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/ II-A 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, Charlie 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 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'll 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/ II-A 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 total $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 gonna focus on our CLS-AX data, but our CFO, Charlie Deignan, 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 the 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 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 experienced 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 corrective 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 four 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 the potential choroidal retinal tissue targeting benefits of suprachoroidal delivery. 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 choroidal 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 five outlines our phase I/II-A 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 via intravitreal injection. They returned one month later, received a dose of CLS-AX, and then returned 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 experienced. 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. Why choose this group of patients instead of patients who had 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 could 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 high need for effective therapy with lower treatment burden.
Importantly, we believe that by conducting the OASIS study 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 seven, 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 were very highly treatment experienced. Some with up to 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 naïve 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 20/32 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 nine, 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. There were no vitreous floaters or dispersion of CLS-AX into the vitreous.
Next, I'll review the promising durability results from 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 swim lane, the column of red dots represents the aflibercept administered at 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 are 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 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 show treatment across all therapies on the left and per-protocol treatment on the right. Importantly, in Cohorts 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 a 100% at the Cohort 4 1 mg dose. Moving now to the interim results of the expansion study. On slide 14, we show the prior anti-VEGF therapy and the treatments administered for all 14 patients who agreed to participate in the expansion 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 Cohorts 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 expansion 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-VEGF 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 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 Cohorts 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 Cohorts 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 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 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 observe that over the six months post-CLS-AX dosing, the visual acuity remained stable on average.
Here you can see that there is 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 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-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 of 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 suprachoroidal. Slide 24 is a case study that supports the biologic effect in an anti-VEGF sub-responder. We can see that the patient entered the study with a relatively good BCVA of 75 letters or 20/32, 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 receives an aflibercept at the screening visit and returns one month later, and you'll note that the subretinal fluid is 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 where the 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 an aflibercept to 182 microns four months after CLS-AX. Importantly, the CST is actually better four months after CLS-AX versus one month after an aflibercept.
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 CLS-AX, there's durable stability in both BCVA and CST. Once again, the anatomy is noted in the upper left. We can see at screening that the patient entered the study with a BCVA of 37 letters and a CST of 228 microns. There's mild intraretinal fluid, there's 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 remains 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 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 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 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. In that cut, we can see the fibrovascular PED as well as subretinal fluid. At baseline, they return 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 a proprietary SCS Microinjector, demonstrated an excellent safety profile at all doses and all time points, including no 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 of ocular hypertension or glaucoma.
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 choroid and 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 experienced 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 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 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 II to III trials. He's a member of numerous clinical trial steering committees and scientific advisory boards. 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. My practice is, as you mentioned, heavily focused on clinical trials from early stage and late stage, new mechanism of action and new delivery methods. I'm excited to be here, especially talking about TKIs. I'm very interested in TKIs for multiple reasons, and we'll discuss that. We also recently published an article about TKIs, really reviewing the landscape, so excited to be here.
Well, thanks again. I enjoyed your article. I thought it was really terrific. Speaking of TKIs, what's your rationale on TKIs, and particularly of CLS-AX administered suprachoroidal to treat wet AMD?
I think as a field, we are always looking to do better than what we currently do with the anti-VEGF agents and, you know, recently with bispecific antibodies. I think TKIs are interesting because of the fact that they can lead to pan-VEGF inhibition. You know, with the VEGF 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 when we target VEGF C and D with other programs. I think this idea of having one injection, you know, doing a pan-VEGF inhibition is very exciting. Excited about CLS-AX because, as you mentioned, the validated delivery system. 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. Here you have suprachoroidal 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 XIPERE for uveitic macular edema. The delivery is very exciting. It's easy, it's predictable. Then the next thing about axitinib is that it is the most potent TKI because it has the highest affinity.
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, 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.
