Good morning, ladies and gentlemen. Thank you for standing by and welcome to Ocular Therapeutix conference call announcing interim results for its U.S.-based phase I clinical trial of OTX-TKI for the treatment of Wet AMD. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. It is now my pleasure to turn the call over to Donald Notman, Chief Financial Officer of Ocular Therapeutix. Please go ahead, sir.
Thank you, Shannon. Good morning, everyone, and thank you for joining us on our conference call to discuss interim results from our U.S.-based phase I clinical trial of OTX-TKI for the treatment of Wet AMD. The press release can be accessed on the investors portion of our website at investors.oculartherapeutix.com. Leading the call today will be Antony Mattessich, our President and Chief Executive Officer, who will also be joined by Dr. Rabia Gurses Ozden, our Chief Medical Officer, and Dr. Peter Kaiser, our Chief Medical Advisor, Retina. Following our prepared remarks, we will open the line for your questions. As a reminder, on today's call, certain statements we will be making may be considered forward-looking for the purposes of the Private Securities Litigation Reform Act of 1995. In particular, any statements regarding our regulatory and product development plans, as well as our research activities are forward-looking statements.
These statements are subject to a variety of risks and uncertainties that may cause actual results to differ from those forecasted, including those risks described in our most recent quarterly report filed August 8th with the SEC and our annual report on Form 10-K, filed on February 28th with the SEC. I will now turn the call over to Antony.
Thanks, Donald, and good morning, everyone. We're really excited to be announcing the news today and sharing with everybody very encouraging interim results from our U.S. phase I clinical study evaluating OTX-TKI for the treatment of Wet AMD. This represents a significant milestone for Ocular Therapeutix. We are very pleased with the data in terms of the safety profile, durability and biological activity. As a next step, we intend to request a meeting with the FDA to discuss this new data, as well as the data from our Australia-based phase I study and agree on an appropriate clinical development plan. Before I hand the call over to Rabia and Peter, who will take you through the specifics of the data, I would like to provide some background on why we are developing OTX-TKI. You probably have heard me say many times before that we begin with the end in mind.
We focus first on evaluating the size and dynamism of a disease state in ophthalmology and then determine the key unmet need in that space. Only then do we consider whether our platform technology enables us to build a therapeutic that could satisfy the key unmet need and potentially become the standard of care. The product candidates in our pipeline are pulled by market need and then enabled by our proprietary hydrogel technology. In Wet AMD, we saw the potential to improve upon today's standard of care by providing patients with a non-biological alternative with improved durability compared with other anti-VEGF medicines. Current anti-VEGF agents need to be continually injected to achieve VEGF suppression to keep the disease in check, creating an injection burden of around four to six intravitreal injections per year.
There have been multiple attempts over these past 20 years to achieve biopharmaceutical-based approaches to increase durability and reduce injection burden. Most have failed, and we believe the opportunity for a more durable solution is substantial. Our goal in developing OTX-TKI is simple. We wanted to develop a non-biologic that marries a potent TKI, axitinib, that we believe is capable of delivering comparable efficacy to today's biologics with our proprietary hydrogel extended release technology to reset the current standard of care in terms of product durability. Where current injections provide adequate efficacy for one to four months, our goal with OTX-TKI was to move the injection frequency to six months and beyond, thereby significantly reducing the injection burden.
We believe that with our encouraging data presented today, combined with our data from our Australia-based phase I study, the potential for OTX-TKI to treat wet NV and other retinal diseases is exciting. With that, let me turn the call over to Dr. Rabia Gurses Ozden and Dr. Peter Kaiser to discuss the data. Rabia?
Thanks, Antony. Let me begin with a background of OTX-TKI. The active ingredient of OTX-TKI is axitinib, a highly selective multi-target inhibitor of vascular endothelial growth factor VEGF receptors 1, 2 and 3, and platelet-derived growth factor, PDGF receptors alpha and beta. Among TKIs currently being evaluated for retinal diseases, axitinib has been shown to have the highest affinity for VEGF receptors, which we believe will result in less off-target effects, potentially improving tolerability and theoretically maximizing the efficacy. High-affinity TKIs enable similar efficacy at a lower drug dose, which may potentially facilitate smaller or fewer implants. While current anti-VEGF drugs bind different isoforms of VEGF in the extracellular space, tyrosine kinase inhibitors bind to the intracellular domains of VEGF and PDGF receptors, inhibiting downstream activation pathways of angiogenesis and permeability.
