with a brief background of your practice?

Thank you, Tom, and congratulations on this data. I'm Arshad Khanani, I'm a surgical and medical retina specialist. I'm in private practice in Reno Nevada, practices as you mentioned, heavily focused on clinical trials from early stage and late-stage clinical trials, new mechanism of action, and new delivery methods, and I'm excited to be here, especially talking about [TKIs ever] 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.

Thanks again. I enjoyed your article. I thought it was really terrific. So speaking of TKIs, what's your rationale on TKIs? And particularly the CLS-AX administered (inaudible) wet AMD.

I think, as I see, we are always looking to do better than what we currently do with the anti-VEGF agents and recently with bispecific antibodies. And I think TKIs are interesting because of the fact that they can lead to pan-VEGF inhibition with the routine trap or antibodies, we are tracking the extra cellular VEGF. Here, we are actually targeting intracellularly and we are able to do a pan-VEGF blockade. We actually have seen better efficacy when we target VEGF C and D with other programs. So I think this idea of having one injection doing a pan-VEGF inhibition is very exciting. Excited about CLS-AX because, as you mentioned, validated delivery system. So when you look at new molecules, you need to look at what are the variables in those molecules. We have hydrogels, you have polymers. And on top of the drug, the delivery system matters. So here, you have suprachoroidal delivery, which is FDA approved. Me and many of the retina physicians who are involved in the trial are now not involved in the trial are using commercially approved XIPERE for uveitic macular edema. So the delivery is very exciting. It's easy. It's predictable.

And then the next thing about axitinib 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 when you look at new MOAs, new 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.

Thanks for your insights. What are your impressions of the data, particularly with respect to safety, durability, and biologic effect.

I think for any new MOA, new molecule 50 is paramount. So it is super exciting to see that at this stage, we have not seen any safety signals 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 a 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 the other TKI programs currently. So I think when you look at the data, it's very easy people on a cross-trial compare the durability. If people want to cross-trial compare the topline 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 derisking your program was a really good idea.

And then in terms of efficacy, you are maintaining BCVA and CST. Of course, in previously treated patients, we don't expect improvement. So I think having a stable BCVA having stable CST is very meaningful, and that has been a primary endpoint for some durability trials for new agents or new delivery system that FDA has approved. And then the last thing is durability. So in a tough to treat population, it's very hard to get durability. These are heavily pre-treated patients needing frequent injections and if you can take a patient on aflibercept that is not well controlled with every four to six weeks of injections and you give them CLS-AX 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 highly patient population that is 1/3 of your practice, and then you're extending patients further out. So what it shows to me is that if you took stable patients, and you give them this treatment, they will go much further than they would with current agents. So really, overall, safety efficacy, durability, and biological effect is positive, in my opinion, to take the program forward.

Thanks for your insight. 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. As I mentioned earlier, we intentionally chose wet AMD patients who are heavily anti-VEGF treatment experienced, as you just alluded to, and all these patients are sub-responders, they all had active disease at screening, and that was confirmed by independent rating center. And these patients have received frequent anti-VEGF injections prior to the study 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 you alluded to, involved a new therapy delivered to the suprachoroidal space for the first time. So naturally, during the course of the study of 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 [caution and treat] given their prior experience with these particular patients. And I think this behavior are somewhat understandable in these early phase trials, and some of our peer companies have noted misbehavior in their trials as well.

So Dr. Khanani, do you agree -- what do you think? What's your perspective on that?

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 injection and even with frequent injections, they are not well controlled. So I think as a clinician and a physician and as a company, I mean, all of us are doing this to help our patients. And if you have 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 with other trials. But I think PhaseIs 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 suprachoroidal space. So I think treating patients if there's 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 four 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 the 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 treat off protocol acutely.

Great. Thank you for your perspective. So Dr. Khanani, you have a lot of experience treating wet AD patients in your busy practice and numerous clinical trials and you've advised a variety of companies. Many of our listeners are not [retina specialists] don't normally look at OCTs in the course of your 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 maybe further discuss some of your impressions and insights.

