Clearside Biomedical, Inc. (CLSD) Q3 2022 Earnings Call Transcript

I would now like to turn the call over to George.

George Lasezkay

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 1/2a 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 2 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 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 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?

Tom Ciulla

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, a proprietary suspension of axitinib, delivered via our SCS Microinjector into a 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 benefits 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 are able to specifically target the effective chorioretinal tissue for potential efficacy benefits, and we can compartmentalize our therapy away from unexpected 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 OASIS Phase 1/2a clinical trial and 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 is an ongoing Extension Study that facilitates an additional three months of follow up for a total of six months.

I want to take a moment to discuss in more detail the patient population we chose for OASIS. We intentionally chose wet AMD patients who were heavily anti-VEGF treatment experienced. All patients were sub-responders with active disease of screening, which was confirmed by an independent reading center. Consequently, we chose the most difficult to treat patients for this study.

So why choose this group of patients instead of patients who had 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 minimized the risk of false signals of biologic effect, since inactive 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 burdens. Importantly, we believe that by conducting the OASIS study in such a patient population, the data is particularly promising since we observed signs of clinically relevant benefits in this first and manned 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 over four years on average and were very highly treatment experience. Some with after 90 prior anti-VEGF injections and all had active disease as confirmed by independent reading center on screening.

It should be noted that unlike treatment [inaudible] 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 our treatment. Our ongoing hypothesis is that the higher doses of CLS-AX in Cohorts 3 and 4 may keep both of BCVA and CST stable throughout the study and thereby show potential for the reduction and 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 and 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 calm 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 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. The blue dots represent additional therapies administered per protocol criteria. The olive color dots represent therapy administrative not in accordance with the defined protocol criteria for traditional treatment. Importantly, in the vast majority of these cases, the independent rating center did not verify the rationale for additional treatment. We detailed the reasons the investigator did not trade per protocol defined criteria in the appendix, which is also available online.

Now, on to the data. Going forward, I’ll focus our 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 part 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 are 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 milligram dose.

Moving now to the interim results of the Extension Study, on Slide 14 we showed 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 and 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 or 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 this additional therapy; to month five, seven of eight patients have not received additional therapy; and to month six, three or four patients have not received additional therapy.

To illustrate this data further, the graphs 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 burdens.

Next, I’ll briefly review the biologic effect we observe 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 know is that over the three month course of 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 remained 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 remains 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 doting, the visual acuity remained stable on average. Here you can see that there are some variability in the visual acuity at the six month time point with arrow bars across 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 was 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 remained stable.

On the right with the post-free treatment 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 biological 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 individually. This is followed one month later at base line with a single dose of CLS-AX administered suprachoroidal.

Slide 24 is a case study that supports the biologic effect at an 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 experience patients. The CST measures 265 microns. The Fovea, subfoveal fluid and the fibrovascular pigment epithelial detachment or FVPED are marked.

The patient receives a aflibercept at the screening visit and returns one month later and you’ll note that the sub-retinal fluid is improved, but does persist to some extent. The patient receives CLS-AX at this baseline visit and then we know 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 through. 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 exhibition occurs and at month six the patient receives additional therapy.

Slide 25 represents another case study that shows that after CLS-AX there is 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 BCVA of 37 and the CST is 228 microns.

This mild intraretinal fluid, this mild subfoveal fluid, as well as the shallow Fibrovascular PED. The patient receives CLS-AX 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.

Slides 26 is another example of the potential durability to the six month timeline, and the upper left the anatomy shows there’s a Fibrovascular PED and Mild subfoveal fluid. The patient entered the study with the 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 action is superior to the fovea in the central subfield, and in that cut we can see the fiber vascular PED, as well as sub-retinal fluid.

At baseline they returned with stable BCVA and the sub-retinal fluid has essentially resolved. The month three and month six visit shows 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 an 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 core like retina.

Our OASIS trial data and the interim Extension Study data showed very encouraging signs of durability and biologic effect in a difficult to treat patient population of anti-VEGF treatment experience sub responders. This durability may compare favorably to other current TKI formulations and investigational intravitreal 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 the all reach a 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 2 clinical trial in the first quarter of 2023 and 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 in 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 1 to 3 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?