We loaded this highly potent TKI axitinib into our programmable, sustained release, biocompatible hydrogel technology that has not been observed to have a propensity for inflammation and formulated it into bioresorbable intravitreal implant. The product candidate delivers axitinib for six to nine months at near zero-order kinetics using a 25-gauge needle that when in the eye has minimal to no visual impact to the patient, is free of antimicrobial preservatives, and bioresorbs completely as it clears from vitreous. The data we are presenting this morning is from our U.S.-based phase I clinical trial, a multicenter prospective randomized double-masked controlled trial evaluating a 600-microgram loading dose of a OTX-TKI in a single implant with a 2-mg aflibercept injection at week four after the implant, compared to a 2-mg aflibercept injections administered every eight weeks in subjects previously treated and controlled with anti-VEGF therapy.
This clinical study was designed to enroll a total of 20 subjects at six clinical sites in the United States who were randomized three to one to OTX-TKI or on-label aflibercept injections. The objective of the trial is to assess the safety, tolerability, and durability of OTX-TKI and to assess biological activity in subjects by measuring visual acuity and anatomical changes of the retina using optical coherence tomography. Our goal in this trial is to answer the question of how long a single 600 mcg OTX-TKI implant containing oxedane keep the subject controlled without the need for retreatment. This study enrolled 21 subjects, 11 males and 10 females. The mean age was 76 for the OTX-TKI arm and 84 for the aflibercept arm. The other baseline characteristics of both arms were similar.
Both study arms received diagnosis of Wet AMD a mean of 18 months before the enrollment and received an average of eight anti-VEGF injections within one year prior to enrollment. At baseline, the OTX-TKI arm had a mean best-corrected visual acuity score of 70.9 ETDRS letters versus a mean of 73.8 ETDRS letters in the aflibercept arm. Mean central subfield thickness was 273.8 microns in the OTX-TKI arm and 240.6 microns in the aflibercept arm. These baseline characteristics provide confidence that previously well-controlled patients were enrolled into both arms to help address our question. I will now turn the call over to Dr. Peter Kaiser to discuss the data. Peter.
Thanks, Rabia. Since this is a phase I trial, let's begin with the safety profile. As of the data cutoff of August 24th, 2022, OTX-TKI has been well-tolerated with a favorable safety profile. No drug-related ocular or systemic serious adverse events have been reported or observed. There was one event of endophthalmitis, and this was in the OTX-TKI arm but occurred following the mandated aflibercept injection at month one. This event was assessed as related to the study injection procedure by the investigator and fully recovered with intravitreal antibiotic and steroid treatment. There were no reported adverse events such as elevated intraocular pressure, retinal detachment, retinal vasculitis, implant migration into the anterior chamber observed in the TKI arm, and most importantly, no subjects have dropped out in either arm.
While all patients were included in the safety analysis, there was one subject who was randomized to the TKI arm who was incorrectly given aflibercept instead of sham injections at month three and month five by the investigator. These were not rescue treatments as the patient did not meet any rescue criteria and in fact had gained over four lines of vision and had only minimal change in retinal thickness when those aflibercept injections were done. This patient required no rescue therapy up to month 12. Since this patient was not treated according to protocol, we excluded this patient from the bioactivity analysis, but included them in the safety analysis.
In addition to safety, this trial was designed to assess biological activity using two validated scales we commonly use in wet age-related macular degeneration trials, including change in central subfield thickness on optical coherence tomography and best-corrected visual acuity from baseline. Since all patients entering this study were previously treated and controlled with anti-VEGF injections, we would expect that both central subfield thickness and best-corrected visual acuity would be stable compared to baseline.
In fact, the results demonstrated stable and sustained best-corrected visual acuity outcomes with a mean change from baseline of -1.3 letters and central subfield thickness with a mean change from baseline of +9.2 microns in the OTX-TKI arm at 7 months. This was comparable to the aflibercept arm dosed every 8 weeks, with a mean change from baseline of -1 letter in best-corrected visual acuity and mean change from baseline of +0.4 microns in central subfield thickness. One of the trial's key observations regarding the durability of OTX-TKI, and it's important to stress that we had predefined rescue criteria. However, investigators were also free to rescue at their discretion. The rescue criteria used in this study were similar to other TKI studies.
In the OTX-TKI arm, 80% of subjects were rescue-free up to six months and 73% of subjects up to seven months following an injection of a single OTX-TKI implant. Overall, patients in the treatment arm saw a clinically meaningful reduction in treatment burden at six and seven months post-treatment with OTX-TKI. Based on this, we plan to file our analysis of both the Australia-based phase I and U.S.-based phase I studies in the upcoming months. We look forward to scheduling a meeting with the FDA to share this data and discuss our plans to advance OTX-TKI into the next phase of development in 2023. We also plan to follow subjects in the phase I trial at least until their respective one-year anniversaries of initial dosing in accordance with the clinical trial protocol. I'll now turn the call back over to Antony.