I think Tom showing cases, I think, is super important to understand the value of a molecule. Many presentations we see, where we 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 neurovascular AMD, but most trials with 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 (inaudible) study where there were a subset of patients after three injections never required injection and 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 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 this new MOA and suprachoroidal delivery and seeing that effect after a (inaudible) and then seeing the effect after CLS-AX, it's clearly convincing to me as a physician that we are seeing biological activity. And there's no question that this molecule is helping patients. Now of course, the learning is how fast it's helping and how long it's helping, and 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 this -- especially this one, is helping our patients control disease, so disease control and durability, both are -- both are being shown by these case studies.

Thanks for your insight 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 3 and 4, all of your prior treatment history going back three years as well as all the subject-level data. So we have every visit, every CST and every BCVA plotted out in the appendix of the deck. And so finally, one last question. What is your opinion of the future of CLS-AX?

I think based on the data you have shown, safety, efficacy and durability, Tom. Obviously, we need to take this program forward. Being involved in all 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-AX delivered [suprachoroidaly]. 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 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 [high need] population and then coming -- designing a trial with an active control with noninferiority in BCVAs 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.

Once again, thanks for your insight. I'm now going to turn the call over to George.

Thanks, Tom. Thanks to you and Dr. Khanani 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 up for questions.

Thank you. Ladies and gentlemen, the floor is now open for questions. (Operator Instructions) Our first question is coming from Andreas Argyrides with Wedbush.

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 then can you also give us more color on how stabilizing BCVA and CST would translate to achieving a primary endpoint against an active comparator? And then for Dr. Khanani, based on the results with their ability around five months or so, where do you see CLS-AX sitting in the treatment paradigm and is stabilizing BCVA and CST the goal for CLS?

Alright. Tom, I think you and Dr. Khanani have a couple of questions which you need to answer. So please proceed.

Well, thanks, Andreas. And thanks for the list of questions. So I think the first question was the next steps and I think 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 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 to month five and only one was treated prior to month five. So I think we have a fairly good sampling of the -- of all the patients in the extension study, but we still want to follow these patients out to the completion of the trial. And so obviously, we will be analyzing the data at the next cut when these patients finish and that will inform our future plans.

And I think your next question is, I think, around just generally a clinical trial design. I think Dr. Khanani alluded to this, and I'll let him expound 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 release therapy that's meant to really stabilize them and reduce treatment burden. The question is, what is the endpoint? And thankfully, we have a model for that with the [port delivery system]. So that was a network study in Phase III trials. It's now commercially approved and available. And in that trial, they had patients with what I would call much more lightly treatment experience. They had a diagnosis of neovascular AMD within nine months. They had two prior treatments, they enroll in the trial, and then the GOLD trial was to stabilize. And so really, the -- if you look at the visual acuity curves even in the label of the prescribing information, you can see that what they've achieved with stability and they compare it to an active comparator that's dosed for its label. And ultimately, they show non-inferiority as Dr. Khanani 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're still need to decide on the best patient population going forward. As Dr. Khanani 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. Khanani, because I think you had some questions specifically for him as well.

Thanks. I think, I agree with you that 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 4 or 5 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 in clinic, which is validated FDA approved. And then we have a molecule that has good safety.

So I think whenever there's a new treatment, not only we 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 this molecule. So that's one patient population. And that's actually a majority of our locations were stuck at between 4 to 8 weeks and maybe that's going to be 8 or 12 weeks with Faricimab or Vabysmo.

So I think taking these patients to longer treatment interval, Tom, you have done a lot of work about real world data and published extensively that even if patients are getting injections every 2 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 new treatment I give does not have adverse events or irreversible vision loss like we have seen with Polatuzumab. 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, able to drive, able to function, I think those are reported parameters, and we see vision loss over time. So under a stable population, obviously, is a no-brainer.

And then I said earlier about higher need population that comes in frequently every 4 to 6 weeks and still have persistent fluid. So I think we're 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, we continue to see the efficacy, safety and durability.

Our next question is coming from Annabel Samimy with Stifel.

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 of clarification questions. So just when you think about defining a sub-responder, is it just about fluid or is it about non-optimal visual acuity or CST? Because the CST, 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.