Dr. Arshad Khanani

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 clinical trials, new mechanism of action and new delivery methods, and I’m excited to be here, especially talking about TKI as ever. I’m very interested in TKIs for multiple reasons and we’ll discuss that and we also recently published an article about TKIs really reviewing the landscape, so excited to be here.

Tom Ciulla

Well, thanks again and I enjoyed your article. I thought it was really terrific. So speaking of TKIs, what’s your rationale on TKIs and particularly on CLS-AX administered super quarterly to treat wet AMD.

Dr. Arshad Khanani

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 bi-specific antibodies and I think TKIs are interesting because of the fact that they can lead to 10 VEGF inhibition.

You know with the routine trap or antibodies we are trapping the extracellular VEGF. Here we are actually targeting intercellularly 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, you know doing a pan-VEGF inhibition is very exciting.

Excited about CLS-AX, because as you mentioned, the validated delivery system. So when you look at new molecules, you need to look at what are the variables in those molecules. You know we have hydrogels, we have polymers, and on top of the drug, the delivery system matter. So here you have suprachoroidal delivery, which is FDA approved. Me and many of the retina physicians who are involved in the trial or now are 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 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.

Tom Ciulla

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

Dr. Arshad Khanani

I think for any new MOA, new molecule, safety is paramount. So it is super exciting to see that at this stage we have not seen any safety signals you know with the other TKI programs. We have had particles, we have had particle migration in the front, we have been involved with all TKI trials. So I think having a good and favorable safety profile is crucial to take the program forward.

And then the other thing here is the fact that we have seen biological effect, which is very hard to see in many other programs. So this patient population is very different than what we enrolled in other TKI programs or we are enrolling in other TKI programs currently. So I think when you look at this data, you know it’s very easy, people want to cross trial compare the durability, people want to cross trial and compare the top line results. I think that’s something to keep in mind that here your bar is much, much higher, because you are taking this patient population that’s difficult to treat.

So having that patient population and the OCTs you have shown, it clearly shows a biological effect, because I think it’s important for companies to see the signal early, otherwise you feel like you see a signal, but there’s no signal and programs fail. So I think de-risking your program was a really good idea.

And then in terms of efficacy, you are maintaining 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 you know 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 just-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 high need patient population, that is a third of your practice, and then you’re extending patients further out.

So what it shows to me, that if you took stable patients and you gave 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.

Tom Ciulla

No, thanks for your insights. I want to briefly touch upon the not per protocol retreatments that we observe and I just want to share my thoughts and hear your perspective. You know as I mentioned earlier, we intentionally chose wet AMD patients who are heavily anti-VEGF treatment experienced and as you just alluded to.

In all these patients of self-responders, they all had efficacies 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 the first time.

So naturally during the course of the study, if the investigators who had previously treated these patients frequently did not know prompt improvement with this novel treatment. Some would err in the side of caution and treat given their prior experience with these particular patients. And I think this behavior is somewhat understandable in these early phase trials and some of our peer companies have noted this behavior in their trials as well. So Dr. Khanani, do you agree, what do you think? What’s your perspective on that?

Dr. Arshad Khanani

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 and even with frequent injections they are not well controlled. So I think you know as a clinician and a physician you know, and as a company I mean all of us are doing this to help our patients. And if you have early stage trial and you’re seeing some fluid, I think its immediate reaction to treat these patients. We have seen that with gene therapy trials, we have seen with other trials. But I think Phase 1’s 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, you know 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 poor delivery system and other modalities where we are doing sustained delivery, including gene therapy as I mentioned.

So I think it’s a learning opportunity. So going forward I think, having discussions about the retreatment criteria with investigators and convincing them that this is a very durable molecule based on the data we have seen, I think that will help physicians understand and not treat off protocol acutely.

Tom Ciulla

Great! Thank you for your perspective. So 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, and I thought it might be valuable for listeners if you might expand a little bit on the OCTK [ph] studies that we reviewed and maybe further discuss some of your impressions and insights.

Dr. Arshad Khanani

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 neovascular 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 Harbor Study where there were a subset of patients after you know three injections never required injection if they were treated PRN. So I think this patient population that you have really enrolled in this trial shows that they have active disease. So number one, that is you know convincing to me, just seeing that these are high need patients with active disease.