Thanks, Rabia and Peter. We are encouraged by the interim results shared today that represent a significant milestone for Ocular and potentially for patients with Wet AMD. Wet AMD is a leading cause of blindness, affecting an estimated 14 million individuals globally and approximately 2 million in the U.S. alone. The data presented today highlights the potential of OTX-TKI to become a highly differentiated product capable of providing a durable anti-VEGF response that improves upon today's standard of care in the management of Wet AMD and with potential in other retinal diseases. I encourage anyone at AAO this week to attend the presentation by Dr. Dilsher Dhoot, who on Friday, September 30 at 3:29 P.M. Central Time will be presenting the OTX-TKI data in more detail.
Thank you for attending the call this morning, and we look forward to discussing our future development plans with the agency and initiating a phase I clinical trial in Wet AMD in Q3 2023. With that, I'd like to open the call for questions.
Thank you. As a reminder, to ask a question at this time, you will need to press star one one on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from Joseph Catanzaro with Piper Sandler. Your line is now open.
Hey, guys. Thanks so much for taking my questions here and congrats on these data. Maybe first two quick ones from me. I know this study wasn't powered to demonstrate non-inferiority on BCVA or central subfield thickness. Maybe Peter or Rabia, if you could maybe put into context the difference you're observing between the two arms in BCVA and CSFT and the clinical meaningfulness of that. Then maybe similarly, you know, you're working with relatively small patient numbers when you're talking about mean values. Peter, you mentioned that one patient who was inappropriately rescued and how they gained letters. Wondering if you could say, you know, how many patients in the TKI saw letter gain improvements at month seven, and if so, you know, how does that compare to the Eylea arm?
Thanks, and maybe I have a follow-up.
If we look at the non-inferiority margin that wasn't performed at this point, you know, being such a small study, there's gonna be very large standard deviations in the group. Bear in mind, there was only five patients in the aflibercept group. The overall outcomes, when we look at mean change in visual acuity is basically very similar. You know, there's really no difference between -1.3 and -1. As I stated at the outset, we would expect really no change in vision. The best example of this would be the Archway Phase III study with port delivery system where the patients were previously treated and very similar to our patients and really gained no vision with either ranibizumab or the port delivery system.
We were really expecting a stability of visual acuity, and we were hoping for it to be sustained for the full seven months that we're announcing today, and that's exactly what we saw. The interesting thing is we really debated that one subject, because obviously being in the OTX-TKI arm and having a very considerable improvement in vision of four lines, so more than 20 letters, you know, it would help our arm to leave him in. Because that patient really wasn't treated according to protocol, and when we asked the investigator, these were not rescue injections. They didn't think the patient needed them. We thought it was best, from a scientific standpoint to really only include the 15 patients who were treated normally.
Now, in terms of visual acuity gains, et cetera, we'll have to wait until Dr. Dhoot's presentation on Friday, which will give us much more clarity about how the differences were between the patients, but suffice it to say, at this point, the results look very similar.
Great. That's helpful. Maybe just one follow-up. Antony, I think you've previously said that achieving, you know, rescue-free rates in the range of 75%-80%, which you've shown here, would really open up the development strategy for the program. Maybe you can just expand upon that and how the recent high-dose Eylea impacts that strategy if at all.
Sure. I mean, I'll start and then let Peter finish because he has a much deeper insight into the regulatory environment. What I've always said is that the commercial hurdle here is lower than the regulatory hurdle. If you can get 50% of patients reliably to an interval of six months, you really have a home run in terms of the commercial potential of the product. The question is the regulatory hurdle may be higher. The true answer is we don't really know exactly what rescue rates we would need to achieve in order to make the product registerable or to be able to preserve the non-inferiority margin.
What you would expect is that if the rescue rates are similar among the Eylea-treated group and the OTX-TKI-treated group, that should not be an issue with the FDA, but we don't know that to be the case. 75%-80% is roughly the rescue rates that you would expect in an Eylea arm of a trial. I'll turn it over to Peter, who has a much deeper insight into what Wiley is thinking and how the FDA looks at this stuff. I think the true answer is nobody really knows right now exactly what the right answer is from a regulatory standpoint. Peter would know better than any other. Go ahead, Peter.
Yeah. I think Antony's right. I mean, obviously nobody has any insight into what Dr. Chambers and the agency is looking for in terms of rescue criteria in a study such as this. None of us feel that this is gonna be a first-line therapy. Although, if you look at the Australia study, our Australia study, we had many treatment naive patients who did incredibly well simply with an injection of OTX-TKI. So maybe I'm wrong with that, and that's certainly something we're gonna be looking at very closely. But, you know, for the most part, when you look at previously treated patients, the only predicate approval that we have to go by is the port delivery system.