Well, 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, safety is paramount. It is super exciting to see that at this stage we have not seen any safety signals. You know, with the other TKI programs, we have had particles, we have had particle migration in the front. We have been involved with all TKI trials. I think having a good and favorable safety profile is crucial to take the program forward. Then the other thing here is the fact that we have seen biological effect, which is very hard to see in many other programs. This patient population is very different than what we enrolled in other TKI programs, or we are enrolling in the other TKI programs currently. I think when you look at the data, you know, it's very easy. People wanna cross-trial compare the durability.
People wanna 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. Having that baseline patient population and the OCTs you have shown, it clearly shows a biological effect. 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. I think de-risking your program was a really good idea. In terms of efficacy, you are maintaining BCVA and CST. Of course, in previously treated patients, we don't expect improvement. I think having a stable BCVA, having stable CST is very meaningful.
You know, that has been a primary endpoint for some durability trials for new agents or new delivery system that FDA has approved. The last thing is durability. In a tough-to-treat population, it's very hard to get durability. These are heavily pretreated patients needing frequent injections. 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 high-need patient population that is a third of your practice, and then you're extending patients further out.
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 agents. Really overall, safety, efficacy, durability, and biological effect is positive, in my opinion, to take the program forward.
Oh, no, thanks for your insights. I wanna briefly touch upon the not per protocol re-treatments that we observe. I just wanna share my thoughts and hear your perspective. You know, as I mentioned earlier, we intentionally chose wet AMD patients who are heavily anti-VEGF treatment experienced. As you just alluded to, in all these patients as sub-responders, they all had active disease at screening, and that was confirmed by independent reading center. These patients had received frequent anti-VEGF injections prior to the study enrollment. One of my colleagues refers to this group of patients as anti-VEGF addicts. 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.
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 caution and treat, given their prior experience with these particular patients. 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. 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 injections. Even with frequent injections, they're not well controlled. 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. 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 with other trials. I think phase Is are obviously a learning opportunity. I think what we have seen here is that biological activity will happen with this molecule delivered to the suprachoroidal space.
I think you know, treating patients, if there's fluid, is our standard of care. I think with new MOA and the sustained delivery, I think that behavior is changing. We actually saw that with the Port Delivery System and other modalities where we're doing sustained delivery, including gene therapy, as I mentioned. I think it's a learning opportunity. 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 you know, treat off protocol acutely.
Great. Thank you for your perspective. Dr. Khanani, you have a lot of experience treating wet AMD 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. 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. 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. Sometimes when patients are enrolled in the trial, they have to have a history of neovascular AMD, but most trials, the TKIs, don't require any fluid. This idea that maybe the disease was burned out and these patients never needed injections, kinda gives this question mark about durability.
We actually saw that in the HARBOR study where there were a subset of patients after, you know, three injections, never required injection, and they were treated PRN. I think this patient population that you have really enrolled in this trial shows that they have active disease. 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 this, you know, new MOA and suprachoroidal delivery. Seeing that effect after aflibercept at screening and then seeing the effect after CLS-AX, it's clearly convincing to me as a physician that we are seeing biological activity. 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. you know, that is gonna really help us design the next stage. at this stage, it is very convincing to me as a clinician that TKIs actually, especially this one, is helping our patients control disease. disease control and durability, both are being shown by these case studies.
No, thanks for your insights and thanks for your comments on transparency. In the appendix of the deck, which is available for download, we actually include, in particular for Cohort 3 and 4, you know, all their prior treatment history going back three years as well as all the subject level data. We have every visit, every CST, and every BCVA plotted out in the appendix of the deck. Finally, one last question. What is your opinion of the future of CLS-AX?
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. I think here I'm seeing a signal that we can actually benefit our high-need patients with CLS-AX delivered suprachoroidal. It's exciting to see that this is not just for a subset of patients. It can actually benefit majority of our patients. 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 gonna see durability that's gonna be even better than what you have already shown.
I think looking at stable patient population, not just the high-need population, and then you know, designing a trial with an active control with non-inferiority in BCVA as primary endpoint, I think that's the way to go forward. It's exciting that I actually, looking at this data learned, 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 gonna turn the call over to George.