Now comes the fact that, how can we help them with this new MOA and suprachoroidal delivery, and seeing that effect after aflibercept at screening and then seeing the effect after CLS-AX is clearly convincing to me as a physician that we are seeing biological activity, and you know there’s no question that this molecule is helping patients.

Now of course the learning is, you know how fast is helping and how long it’s helping and you know that is going to really help us design the next stage. But at this stage it is very convincing to me as a clinician that TKI is actually this, especially this one is helping our patients control disease, so disease control and durability, both are being shown by these case studies.

Tom Ciulla

No, thanks for your insights and thanks for your comments on transparency. So in the appendix of the deck which is available for download, we actually include in particular for Cohort 3 and 4 you know all their prior treatment history going back three years, as well as all the subject level data. So we have every visit, every CST and every BCVA plotted out in the appendix of the deck.

And so finally, you know one last question, what is your opinion of the future of CLS-AX?

Dr. Arshad Khanani

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 TKI’s, I personally always thought that TKI’s 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 deliver suprachoroidally. So it’s exciting to see that this is not just for a subset of patients. It can actually benefit majority of our patients.

And you know going forward, obviously now you have seen biological activity. If you do a controlled trial with a comparator in stable patients, I think you’re going to see durability that’s going to be even better than what you have already shown. So I think looking at stable patient population, not just a high need population and then coming – you know designing a trial with an active control with non-inferiority in BCVS primary endpoint, I think that’s the way to go forward. But 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.

Tom Ciulla

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

George Lasezkay

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.

Question-and-Answer Session

Operator

Thank you. [Operator Instructions] Our first question is coming from Andreas Argyrides with Wedbush, please go ahead.

Andreas Argyrides

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, informed planning and expectations for the Phase 2, specifically around dose and patient selection? And can you also give us more color on how stabilizing BCVA and CST would translate to achieving a primary endpoint against an active competitor?

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.

George Lasezkay

All right, Tom. I thank you and Dr. Khanani have a couple of questions that you need to answer, so please proceed.

Tom Ciulla

Well, thanks Andreas and thanks for this list of questions. So I think the first question was you know next steps, and I think you know the important point here is that this is interim data with regard to the Extension Study.

So we want to follow the patients to the end of the Extension Study and you know validate and confirm these initial results. But I do want to point out that as I mentioned, eight of the patients in the Extension Study have made it to – that’s eight of 12 patients in the Extension Study have made it to month five and only one was treated prior to month five. So I think we have a fairly good sampling of all the patients in the Extension Study, but we still want to follow these patients out to the completion of the trial.

And so obviously we’ll be analyzing the data at the next cut when these patients finish and that would form our future plans. And 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 expand on it as well. But so the point I think you’re making is that, if you have treatment experience patients and you provide a sustained belief therapy, that’s meant to really stabilize them and reduce treatment burden. You know the question is what is the endpoint, and thankfully we have a model for that with the poor delivery system.

So that was a – that was study in Phase 3 trials. It’s now commercially approved and available and in that trial, you know they had patients with what I would call much more lightly treatment experience. They had a diagnosis in neovascular AMD within nine months. They had two prior treatments, they enrolled in the trial and then the goal of the trial was to stabilize.

And so really the – if you look at the Visual Acuity, because even in the label, the prescribing information, you can see that what they’ve achieved was stability and they compare it to an act of comparative 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 the interim data and we’re still – we still need to decide on the best-in-patient population going forward. As Dr. Khanani mentioned, in less treatment experienced patients we might expect even better signs of biological effect and durability.

So now, I’m turning this over to Dr. Khanani, because I think you have some questions specifically for him as well.

Dr. Arshad Khanani

Thanks Tom. 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 four or five after the surgery or after the last refill, if they met pre-specified disease activity criteria, and those were very strict criteria.

So I think the bottom line for me is the fact that the differences we have here, right? We have suprachoroidal delivery, which is in clinic, which is validated, FDA approved you know, 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 you know this molecule. So that’s one patient population and that’s actually the majority of our patients who are stuck at between four to eight weeks, and maybe that’s going to be eight or 12 weeks with faricimab or [inaudible].