In that study, obviously, there were very few rescues, but there were rescues in the port arm. As Antony pointed out, we don't know, and it's something we will work with the agency to come up with a number that would be reasonable in terms of rescue injections. I was very pleased with the 80% rescue-free interval at up to six months and the 73 at seven. This is much higher than I could have hoped for and will help us when we design our next study.
Okay, perfect. Thanks so much for taking my questions and congrats again.
Thanks, Joe.
Thank you. Our next question comes from the line of Jonathan Wolleben with JMP Securities. Your line is now open.
Hey, good morning. Congrats on the data, and thanks for taking the questions. Just a couple for me as well. The visual acuity and retinal thickness data you provide here, does that include the patients who are rescued in the OTX-TKI arm? And if so, what does that look like if those patients are removed from the analysis?
The data is including rescue in both arms, I might add. When we did the analysis without rescue, the results were, I mean, with basically last observation carried forward, the results were actually very similar.
Perfect. You discussed the treatment criteria in the past. We know what that is, but wondering if you could tell us the reasons for the rescue in the three and four patients in the TKI arm at six and seven months, and if there were any multiple rescues?
In terms of the reason for rescue, this is something we're gonna discuss at the presentation on Friday, so I don't want to steal any of Dr. Dhoot's, you know, his presentation. There were patients who were rescued more than once. Yes.
The last one, for me, if I may, for Dr. Kaiser, probably. When we think about the use case for OTX-TKI, and we're seeing such good data in patients well controlled on anti-VEGF, you know, what percentage of the population do you think this represents where you could have patients with a good response and treat and extend them to the six- and seven-month time point?
Well, speaking as a retina specialist, these are the majority of my patients. Patients do very well on anti-VEGF injections. This is well known. You know, most likely, barring a study in treatment naive patients by a TKI company, including ours, you know, anti-VEGF will remain the first line therapy. The issue is, of course, that these patients, if you look at real-world studies, simply don't follow up the amount of times they need to follow up to get the injections they need. That's even with longer acting drugs like we have currently, and may have in the future.
I would envision that you would use still anti-VEGF at baseline, and then when we get patients controlled very similar to the patients in this study, we would give them a TKI injection. As needed, we would give them additional anti-VEGF. This is very similar to how we use the port delivery system now. If we put the port in and every so often in between, we need to supplement with an anti-VEGF injection, we don't really consider that a failure of the port. It's just some patients have a higher need for an anti-VEGF therapy.
The exciting thing about this is although we're gonna have to come up with a number to retreat, say at phase III, like the port delivery system did, we know that looking at the early data that it lasts longer than six months. We would expect in reality that that's probably how we'd use it. We would keep basically following the patients. By then, maybe we'll have in-home OCTs, so we can follow them very closely. Only rescue as needed with an anti-VEGF injection.
Very helpful. Congrats again on the data.
Thanks, John.
Thank you. Our next question comes from the line of Chris Howerton with Jefferies. Your line is now open.
Hi. Good morning. Really appreciate you taking the questions and offer my congratulations as well. Perhaps from me, a couple questions. First of all, could you comment at all on any observations of the durability of the implant itself? Anything like, you know, residual observations of the actual implant or anything you'd like to say about that? Secondly, I'm curious if you could articulate in a little more detail what the expectations for the next steps might be in terms of discussing with the FDA any manufacturing work that needs to be done. I think, Antony, you mentioned a trial will start in 2Q or 3Q of next year. Would love to get a little preview of your thinking there. Thank you so much.
Well, I'll take the first question, and I'll have maybe Rabia to talk about the second in terms of manufacturing. In terms of the first question, you know, obviously we have to rely on the investigators to tell us if they still see the implant in the eye. It is something that usually you could see, but in some cases may be very difficult to see, especially if it's along the inferior vitreous base. In general, at the time points we're discussing today, the implant was still visible. Not in all patients obviously, but I wouldn't take that as a sort of a PK study to tell us how long these are lasting in humans.
In all our studies previously, including the Australia study, we would expect this to last anywhere from six to nine months, and we would anticipate that to be the case with all these patients. Rabia, I'll turn it over to you for manufacturing.
Sure. Thank you, Peter. What we have seen in our trials so far, the implants as Peter was mentioning is lasting, you know, six to nine months, about seven and a half to eight months. It's very programmable. We see a terminal release of the drug from the implant when the hydrogel completely bioresorbs. With our formulation work, we of course keep working on our formulation to just have our, you know, the final trials due with the commercial grade formulation.