Thanks, Tom. Thanks to you and Dr. Khanani for that discussion. I wanna 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. If you have any questions or comments, please press star one on your phone at this time. We ask that while posing your question, you please pick up your handset if listening on speakerphone to provide optimum sound quality. Please hold while we poll for questions. Thank you. Our first question is coming from Andreas Argyrides with Wedbush. Please go ahead.
Hi. 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 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 durability around five months or so, where do you see CLS-AX fitting in the treatment paradigm? And is stabilizing BCVA and CST the goal for CLS-AX? Thanks.
All right, Tom, I think you and Dr. Khanani have a couple of questions that you need to answer, so please proceed.
Well, thanks, Andreas, and thanks for this list of questions. I think the first question was, you know, next steps. I think, you know, the important point here is that this is interim data with regard to the extension study. We wanna follow the patients to the end of the extension study and, you know, validate and confirm these initial results. I do wanna 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.
I think we have a fairly good sampling of all the patients in the extension study, but we would still want to follow these patients out to the completion of the trial. Obviously we'll be analyzing the data at the next cut when these patients finish, and that will inform our future plans. I think, you know, 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.
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, you know, the question is what is the endpoint? Thankfully, we have a model for that with the Port Delivery System. That was studied in phase III trials. It's now commercially approved and available. In that trial, you know, they had patients with what I would call, you know, much more lightly treatment experienced. They had a diagnosis of neovascular AMD within nine months. They had two prior treatments. They enroll in the trial.
Then the goal of the trial was to stabilize. Really, if you look at the visual acuity curves, even in the label of the prescribing information, you can see that what they've achieved was stability, and they compare it to an active comparator that's dosed per its label. Ultimately they show non-inferiority, as Dr. Khanani alluded to, and that led to approval. We have a model for a therapy that is approved for essentially maintenance of stability or. Again, we're still analyzing this interim data, and we 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.
I'll now turn this over to Dr. Khanani, because I think you had some questions specifically for him as well.
Thanks, Tom. I think I agree with you that we have a model to go after. I think in that trial, as you remember, patients were allowed to get supplemental injection at month four or 5. After the surgery or after the last refill, if they met pre-specified disease activity criteria, and those were very strict criteria. 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, you know, and then we have a molecule that has good safety. 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.
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. I think looking at it, clearly, the stable patients on current treatment can go longer with, you know, this molecule. That's one patient population, and that's actually majority of our patients who are stuck at between four to eight weeks, and maybe that's gonna be eight or 12 weeks with faricimab or Vabysmo. 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, you know, every two months or so, they don't come to our clinic, and their vision is worse over time. 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 wanna make sure that any new treatment I give does not have adverse events or irreversible vision loss like we have seen with brolucizumab. I think the fact is that if you 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 vision loss over time. Under a stable population, it's a no-brainer. I said earlier about higher-need population that comes in frequently every four to six weeks and still have persistent fluid. I think we are still learning if we can add on this therapy or use this therapy primarily for that patient population. The last question obviously always is naïve patient population. I think after controlling the disease acutely, this will also fit in nicely. I think broad patient population may benefit from this molecule if obviously, you know, we continue to see the efficacy, safety and durability.
Okay, great. Thanks for the insights and congrats on the results.
Thank you. Our next question is coming from Annabel Samimy with Stifel. Please go ahead.
Hi, thanks for taking my question and congratulations on some strong data.
Thank you.
I'll just reiterate the point. You guys are doing a great job of explaining everything. I'm just gonna ask for a couple clarification questions. 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 CST? Because the CST you said reached sort of a floor, so therefore you're not really seeing improvement. Would you have seen improvement in visual acuity as well? Is it only fluid that makes them a non-responder? I guess that's one of the points that I wanna understand better.
Tom.
Um, that's-
I think.
Yeah, it's a great question, Annabel. The question I think is, you know, what is a non-responder? I don't think, you know, it's a binary determination. They're either a non-responder or responder. That's why, you know, I call them sub-responders.