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 you know every two months or so, if 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 brolucizumab.

So I think the fact is that if we can take those current patients and give them less frequent treatment, I think we will be able to stabilize their visual acuity longer. I think it’s all about having patients keep their independence, you know able to drive, able to function. I think those are reported parameters and we see vision loss over time. So under a stable population, obviously it is a no brainer.

And then I said earlier about higher need population that comes in frequently, every four to six weeks and still have persistent fluid. So I think we are still learning if we can add on this therapy or use this therapy primarily for that patient population.

And then the last question obviously always is naive patient population. I think after controlling the disease acutely, this will also fit in nicely. So I think broad patient population may benefit from this molecule if obviously you know we continue to see the efficacy, safety and durability.

Andreas Argyrides

Okay, great. Thanks for the insights and congrats on the results.

Operator

Thank you. Our next question is coming from Annabel Samimy with Stifel, please go ahead.

Annabel Samimy

Hi! Thanks for taking my question and congratulations on some strong data. I’ll just reiterate the point. You guys are doing a great job of explaining everything. So I’m just going to ask for a couple of clarification questions.

So just what do 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 CSTs had 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? I guess that’s one of the points that I want to understand better.

George Lasezkay

Tom, I think…

Tom Ciulla

Yeah, it’s a great question Annabel. So the question I think is you know what is a non-responder and I don’t think it’s a binary determination. They are either a non-responder or responder and that’s why you know I call them sub-responders. Yeah, and a couple of items here.

So you know as clinicians, as investigators, as sponsors of trials, we like CST because it’s convenient. It’s a convenient measurement. You’re measuring the central one millimeter that includes the foveal and it includes the thickness of the retina, and that would encompass often sub-retinal fluid into retinal fluid. So it’s an easy, convenient measurement. The machine in clinic automatically fences it out for you within a minute. And so it’s numerical, it’s easy to graph, it loans itself well to statistical analysis.

But CST doesn’t correlate perfectly with vision and I think this is 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 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, and all of this isn’t captured by the CST. But again, we like CST because it’s convenient, it loans itself well to 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. You know the CST was essentially normal, but yet when you look at the actual anatomy of the images, you can see that there is mild sub-foveal fluid, there is mild intra-retinal fluid, and so I think it is important to look at these cases.

And I think you know when I think of sub-responders, I think of patients that have persistent fluid on the OCT and again, the images that we see in OCT are almost – are printed out almost immediately. So it’s convenient and I think most clinicians would consider you know persistent fluid on an OCT image after an anti-VEGF injection as a sub-responder.

So there’s not a – 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 persistence fluid has been shown over time to be dabbed [ph]. There’s a paper from the cat study that showed that patients who have persistent intra-retinal fluid over two years have a worse prognosis visually.

So I guess to summarize, you know there aren’t these clear cut correlations that we all like. CST is really something that we conveniently plot. The images as retina specialty 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?

Dr. Arshad Khanani

No, I agree. I think those are great thoughts Tom. One thing I would add is that you know, 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. You know CST and OCT images are not subjective. They are 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 and of course that’s not a regulatory endpoint vision is. But I think we know from multiple trials as you mentioned, [inaudible] 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 are kind of 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 fission 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.

Annabel Samimy

Okay, but there is 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 and why we could not aid better Visual Acuity?

Dr. Arshad Khanani

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

Tom Ciulla

Sure, yeah sure. And I’ll make the next one.

Dr. Arshad Khanani

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 get worse over time. So I think yes, we don’t expect Visual Acuity improvement even in patients who don’t have long term disease. Like in the poor delivery system, we saw that patients, as Tom said at very recent disease and they got stabilized with minimum of two anti-VEGF injections, we didn’t see Visual Acuity improvement, but rather maintenance.

So I think the acute improvements happen quickly, but there’s long term Visual Acuity loss because of non-compliance, because of CST fluctuations. So those are my comments to your question. Tom?

Tom Ciulla

Yeah, so let me – I sometimes work with you know retina specialists. We’re too close to it to really, let me broaden the focus. So with treatment naive patients, you know we have approved agents that are treated with what I call induction dosing, they are given monthly therapies initially.