What we are trying to do is to marry the implant, the hydrogel, to the axitinib so that it completely clears everything completely from the vitreous when the implant you know and leaving it you know clean space for the next implant. That's the goal, and that's what we are working on. It's working well. In terms of our plans for the next year, as I mentioned, now with this data and Australian data, we're gonna have a discussion with FDA. Our goal is to start a phase II, but very similar to upcoming phase III studies. From the design perspective in Q3 of next year and start a diabetic retinopathy trial in the Q1 of next year.
Got it. Okay. That's really helpful. Thank you for clarifying that. I'm not sure if there's any other analysts on the line, but maybe I'll just sneak one more question in. I know that we're gonna have the detailed presentation at AAO on Friday. Dr. Kaiser, you mentioned some of the points that will be presented there. Is there any other kind of key updated detailed information you'd like to draw our attention to that will be presented there? Thank you.
Well, I think the things that if I were an analyst I'd be looking for are the cases. You know, when you have a small study like this, myself and I consult for companies, we in a phase I study, the most important thing is to look at the patients and see how they're actually doing. You know, how many treatments right up to enrollment versus how many treatments thereafter. You know, are these patients who are just kind of burnt out or are these patients very active? I'll just tell you, just like we talked about in the call today, you know, these patients on average had about 8 injections in previous year. Just shows you how active they actually are before they were enrolled in the study.
I'd wanna look at the cases. I'd wanna look a little bit more closely at safety to see if there's anything there. You know that we're required to talk about anything bad, so I wouldn't expect anything to come out, but I'd certainly wanna look at the safety part of the presentation. Finally, since this is a randomized active control study, most phase I studies are not actively controlled with our best treatment currently, which is Q8 week of aflibercept. You know, how do those visual acuity curves look like? How do the OCT curves look like? You know, are these right on top of each other? Are we seeing like the aflibercept arm come out earlier or not?
You know, these are all things that I would look for if I were sitting in the audience, on Friday. I hope that answered your question.
Yeah. No, that's excellent. I really appreciate it, and thanks again and congratulations on the progress and the great data.
Great. Thanks, Chris.
Thank you. Our next question comes from the line of Yi Chen with H.C. Wainwright. Your line is now open.
Congratulations on the data. Thank you for taking my question. My first question is, in the upcoming phase II trial, do you plan to administer a 2 mg aflibercept injection four weeks after the implant? If you do not administer this aflibercept dose four weeks after the implant, how would that change the data readout? Thank you.
It's a great question. It's one that internally we'll be wrestling with as well as when we speak with Dr. Chambers at the agency. Remember that in our Australia study, the majority of patients were not treated with anything but OTX-TKI. They did not receive the one-month injection of aflibercept. You know, so we have to really come to grips as to which one of those options we want to proceed with. The phase I in Australia would suggest we don't need that first mandated injection at month one. It's one of those things that we're going to be looking at very closely. At this point, we have nothing to announce in terms of study design for phase II.
We need to do a more analysis of this, as well as discuss with the agency.
Yeah, just to build on that point, the only reason for that month one or week four aflibercept injection is that we understand that the mechanism of the TKI, because it works intracellularly, takes a little while to kick in. What we want to do with that is to make sure that there were no sort of false early rescues in the trial. We looked at data 24, 28 weeks. There is really no way that aflibercept is still active at that point. Whether we do it or whether we don't depends entirely on how the investigators treat those patients in the early days. We're very confident that four-week injection really had no effect on what we saw at month six and month seven, because that's really the TKI that's working there and not the aflibercept.
Got it. My follow-up question is, could you comment on the different population between the Australian and the US phase I trial and how that may contribute to the data readout, and whether you plan to stick with the U.S. trial population going forward? Thank you.
There's actually some very large differences in the enrollment criteria between the Australia study and the U.S. study. Both studies allowed previously treated patients into the study, but the Australia study also allowed treatment-naive patients into the study. Specifically, we wanted patients with a lot of excess fluid because we kinda wanted to see what happened to that fluid. The U.S. study was more similar to other TKI clinical studies that have been performed in the U.S., where the patients are better controlled, so much less fluid at baseline versus the Australia study. You know, it's interesting.
I'm very excited about the Australia data because to date, nobody has really been able to reduce fluid in treatment-naive patients, and we did in the vast majority of our patients up to six months. It's an interesting dilemma we have, again, you know, I'm not trying to be coy here. We really wanna discuss this with the agency in terms of what possible labeling differences we could get if we enroll similar to other TKI companies or if we do something totally different and go after all comers basically, which we possibly could do. This has not been decided. We're not announcing anything about our phase II at this time. We have options, and I really like when you're designing studies to have options.