Great question, Annabel. So the question, I think, is what is a non-responder? And I don't think it's a binary determination. They're either a non-responder or responder. And that's why I call them sub-responders. Yes. And a couple of items here. So as clinicians, as investigators, as sponsors of trial, we like CST because it's convenient. It's a convenient measurement. You're measuring the central 1 millimeter that includes the fovea. And it includes the thickness of the retina and that would encompass often sub-retinal fluid and intra-retinal fluid. So it's an easy, convenient measurement, the machine, in clinic, automatically potentially (technical difficulty) within a minute.

And so it's numerical, it's easy to graph. It loads itself well the 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 could have atrophy, which often occurs in wet AMD, they have dry AMD as well. So they had atrophy. You can have scarring from uncontrolled neovascular AMD. You can have fluid under the RPE layer, which we call a pigment epithelial detachment. And all of this isn't captured by the CST. But again, we like CST because it's convenient, it loads itself well for analysis and graphing.

And so when we think of sub-responders, CST 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, the CST was essentially normal. But yet when you look at the actual anatomy of the images, you can see that there is mild subfoveal fluid, there is mild intra-retinal fluid. And so I think it is important to look at these cases. And I think when I think of sub-responders, I think the patients that have persistent fluid on the OCT.

And again, the images that we see in OCT are almost -- are printed out almost immediately. So it's convenient. And I think most clinicians would consider persistent fluid on an OCT image after an anti-VEGF injection as a sub-responder. So there's not -- I don't think there's a clear cut definition, but I do think that having patients with persistent fluid after anti-VEGF therapy is quite common. It's at least 30% of our patients. And persistent fluid has been shown over time to be bad. There's a paper from the CAP study that showed that patients who have persistent intra-retinal fluid over 2 years have a worse prognosis digitally.

So I guess to summarize, there are not these clear-cut correlations that we all like. CST is really something that we conveniently plot. The images as retina special, is really what we like to see. And we have paper suggesting that at least 30% of patients -- some papers suggest more, at least 30% of patients have persistent fluid on the OCT image and most retina specialists would agree that those are sub-responders. Dr. Khanani, any more thoughts? Do you agree?

No. I agree. I think those are great thoughts, Tom. One thing I would add is that in a busy clinical practice and seeing 80 to 90 patients. And the visual acuity in clinical practice actually could be variable because of dry eye, because of poor effort, CST and OCT images are not subjective. They're objective tests, and they give us the data right away. We call it a VEGF meter. So having fluid or having disease activity on OCT is what we treat patients for exclamation. And of course, that's not a regulatory endpoint vision is. But I think we know from multiple trials, as you mentioned, HAWK and HARRIER, CATT, 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 I know where clinic getting monthly injections, we may see them in a week or 2 after the injection, and they may not have fluid and then they come back in a month and they're fluid. Those are suboptimal responders because they're having fluctuations in their fluid status. They are 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 CST or improve fluid than what it was with standard frequent injection, I think that's going to be meaningful for our patients in the future.

Okay. But there is no expectation that you would be improving visual acuity on that. Just you don't want worsening up. so you want to maintain stability. I mean, I guess I'm trying to understand the visual acuity side of it, why not better visual acuity?

Yes. I think that's a really good question. Tom, can I take that?

Sure. Yes, sure. And I may add some.

Yes, perfect. So I was -- these are super high-need patients. It's all about maintaining where they are, otherwise, or the CST 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 port delivery system, we saw that patients, as Tom said, a very recent disease, and they got stabilized with minimum of 2 anti-VEGF injections, we didn't see visual acuity improvement but rather maintenance. So I think the acute improvements happen quickly, but there is long-term visual acuity loss because of non-compliance because of CST fluctuations. So those are my comments to your question. Tom?

Yes. So let me -- sometimes it's retrospection were too close to it to really -- let me broaden the focus. So with treatment-naive patients, we have approved agents that are treated with what I call induction dosing, they're given monthly therapies initially. And if you look actually on your prescribing information, 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 is somewhere in the order of -- depending on the trial and the therapy, but somewhere in the order of 8 to 10 letters on average.

So they improve within the first 3 or 4 months by 8 to 10 letters. Then the curve plateaus. And so these patients come in every 4 to 6 weeks. And their visual acuity is what it is. And these are the -- one of my colleagues calls, these are the VEGF 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 and persistent fluid leads to a visual decline from that plateau.