And if you look actually on their 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 you know depending on the trial and the therapy, but somewhere in the order of eight to 10 letters on average. So they improve within the first three or four months by eight to 10 letters.

Then the curve plateaus and so these patients come in every four to six weeks, and their Visual Acuity is what it is. And these are the – you know one of my colleagues call it, these are the VEGF addicts. 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 you know persistent fluid leads to a visual decline from that plateau.

And as Dr. Khanani mentioned, almost 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 experience patients, they’ve already undergone that induction phase. You know it’s inherent in their prior treatment and they were on the plateau. So you could see from the swim lane plots, we show both, you know six months prior and up to three years prior. These are patients receiving frequent injections. So they’ve already plateaued and we don’t expect them to improve.

Now in other patient populations, as Dr. Khanani mentioned, the treatment naive patients, they have potential to see improved vision. So I think we answered your question. Any follow up? Has that been cleared?

Annabel Samimy

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 2, you have a pretty good model as you said, where you want stability and BCVA as well as SCT. Is there any other end point that you’re – I mean obviously you’re looking at the reduction with the 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 going to be like a key endpoint that people look at outside the durability?

And then, the treatment, do you have any intention of moving into 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 in these patients. Do TKIs have that rapid effect as well or do you just not know at this level – at the stage, because there hasn’t been study in that treatment naive population.

Tom Ciulla

Annabel, those are great questions. So let me start with the first one. So the question is you know the end point, and as Dr. Khanani mentioned, the primary endpoint for trials is generally visual function, so in this case Visual Acuity. So that has to be the primary end point.

And so you know generally in these trials, as we keep using the port delivery system as a model, but it’s a good model, is you know can we maintain. Half the patients undergo induction and after they’ve risen, you know their Visual Acuity has risen to the plateau, can we maintain their Visual Acuity. Often a non-inferiority trial with standard of care, you know fixed frequent injections and so Visual Acuity almost always is the primary endpoint. These other endpoints are interesting because they support the primary endpoint, you know they suggest biologic mechanism.

And then a little bit more about, your first question on visual improvement. Patients who have chronic neovascular AMD or neovascular AMD with elements of geographic atrophy, those patients often can’t improve because they have scaring. So I just wanted to follow that up.

And then 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 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 activity in very difficult to treat patients and this opens up potentials for a variety of patient populations that Dr. Khanani alluded to.

Dr. Khanani, any other follow-up comments.

Dr. Arshad Khanani

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 micro particle 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.

Annabel Samimy

Okay, thanks a lot.

Operator

Thank you. Our next question is coming from John Wolleben with JMP Securities. Please go ahead.

John Wolleben

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 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 set schedule. How are you thinking about I guess durability affecting your practice and patience?

Dr. Arshad Khanani

Thanks. That’s a really, really good question. So I think there’s 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 and 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 are different in all aspects. Once you dive into real world. So I think once we have control data about how, how long we can take majority of patients, then you will 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 him.

You know 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. So 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’ll only see that patient that often given that you are not looking for intraocular inflammation, given you are not looking for like we did for poor delivery, you know congenital 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 four or five months on this molecule or six months, that was on one 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 the 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.

John Wolleben

It’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 at both Cohorts 3 and 4. 4 a little bit better, smaller number of patients sort of follow up. But then when you factor in CST, it looks like it’s worsening a bit in Cohort 4, while Cohort 3 is seeing stable, improving but then Visual Acuity dropping off in Cohort 3 is the one to follow-up. How do you factor in all these things? Safety we don’t have it by does, but and looks good so far. So what’s the most important metric for you guys when you’re thinking about a preferred dose moving forward?

Tom Ciulla

Well, I think the most important things that we follow the patients in the Extension Study to see you know what happens in a broader patient population. And you know your point about the BCVA and CST, as I mentioned in my prepared comments, 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 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 division drops off at month six, because it’s driven by one patient and [Audio Gap] since these patients went six months. And same with CST, you know again the sample size drops meaningfully as you can get to that final six month visits. Only three 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 can conclude that on the CST curves the Cohort 3 looks like it improves and Cohort 4 looks like it worsens slightly.