Yeah. Subresponder.
Yeah. A couple of items here. 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 1 mm that includes the fovea, and it includes the thickness of the retina, and that would encompass often subretinal fluid and intraretinal fluid. It's an easy, convenient measurement. The machine in clinic automatically prints it out for you within a minute. You know, it's numerical. It's easy to graph. It lends itself well to statistical analysis. CST doesn't correlate perfectly with vision. 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 AMD, so they have dry AMD as well, so they have atrophy. You can have scarring from uncontrolled neovascular AMD. You can have fluid under the RPE layer, which we call a pigment epithelial detachment. All of this isn't captured by the CST. Again, we like CST because it's convenient. It lends itself well to analysis and graphing. When we think of sub-responders, CST doesn't capture all of it. 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.
When you look at the actual anatomy of the images, you can see that there is mild subfoveal fluid, there is mild intraretinal fluid. I think it is important to look at these cases. I think, you know, when I think of sub-responders, I think of patients that have persistent fluid on the OCT. Again, the images that we see on OCT are printed out almost immediately. It's convenient, and I think most clinicians would consider, you know, persistent fluid on an OCT image after an anti-VEGF injection as a sub-responder. 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. Persistent fluid has been shown, you know, over time to be bad. There's a paper from the CATT study that showed that patients who have persistent intraretinal fluid over two years have a worse prognosis visually. I guess to summarize, you know, there aren't these clear-cut correlations that we all like. CST is really something that we conveniently plot. The images, as retina specialists, is really what we like to see, and we have papers suggesting that at least 30% of patients, and 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. Khanani, any more thoughts? Do you agree?
No, I agree. I think those are great thoughts, Tom. One thing I would add is that, you know, in a busy clinical practice, I'm seeing 80-90 patients, and the visual acuity in clinical practice actually could be variable because of dry eye, because of poor effort. You know, 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, you know, fluid or having, you know, disease activity on OCT is what we treat patients for as clinicians. Of course, that's not a regulatory endpoint. Vision is. 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.
All these patients that are in our clinic getting monthly injections, we may see them in a week or two after the injection, and they may not have fluid, and then they come back in a month, and they have 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. The hope is that with this molecule, if we can stabilize CST or improve fluid than what it was with standard, you know, frequent injection, I think that's gonna be meaningful for our patients in the future.
Okay. There's no expectation that you would be improving visual acuity on that. Just you don't want worsening of it, so you want, and you want to maintain stability? I mean, I guess I'm trying to understand the visual acuity side of it.
Yes. Yeah.
Why would you not want a better visual acuity?
Yeah. I think that's a really good question. Tom, can I take that?
Sure. Yeah. Sure. I may add some.
Yeah. Sure. Yeah. Perfect. You know, these are super high-need patients. It's all about maintaining where they are. Otherwise, you know, or the CST fluctuations, they're gonna get worse over time. 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, you know, as Tom said, had very recent disease, and they got stabilized with minimum of two anti-VEGF injections. We didn't see visual acuity improvement, but rather maintenance. I think the acute improvements happen quickly, but there's long-term visual acuity loss because of non-compliance, because of CST fluctuations. Those are my comments to your question, Tom.
Sometimes we're, you know, as retina specialists, we're too close to it. Let me broaden the focus. With treatment naïve patients, you know, we have approved agents that are treated with, you know, what I call induction dosing. They're given monthly therapies initially. 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 naïve patients who undergo this initial induction phase. The visual acuity improvement is somewhere on the order of, you know, depending on the trial and the therapy, but somewhere in the order of, you know, 8-10 letters on average.
They improve within the first 3 or 4 months by 8-10 letters. The curve plateaus. These patients come in every 4-6 weeks, and their visual acuity is what it is. These are the, you know, what 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 we know persistent fluid leads to a visual decline from that plateau. As Dr. Khanani mentioned, he's published extensively on real-world outcomes, and we know that in the real world, patients can't keep up, and ultimately, they lose vision from that plateau. In this treatment-experienced patients, they've already undergone that induction phase.