And as Dr. Khanani mentioned, (technical difficulty) 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 patients, they've already undergone that induction phase. It's inherent in their prior treatment. And they're on the plateau. So you could see from the swim lane plots we show both 6 months prior and up to 3 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. Khanani mentioned, in treatment-naive patients, there's potential to see improved vision. So I think we answered your question. Any follow-up? Does that seem clear?

Yes. No, that actually hits it exactly. And just, I guess, following on to the treatment experience treatment-naive population. So as you move into Phase II, you have a pretty good model, as you said, where you want stability in BCVA as well as OCT. Is there any other end point that you're -- I mean, obviously, you're looking at the reduction any further treatment or reduction of treatment burden. Is it strictly about stability in BCVA and OCT or you also need that reduction in treatment? Is that going to be like a key endpoint that people look at outside the durability? And then the treatments, do you have any intention of moving into 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? Did 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?

Annabel, this is a great question. So let me start with the first one. So the question is the endpoint. And as Dr. Khanani mentioned, the primary endpoint for trials is generally visual function. So in this case, there's more acuity. So that has to be the endpoint. And so generally, in these trials, we keep using the port delivery system as a model, but it's a good model is, can we maintain -- after patients undergo induction after they've risen, their visual acuity has risen on that to the plateau, can we maintain their visual acuity often a non-inferiority trial with standard of care fixed frequent injections. And so visual acuity almost always is the primary endpoint. These other endpoints are interesting because they support the primary endpoint. They suggest a biologic mechanism.

And then a little bit more about your first question on visual improvement. Patients who are -- have chronic (inaudible) vascular AMD or chronic measured vascular AMD with elements of geographic atrophy. Those patients often can't improve because they have scarring. So I just wanted to follow that up. And then your second question, would we enroll treatment-naive 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 out to the completion. But the beauty of this patient population is that we've shown a biologic effect in a very difficult to treat patients. And this opens up potential for a variety of patient populations that Dr. Khanani alluded to. Dr. Khanani, any other follow-up comments?

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 TKIs help control disease. Of course, your technology is different because not a hydrogel or a polymer or microparticle 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.

Our next question is coming from Jon Wolleben with JMP Securities.

Congrats on the data, and thanks for the oral release. One for Dr. Khanani, if I may, and then a follow-up for management. Just wondering 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 lengthen that frequency? Or you said that you want to see your patients on a schedule? How are you thinking about, I guess, durability affecting your practice and patients?

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, we 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 real world. 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 this molecule, you may want to see a monthly initially to see how fast you get to disease control.

And then once you figure out what's called a sweet spot, we do treat and extend in our clinic currently with anti-VEGF 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're not looking for like we did for delivery, conjunctival erosions and retraction and endophthalmitis. So I think you have to balance the efficacy, safety and durability. But if I have a patient that can go 4 or 5 months on this molecule or 6 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 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 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.

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 of both Cohorts 3 and 4, 4 a little bit better, smaller number patients, shorter follow-up. But then when you factor in CST looks like it's worsening a bit in Cohort 4, well Cohort 3 seeing stable improving, but then visual acuity dropping off in Cohort 3, the longer follow-up. How do you factor in all these things? In safety, we don't have it by dose, but do 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?

(technical difficulty) Point about on the BCVA and CST, as I mentioned in my prepared comments, as -- since it is an interim analysis, the sample size really drops quite significantly as you hit month 6. In fact, for the BCVA curve, when we exclude data after additional therapy, that month 6 time point really only consists of 3 patients. And I think 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 6 because it's driven by one patient. And the error bars crossed the 0 no change line. So I would say that overall, the visual acuity is stable, particularly since these patients went 6 months. And same with CST, again, the sample size drops in unison to get that final 6-month visits only 3 patients, if we exclude patients after additional therapy.

And then 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 could conclude that on the CST curves, the Cohort 3 looks like it improves and Cohort 4 looks like it worsened slightly, but sample size is really small. And I think if anything, you need to look at the mean of the 2 groups in order to increase the sample size a little bit. And the mean looks quite stable. And if anything, one could conclude that the CST gets better at 6 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 BCVA stable over 6 months.