But sample size is really small and I think if anything, you need to look at the mean of the two groups in order to increase the simple size a little bit, and the mean looks quite stable. And if anything, you know one could conclude that the CST gets better at six months, but again small sample sizes, we don’t want to make much of it. I think overall we’d say that the CST and BCVA is stable over six months.

And then the second part of your question…

John Wolleben

You touched on it Tom. I guess maybe just a follow up. Are you guys planning on bringing one or two doses forward into a Phase 2 program?

Tom Ciulla

Yeah. So I think at this point we just, we need to see more data and wait for that – the final analysis. But I think the good thing is that we saw really pristine safety. We saw really no safety signals at all at both doses and I think 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 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 deciding.

John Wolleben

Got it. Thanks for taking the questions and congrats on the data.

Operator

Thank you. Our next question is coming from Yi Chen with H.C. Wainwright. Please go ahead.

Yi Chen

Thank you for taking my questions. 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?

Dr. Arshad Khanani

Well, that’s a great question. So as I mentioned, at screening, the patients were all assessed by independent reading center and the independent reading center defined active subfoveal choroidal neovasculat membrane as having subfoveal choroidal neovascular membrane on angiography which leaks, and having either subfoveal sub-retinal fluid or intra-retinal fluid in the central subfield at the OCT. So yes, they had to have fluid on the OCT and in subfoveal.

Yi Chen

So is there a reason that you, you know the clinical study would exclude patients who do not have excess fluid.

Dr. Arshad Khanani

So we excluded patients who don’t have active 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 that fluid, we did not specify. They just had to have an active choroidal neovascular 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 reading center.

Yi Chen

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

Tom Ciulla

You know I’m not sure what you mean by excess fluid. We didn’t exclude patients who had lots of fluid, but because these patients were all treatment experience, they are not going to have lots of fluid unless they are treatment naïve. And it goes back to my comments earlier with Annabel, where you know patients when they are first diagnosed oftentimes will have very thick OCTs, because acuity would have dropped. The undergo induction dosing, which is often monthly, and then the OCTs improve, the vision improves and then they are on the plateau of that Visual Acuity curve. And they often have some patients respond and become inactive and some patients have smouldering leakage or leakage that comes back if they go too long between treatments.

Yi Chen

Okay. And would you expect the upcoming Phase 2 trial to have the same criteria?

Tom Ciulla

Well, we’re still evaluating all of them. 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.

Yi Chen

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

Tom Ciulla

I’m not sure if I understand the question, can you expand?

Yi Chen

So for example, for the three month’s 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 a real world practice scenario in terms of rescue free rate.

Tom Ciulla

Again, I’m not sure if I understand the question, but you know in the real world some patients – I think the most common treatment regimen is a treat and extend regimen. So patients, like for example, a naive patient went on to go monthly induction dosing, the Visual Acuity improves, the OCT improves. They go to the, to the plateau, that Visual Acuity improvement curve and then oftentimes the interval is extended.

I think most retina specials will extend by two weeks at a time, and then you know in subsequent visits if a fluid starts to recur or the vision starts to drop, they’ll then contract by two weeks and there are patients who have kind of a – almost a personalized integral where they can go and it’s very hard to get patients beyond two 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 regimens?

Arshad Khanani

Yeah, of course Tom. I think, the question is how does real world practice differ from clinical trials and you know this off-protocol treatment versus protocol treatment. So I think when I’m participating in a trial, obviously I want to make sure that you know is 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 end up having patients who actually get worse in the trial.

Here that’s not the case. I think these are high need patients as we 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 him 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 that ‘hey, you know this treatment is working. It is going to improve. You just have to be, 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 you know other TKIs. The reason is the criticism TKI studies get it well, you’re enrolling these stations, you have not shown fluid for the last five years. What if the disease is burned out and you’re just treating them because you’re scared about disease coming back or patients getting active.

This is the only TKI study that we have participated in actually is requiring active fluid. So this actually, shows a biological activity and it’s convincing for the community and the clinician that TKI is clearly can benefit our patients.

Operator

Thank you. Our next question is coming from Serge Belanger with Needham & Company. Please go ahead.

Serge Belanger

Hi! Good morning. Thanks for taking my questions. I’ll just stick with two. First one for Tom. Can you just talk about, in your plans for the Phase 2 trials, 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 2 trial?