The thing that's really important to me is the phase II study design that we sit on will be approvable in terms of the outcome. In other words, many phase II studies basically use reduction in treatment burden for their primary outcome and then visual acuity as their secondary outcome. We're not gonna do that because reduction of treatment burden is not an approvable endpoint, only vision is. The outcome for our study will absolutely be one that we could use for an identically designed study in phase III should the phase II be positive. That gives us the best chance of success in phase III.
I think to add on that, I mean, clearly the first rule, there's gotta be something that will get us approval. It has to be, has to pass regulatory muster. The other element that we really wanna design into it is how we see the product actually being used. I mean, the way we envision the market going forward is really for almost more like the asthma market, where you take your combination Advair as your baseline therapy, and if you have an exacerbation, you use your rescue inhaler. We sort of see the VEGF market moving in that direction where TKIs or OTX-TKI will be given once every six or nine months as sort of your baseline VEGF therapy. It will dramatically reduce any kind of a breakthrough from a VEGF perspective.
If you have an acute exacerbation, then you may need to be rescued from time to time. If that's the vision of how the product will be used in the future, what we'd wanna do is, like I said, understanding the first order of magnitude, we have to get regulatory approval, but we also have to support how we see this product being used in the future. We marry those two things together, we have a real opportunity here. We think with the data that we've seen and with the way the market works and the unmet need in the market that we have a perfect opportunity to marry those two things together, regulatory acceptability and market acceptance in a phase II/III program.
Thank you.
Thank you. Our next question comes from the line of Dane Leone with Raymond James. Your line is now open.
Hi, guys. This is Sean on for Dane. Congrats on the promising data. A couple from us. First, can you provide any additional detail on the timing of the endophthalmitis and any detail around the adjudication as related to the aflibercept injection? Secondarily, you discussed a reformulation for the single insert. Could you provide any detail on how the data today impacts your plans for a phase II and implementation of any new formulation?
Well, I'll handle the formulation question first because I think we've heard a lot of noise on this. One thing I think is important is to really frame how delivery companies work with formulations and how the regulations work. Many of you will know that in our first phase I trial in Australia, we had a single 200-mg load in a single insert that was injected through a 27-gauge needle. We assumed at the time that 200 mg would be enough to be well above the IC50 and be able to give us the maximal efficacy. We realized that that was not the case, and that we needed to go up in dose.
We just used the formulation that we had, the 1x 200 mg load. We got to 400 mg that way with two inserts and two injections and then three inserts and three injections. We realized that that's not a commercially viable formulation. You're not gonna want three inserts floating around in there. We decided that in our phase I-B that we would formulate a 600 mg load into a single insert, which we did, and we've been very excited by the data that we've seen. Clearly, the drug release rate, which is what really drives the efficacy, is above the level that we need to be in order to get a substantial efficacy out of this product.
We're gonna do what we always do, which is the next time around, we're gonna improve the formulation even more. There's opportunities for us to do that, both in terms of building in a lower drug load and a higher drug release rate, which would give us the ability to potentially have it act faster and maybe in some cases even act better if we can increase that drug release rate. With a lower drug load, we can then have less or no residual drug when the implant bioresorbs.
We have a very good problem in that our hydrogel actually goes away reliably and goes away fairly quickly, so that we don't have a situation where we have a depot that no longer has drug in it that's floating around in the vitreous. Having foreign bodies in the vitreous is just not a good thing. You wanna minimize as many foreign bodies as you have. We have a very good problem that we actually have our drug lasting a little longer than our hydrogel. We can adjust that. That's exactly what we're gonna do as part of our phase II. In the drug delivery world, we only need our final formulation in our final phase III clinical program.
We will continue to iterate because we think we can get better and better formulations as we go on, and we don't have to go back and start from the beginning. We actually leverage all the data that we've had in the past and build a better and better formulation. When I say that we begin with the end in mind, I mean that very sincerely. We are building a product that will become the standard of care, not building a product that will get to the next data stage in order to be able to put out data that looks impressive, but potentially with a formulation that is not commercially viable. We're really excited about being able to iterate, one, two, maybe three more times before we get the final formulation.
In each stage, we'll be getting a better and better formulation, which is exactly what we did between phase I in Australia and phase I-B in the U.S. In a very, very short timeline, we're able to come up with a better formulation, and I say we can do it again with the phase II. I think I hand off to Peter for the first part of your question.