And then on second part of your question (technical difficulty) we see more data and wait for that the final analysis. But I think the good thing is that we saw a really pristine safety. We saw really no safety signals at all at both doses. And I think the biologic effect. In fact, all the cases I showed were from Cohort 3 because we had just slightly longer follow-up. So I think the biologic effect is there in cohort 3, and we're going to analyze Cohort 4 and 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, we're still designed.

Our next question is coming from Yi Chen with H.C. Wainwright.

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 screening, the patients were all assessed by an independent reading center. And the independent reading center defined active subfoveal choroidal neovascular membrane as having subfoveal choroidal neovascular membrane on angiography, which leads and having either subfoveal -- sub-retinal fluid or intra-retinal fluid in the central subfield of the OCT. So yes, they had to have fluid on the OCT in central subfield.

So is there a reason that you -- the clinical study would exclude patients who do not have access to it?

So we excluded patients who don't have after disease who don't have fluid. But we included patients who had fluid, who had sub-retinal intra-retinal fluid in the central subfield. And the degree of that fluid, we did not specify. They just had to have an active choroidal neovascular vascular membrane, because these patients were heavily treated, most of them did not have very thick CSTs, but these were patients who had high-need patients who came back frequently. So they had fluid on their OCT as well as an actively leaking subfoveal choroidal neovascular membrane on the angiogram as defined by the reset.

Does that suggest CLS-AX is not as good a drug for those patients who do not have excess fluid?

I'm not sure, what you mean by excess fluid. We didn't exclude patients who had lots of fluid. But because these patients are all treatment experienced they're not going to have lots of fluid unless they're treatment naive. And it goes back to my comments earlier with Annabel, where patients when they're first diagnosed, oftentimes, they'll have very thick OCTs, the visual acuity will have dropped, they undergo induction dosing, which is often monthly. And then the OCTs improved, the vision improves. And then they're on the plateau that there's an acuity curve. And they often have some patients respond and then 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 enrollment criteria?

Well, we're still evaluating all the -- we have a lot of potential with this agent, and we're still evaluating. We're still waiting for the final analysis from the extension study.

Okay, got it. And so regarding the rescue free rate versus the rate per protocol criteria, would you say the former one would be more similar to a real-world practice scenario?

I'm not sure if I understand the question. Can you expand?

So for example, for the 3-month time point, you reported 69% of patients did not receive additional therapy versus 92% who did not receive additional therapy per protocol criteria. I'm asking whether the former situation would be more similar to real world practice scenario in terms of rescue free rates?

Again, I'm not sure if I understand the question, but in the real world, some patients -- I think the most common treatment regimen is a treatment-extend regimen. So patients -- 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, the interval is extended. I think most retina specialists will extend by 2 weeks at a time. And then in subsequent visits, if the fluid starts to recur, the vision starts to drop they'll then contract by 2 weeks. And there are patients who have kind of almost a personalized interval, where they can go. And it's very hard to get patients beyond 2 months with current agents. So I think that's probably what we see in the real world. Dr. Khanani, do you want to expand since you have a busy practice and are most familiar with real world treatment regimen?

Yes, of course, Tom. I think the question is, how does real world practice differ from clinical trials and this off protocol treatment versus protocol treatment. So I think when I'm participating in a trial, obviously, I want to make sure that it's designed well and it has safety net for my patients. And some trials have criteria that are unrealistic and they do OCT and vision and this and that, and then you ended 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 discuss. 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 the next stage, so we can convince our colleagues said, hey, 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 this patient population. So this patient population, as I said, is very different than other TKI studies, whether you look at 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 5 years. What are the diseases 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 fluid. So this actually shows the biological activity and it's convincing for the community and we as a clinician that TKI clearly can benefit our patients.

Our next question is coming from Serge Belanger with Needham & Company.

I'll just have 2. First one for Tom. Can you just talk about in your plans for the Phase II trial, you mentioned also evaluating CLS-AX in diabetic retinopathy patients. Just curious if that would be a separate study or it would be part of the Phase II trial? And then secondly, for Dr. Khanani, given your expertise with parsing kinase inhibitors, the drug class that's been around for a long time, but I think has had mixed results in the retinal diseases so far. And some of it has been due to the delivery mechanism. But just curious why you think it's been difficult for this drug class? Is it a question of finding the right molecule in the right delivery mechanism or the treatment burden provides a high hurdle for success?