You know, it's inherent in their prior treatment, and they were on the plateau. You could see from the swim lane plots we show both, you know, six months prior and up to 3 years prior. These are patients receiving frequent injections. They've already plateaued, and we don't expect them to improve. Now, in other patient populations, as Dr. Khanani mentioned, in treatment naïve patients, there's potential to see improved vision. I think we've answered your question. Any follow-up? Did that seem clear?
Yes. No, that actually hits it exactly. Just, I guess following on to the treatment-experienced, treatment naïve population. 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 endpoint that you're looking at? I mean, obviously you're looking at the, you know, 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 burden? Is that gonna be, like, a key endpoint that people look at outside the durability? Then, the treatment, do you have any intention of moving into treatment naïve 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 naïve population?
Annabel, those are great questions. Let me start with the first one. The question is, you know, the endpoint. And as Dr. Khanani mentioned, the primary endpoint for trials is generally, you know, visual function. In this case, visual acuity. That has to be.
Mm-hmm.
The endpoint. Generally, in these trials, as we keep using the port delivery system as a model, but it's a good model, you know, can we maintain after patients undergo induction, after they've risen, you know, their visual acuity has risen on that plateau, their visual acuity in a non-inferiority trial with standard of care, you know, fixed frequent injections? Visual acuity almost always is the primary endpoint. These other endpoints are interesting because they support the primary endpoint. You know, they suggest a biologic mechanism. You know, a little bit more about your first question on visual improvement.
Patients who have chronic neovascular AMD or chronic neovascular AMD with elements of geographic atrophy, those patients often can't improve because they have scarring. I just wanted to follow that up. Your second question, you know, would we enroll treatment naïve patients in the next trial? You know, I think you answered your own question. We just don't know yet. We wanna follow the patients in the expansion trial out to the completion. 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, you know, 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. 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 gonna have activity in every other patient population. We're still learning about how fast TKIs, 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. 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.
Okay. Thanks. Thanks a lot.
Thank you. Our next question is coming from Jon Wolleben with JMP Securities. Please go ahead.
Thanks for taking the questions, and congrats on the data, and thanks for the thorough release. One for Dr. Khanani, if I may, and then a follow-up for management. Just wondering, you know, how frequently do you wanna see your patients today? And when we have these 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 wanna see your patients on a set schedule? How are you thinking about, I guess, durability affecting your practice and patients?
Thanks. That's a really, really good question. I think there is a difference in following these patients in clinical trials versus following these patients in clinical practice. Obviously in clinical trial, we wanna 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. 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. 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 wanna see them monthly initially to see how fast you get to disease control.
Once you figure out what's called a sweet spot, so you know, we do treat and extend in our clinic currently with anti-VEGF trying to find the 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 Port Delivery, you know, conjunctival erosions and retraction and endophthalmitis. I think you have to balance the efficacy, safety, and durability. 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.
Lastly, we have, you know, home monitoring and OCT, home OCT, and other things that are coming in the pipeline where we'll be able to monitor these patients remotely. Overall, I think using technology and new mechanism of action, we'll be able to significantly decrease treatment burden for our patients, and that's my hope.
That's very helpful. Maybe one for Tom. When you're thinking about going to subsequent studies and dose selection, we see pretty good durability at both Cohorts 3 and 4 a little bit better, smaller number of patients, shorter follow-up. When you factor in, CST looks like it's worsening a bit in Cohort 4, while Cohort 3 staying stable, improving, but then visual acuity dropping off in Cohort 3 with a longer follow-up. How do you factor in all these things? Safety, we don't have it by dose, but everything looks good so far. What's the most important metric for you guys when you're thinking about a preferred dose moving forward?
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. You know your point about the BCVA and CST, as I mentioned in my prepared comments, you know since it is an interim analysis, the sample size really drops quite significantly as you hit month six. In fact, for the BCVA curve, when we exclude data after additional therapy, that month six time point really only consists of three patients. 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.
Um-