Yeah. It's unfortunate when anybody develops endophthalmitis in a clinical study. In this case, the endophthalmitis case occurred within a week after the aflibercept injection. It was treated with intravitreal antibiotics and steroids. Thankfully, the patient's vision returned back to baseline. Obviously, there was a slight reduction around the time of the endophthalmitis. The good news is the patient has also remained on study and has done very well after the endophthalmitis event. In terms of endophthalmitis, you know, this is something we see unfortunately. It's an injection-related complication that occurs in almost all clinical studies. It's unfortunate when it occurs, but it is related really to the injection procedure itself. In this case, the injection happened to be aflibercept, but it was injection-related and not drug-related.
A very experienced investigator was the one who reported, treated, and agreed that this was a injection-related complication, not a drug-related complication. Does that answer your question?
Yes. Thank you so much.
Thank you. Our next question comes from the line of Georgi Yordanov with Cowen. Your line is now open.
Hey, guys. Thank you so much for taking our questions and congratulations on the data. Just maybe to start, real quick with a clarification, just as we try to compare this to other programs. We want to confirm when you talk about the six-month PK duration, the six and seven-month duration, this is from the time patients received the implant, not from the induction with the anti-VEGF that happened a month after that, right?
That is correct. The six-month and seven-month data is from baseline in the study.
Great. Maybe just to follow up on the endophthalmitis question. I guess maybe for Dr. Kaiser, when does that side effects usually occur in other injection procedures, just based on your practice and experience? Maybe just more broadly speaking, what is usually the rate of endophthalmitis that you see with Eylea? I guess eventually, what would you be comfortable with from an intravitreal product like OTX-TKI?
Endophthalmitis usually occurs after an injection within, you know, roughly seven-10 days. That's what we'd expect. It doesn't occur the day after, the next day usually. It takes a little while to percolate. General injection-related endophthalmitis is not as bad as other endophthalmitis that we get. In terms of your second question, it's a little bit difficult because obviously when you look at Eylea across the country, the rate is rather low. We usually quote to patients one in 1,000. But unfortunately in clinical studies, because one patient will dramatically increase that rate. Just to give you a comparator, the closest comparator study to what we're doing here is the Archway study. Recall in the ranibizumab arm.
Now, I'm not talking about the port delivery arm where they had a very high endophthalmitis rate, but in the ranibizumab arm, their rate was about 0.6%. They had the one case like we had. We do see endophthalmitis in almost every study. It doesn't matter what the drug is that's being injected. We saw them in faricimab studies. We saw them in the brolucizumab studies. You know, injection-related endophthalmitis is a known complication that we see in pretty much across our practices as well as across clinical studies.
Great. No, that's very helpful. Then just finally, can you remind us the needle gauge that you're using with OTX-TKI? Does your reformulation work plan to kind of improve on that? Is that gauge like something that retinal physicians are comfortable with when they do intravitreal injections?
Yeah. In the Australia study, we used 27-gauge in the one by 600, which was used in the U.S. as well as in later cohorts in the Australia study. It was slightly larger at 25-gauge. We plan for all future formulations to fit through that 25-gauge needle, which is a very small needle and it's something that as a retina specialist, we're very used to using. Just as a case of comparison, the only approved polymer for retina right now is Ozurdex, and that uses almost a 23 or even the 22-gauge needle, which was originally there, so a much larger needle. We're used to using needles of this size. 25-gauge is easily used for an injection.
This is great. Thank you so much. Congratulations again on the positive data.
Thank you. Our next question comes from the line of Yuan Zhi with B. Riley. Your line is now open.
Congratulations on the data team, and a couple of questions from us. First, hypothetically speaking, if you add one more Eylea injection as the induction, do you expect the result to be better or difference between OTX-TKI arm and Eylea arm to be smaller in terms of BCVA and the CSFT?
Obviously, the study wasn't designed to answer that question, so it's a hypothetical question. My hypothetical answer is I don't think so, right? The reason I don't think so is you know, we may not have even needed that anti-VEGF injection at all. Obviously you lower the number of injections, you lower the treatment burden, that would be even better. You know, some companies think that you need multiple anti-VEGF combined with TKI, but really, if you have a good TKI that truly blocks the VEGF receptor's downstream activation, which is what we're trying to do here, you really shouldn't need an additional anti-VEGF unless for some reason the implant wasn't releasing right away.
Some people feel that the main reason to need an anti-VEGF is that the polymer doesn't release immediately, and so you need to somehow cover the patient with an anti-VEGF injection during that time, and then as the polymer starts to release, then you're good. In our case, in the Australia study, we showed that that wasn't true because we were getting very quick results both on OCT as well as visual acuity in that Australia study. I'm not sure that you need the second one. I'm not even sure we need the first.
This is something that obviously we're gonna take internally, and really analyze along with our scientific advisory board to come up with sort of the best idea for a phase II study.