So I'll take that first question and turn the second question over to Dr. Khanani as you requested. So I think you asked about diabetic retinopathy in potential study design. And again, we're considering all options. We think we have a lot of potential with this therapy. And so we mentioned it in our remarks as a potential, it's an obvious potential cases and how we design that trial. Again, we're still considering all options. And I'll turn the second question over to Dr. Khanani.

Thanks, Tom. By the way, I agree with diabetic retinopathy, the VEGF levels are low, and we have standard treatments in anti-VEGF, the majority of the patients are not getting those treatments, because of the frequency of visits. So I think there's some indication obviously to look into. The second question about as a field, what do we think about TKIs because we have had 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 the adverse events, pressure issues, corneal toxicity, particles going to the front of the eye. But I think we have evolved from the version 1 of TKIs like GB-102 to now in a situation that you have a delivery -- supercoil 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 as I said, I always am conservative in terms of looking at things and how we saw the TKIs are probably best fit for very stable patients receiving injections every 2 or 3 months and maybe if we can go to 6 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 need. So I think we still need to generate evidence. And the reason for that is that we have really good treatments currently. We have multiple FDA approved treatment, and we have a (inaudible) that can take patients longer, but it's incremental benefit. It's not a 6-month benefit. It's not a 5-month benefit. It's close to anywhere from 2 to 4 months. And we are moving that needle forward. We are getting these patients stretched out a little bit longer than what we 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 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.

Our next question is coming from Mayank Mamtani with B. Riley.

Congrats on the data. So maybe just sticking with the prior sort of thematic conversation with Dr. Khanani. So induction therapy has also been very different across these TKI studies, doctor? So could you just comment on -- as you think of going forward with this agent, like what have been the learnings here? And 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 -- as you know, the high-dose Eylea, obviously, discussion was very irrelevant. 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.

Sure. I think those are all excellent questions. And you're right, depending on the TKI trial, whether you get an aflibercept or anti-VEGF at screening or you get it 4 to 6 weeks prior, and then you'd get it a month after you dose with TKI. So it is variable between trials. So I think this Phase 1 is a learning opportunity for us. Once we get full data set, we'll be able to see where we want to 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 and so that they don't get worse over time. But here, unlike other studies, there was no aflibercept given a month after TKI. So we are actually seeing an effect post dosing at 2 or 3 or 4 months, which is actually directly a result of the TKI not a result of anti-VEGF 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 high-dose EYLEA, obviously, that's a very detailed conversation for a later time. But I think, again, as I said, 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 2 week at a time, you're not seeing a benefit that's lasting 6 months. So I think it's always good to have new agents, but I think a new mechanism of action designed for sustained delivery is clearly exciting.

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 product protocol observations. What could have been the reason for that? Can you just clarify that?

Sure. In terms of follow-up, we have data in all the patients who enrolled in the parent study -- in the stream of parent study. And then those patients, as George mentioned initially were often have the opportunity to participate in the extension study. And we haven't had any of those patients, who actually chose to participate in the extension study, showed up for their month for visits. So far not show for their subsequent visits or tell us that they're not going to show up for the subsequent business. I believe if you look at the swim lane plot, you'll see that there's still patients who have showed up for month 4, 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.

Thank you. As there appear to be no further questions in queue, I will hand it back to Mr. Lasezkay for any final comments.

Thanks. Thank you for your time and attention this morning, I'd especially like to thank Dr. Khanani for joining us on the call today. I think we had a great discussion. I want to note that we have -- Clearside has some active investment conference schedule coming up, starting with the Stifel Healthcare Conference next week. We also look forward to participating in the BTIG Ophthalmology Day, the Piper Sandler Healthcare Conference and Cantor's Medical & Aesthetic Dermatology, Ophthalmology & MedTech Conference. We appreciate your continued interest in Clearside, and we look forward to updating you on our progress in the future. Operator, you may now disconnect.

Thank you, ladies and gentlemen. This does conclude today's conference call. You may disconnect your lines at this time, and have a wonderful day and we thank you for your participation.