And then secondly for Dr. Khanani, given your expertise with tyrosine kinase inhibitor it’s a drug class that’s been around for a long time, but I think it’s had mixed results in retinal diseases so far and some of it has been due to the delivery mechanism. But just curious, why you think it’s been difficult for this drug class? Is it a question of finding the right molecule and the right delivery mechanism or the treatment burden provides a high hurdle for success? Thanks.

Tom Ciulla

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

And I’ll turn the second question over to Dr. Khanani.

Arshad Khanani

Thanks Tom. By the way, I agree with diabetic retinopathy, the VEGF levels are low and you know we have standard treatments of anti-VEGF, but majority of the patients are not getting those treatment because of the frequency of visit. So I think that’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 adverse event, you know pressure issues, corneal toxicity, particles going to the front of the eye.

But I think we have evolved from the version one of TKIs like GB-102 to now in a situation that you have a delivery, you know suprachoroidal delivery which is validated and an FDA approved. And then you have a space where you are avoiding exposure to the front of the eye or to the vitreous cavity. So you know as I said, I always am conservative in terms of looking at things and I always thought that TKIs are probably best fit for very stable patients receiving injections every two or three months and maybe if we can go to six months, that would be meaningful.

But here for the first time, I’m seeing this activity in these patients that actually were very, very high need. So I think we still need to generate evidence and the reason for that is that we have really good treatment. Currently we have multiple FDA approved treatment and we have you know revised for now that could take patients longer. But it’s incremental benefit, it’s not a six month benefit, it’s not a five month benefit. It’s close to anywhere from two to four months and we are moving that needle forward. We are getting these patients stretched out a little bit longer than 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 you know the trials continue to generate data on multiple TKI programs. So we’ll see where it takes us, but at least for this program I’m pleased to see that we are seeing biological activity in a very safety favorable, safety profile that really points to taking this program forward.

Operator

Thank you. Our next question is coming from Mayank Mamtani with B. Riley. Please go ahead.

Mayank Mamtani

Good morning team. Thanks for taking our questions and congrats on the data. So maybe just speaking with the prior sort of thematic conversation with Dr. Khanani. So induction therapy has also been very different across these TKI studies doctor. So could you just comment on, you know as you think of going forward with this agent, like what have been the learning’s here and especially if we think about active disease, making sure that you’re getting that induction is important. So could you maybe comment on that and also at AAO as you know, the high dose earlier, obviously discussion was very relevant. So maybe if you could also put that in context would be very helpful, and then I have a follow up for Tom about the data today.

Arshad Khanani

Sure. I think those are all excellent questions and you’re right you know. Depending on the TKI trial, whether you get an aflibercept or anti-VEGF screening or you get it four to six 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 you know unlike other studies, there was no aflibercept given a month after TKIs. So we are actually, being in effect post dosing at two or three or four 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 cost 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, I mean 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 two weeks at a time. You’re not seeing a benefit that’s lasting six months. So I think it’s always good to have new agents, but I think a new mechanism of action designed for sustained delivery is clearly exciting.

Mayank Mamtani

Thank you, that’s very helpful. And maybe for you Tom, in terms of follow-up, as part of the trial protocol, maybe I missed that. Was there any patients lost in in follow-up or did you catch all of them, and if there was any, any of those protocol observations, what could have been the reason for that? Can you just clarify that?

Tom Ciulla

Sure in terms of follow-up, we have we have data in all the patients who enrolled in the parent study, in the three month parent study. And then those patients as George mentioned initially were offered the opportunity to participate in the Extension Study and we haven’t had any of those patients who actually chose to participate in the Extension Study and showed up for their month four visit. So far not sure if there were subsequent visits or tell us that they are not going to show up for their subsequent visits.

I believe you can if you look at the swim lane plots, you’ll see that there are still patients who have showed up a month forward 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 are dropping out.

Mayank Mamtani

Yeah, thanks for taking my questions and congrats again.

Operator

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

George Lasezkay

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 an active investment conference schedule coming up starting with the Stifel Health Care Conference next week. We also look forward to participating in the BTIG Ophthalmology Day, The Piper Sandler Health Care Conference and Cantor Medical and Aesthetic Dermatology & Ophthalmology and 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.

Operator

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.