Got it. Thank you for the clarification. One more from us. For the control arm, did all patients receive Eylea on time every eight weeks?
When you look at a study, the answer is the injection fidelity of the aflibercept arm was good. I don't have the exact numbers off the top of my head. There's obviously eight weeks ±1 week in a clinical study. It's not always possible to get a patient in exactly when the visit should be. There's always a slight range to that. But in general, the patients did receive. It wasn't like the aflibercept arm missed a bunch of injections. That's not the case.
Got it. Thank you.
Thank you. As a reminder, to ask a question at this time, please press star one one on your touch tone telephone. Our next question is follow-up from Jonathan Wolleben with JMP Securities. Your line is now open.
Hey, thanks for taking the additional question. Just wondering about diabetic retinopathy and the opportunity. Can you discuss a little bit about, you know, number of patients, what we know about anti-VEGF sales, the unmet need there, and then I guess following that, the translatability of Wet AMD to diabetic retinopathy data.
You've hit one of my pet projects, which is diabetic retinopathy. As you would well think, anything that works so well on a VEGF receptor downstream activation should work just as well in diabetic retinopathy. But I wanna back up and answer part of your question first, which is we have two approved products to treat diabetic retinopathy in Eylea and Lucentis. And certainly we could use Avastin off label. But we don't use it, right? I can count on one hand how many patients of mine with diabetic retinopathy in the absence of diabetic macular edema, so I'm just treating their diabetic retinopathy, that I actually use these approved products. Patients just simply don't accept the injection frequency that high.
Now the Port Delivery System from Genentech, Roche, they're also looking at improving diabetic retinopathy scores with every six-month refills. But if you ask a patient, they don't, especially a young patient, diabetic patients are in general much younger than AMD patients, Wet AMD patients. So they're not as willing or wanting to have a surgical procedure done. But if we could do every six months or maybe even longer, because you know, the VEGF load that we're trying to sort of overcome with the treatment is lower in diabetic retinopathy than it is in Wet AMD. So maybe we could even go with even a lower injection frequency.
For us, we're incredibly excited about the idea of using this for diabetic retinopathy and speaking as a retina specialist, you know, if I could easily convince my patients, even my young patients, hey, come in every six months or so, I'll give you the shot, and it's gonna reduce everything in terms of retinopathy, future complications, which is the whole idea of reducing the diabetic retinopathy severity score. Towards this end, we are doing a diabetic retinopathy study. This has been announced. I'm looking forward to the results of this study.
The interesting thing, if you kinda think about it for a moment, is if we could show in that study that it works, the diabetic retinopathy regulatory pathway is actually easier than the Wet AMD pathway when it comes to tyrosine kinase inhibitors. Why do I say that? Well, you still can do a placebo-controlled study in diabetic retinopathy. This is very ethical study, as long as you obviously have a rescue in that placebo control arm, the sham arm. Whereas a Wet AMD study has to be controlled with Eylea at this point. The agency is not allowing us to use faricimab as a control group yet.
From that standpoint, doing a placebo-controlled study is much easier in phase III to hit the primary than it would be to do a non-inferiority study in Wet AMD. That's why it's my pet project because I would be super excited for that to be our sort of first foray, but we'll have to see. You know, at this point, I'm not announcing anything. I'm just saying it's a pet project.
Very helpful context. Thank you.
Thank you. I'm currently showing no further questions at this time. I'll turn the call back over to Antony Mattessich for closing remarks.
Well, thanks everyone for joining us on this call and for asking the questions. One of the things we're really excited about is that we're announcing this data just before the AAO. We'll actually have the big presentation obviously with Dilshad Dhoot on Saturday, or sorry, Friday afternoon. Peter Kaiser is also gonna be presenting at Eyecelerator on Thursday, talking a bit about the Australian data, but now can throw in a little bit of the data that we have in this trial as well. We hope the questions keep coming.
We've been living with this data pretty intently now for at least a few days, and we've been looking at it from all different angles, and we actually think that as we look at it more, we like it more. It's going through the AAO to have people come back with questions, to have them bounce off other key opinion leaders, to be able to look at pictures, 'cause a picture really means 1,000 words. If you look at some of these OCTs at month seven, it really is spectacular what these things look like in patients who have really not had treatment for seven months. So keep the questions coming.
I think a lot of the people on this call and a lot of people listening will be at the AAO. We'll be available for additional questions as they come up. But we could not be more excited headed into the AAO, and we really wanna dig into the data. Thank you very much for your attention and for the continued story of how we're trying to bridge the gap between what we see in clinical trials and what happens in the real world in terms of preserving vision of people living with both diabetic macular edema and retinopathy, as well as Wet AMD. Thank you very much for your attention today.
Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.