Participants
- Antony Mattessich, Chief Executive Officer
- Arshad Khanani, KOL
- Peter Kaiser Chief Advisor for Retina
- Rabia Ozden, Chief Medical Officer
- Donald Notman, Chief Financial Officer
- Chris White, Chief Business Officer.
Good day, and welcome to the Ocular Therapeutics Conference call announcing 12-month data from the US-based Phase 1 clinical trial evaluating OTX-TKI for the treatment of wet AMD. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. Instructions will be given at that time. As a reminder, this call may be recorded.
I would now like to turn the call over to Antony Mattessich, Chief Executive Officer. You may begin.
Antony Mattessich, Chief Executive Officer
Hello, and thanks for attending the Ocular Therapeutics Press Conference for our 12-week top-line data for OTX-TKI. Let me start first by emphasizing how encouraged and excited we are with this data as it continues to support a product profile with the potential to set the standard care of durability in wet AMD, which is the highest unmet need in the space. I'll be very brief so we can get directly to Arshad Khanani.
As I mentioned, Arshad is important not only because he will be presenting the data but also because Arshad is our largest enroller, has by far the most clinical experience treating patients with OTX-TKI than anyone else in the world.
After Dr. Khanani completes his presentation, Dr. Peter Kaiser will follow up with a bit of the discussion on the new paradigm that we believe that continuous dosing can bring into the market. We'll then open the floor up for questions, joining Dr. Khanani and myself to help answer those questions will be Dr. Peter Kaiser, our Chief Advisor for Retina, Dr. Rabia Ozden, our Chief Medical Officer, Donald Notman, our Chief Financial Officer, and Chris White, our Chief Business Officer.
Just before handing it off to Arshad, I want to get everybody's attention to slide two. You'll notice that we will be making forward-looking statements. With that, I will hand it off to Arshad and get to the exciting data as soon as possible.
Arshad Khanani, KOL
Thank you, Anthony. Good morning, everyone. I'm really excited today to present the first-time data for the 12 months from this study.
As practicing physicians, we know that there is a big unmet need for our patients with neovascular AMD to receive treatments that have better durability. And as a field, we have been looking at durability for almost a decade now, and we have made changes where we have agents that can last three to four months instead of one to two months. But even with those agents, we have a large number of patients who still need treatment very frequently.
I am super excited to be an investigator in many trials looking at sustained delivery. And today, I'm really excited to cover OT-XTKI. As you are aware, OT-XTKI uses a proprietary Elutyx polymer matrix, and this is bioabsorbable, and this enables sustained targeted drug delivery. And it has a TKI, and I've been involved with all the TKI trials, and this one has Axitinib, which is a multi-target tyrosine kinase inhibitor. With TKI, you need to make sure you look at the drug that's present in TKI because the concentrations and the inhibition of the receptors is different in terms of affinity.
So when you look at Axitinib, this is on slide three, it's a highly selective inhibitor of all VEGF and PDGF receptors with very high affinity and low solubility compared to other ocular TKIs.
As an investigator, when I started participating in this trial, I was very thrilled to see that this is a very easy injection. It's a single implant that's administered by a 25-gauge needle. And the hope is that the target release is 9 to 12 months. And as I said earlier, it's completely bioresorbable.
So hopefully, after looking at the data today, you'll be able to see that this implant can really help patients with neovascular AMD decrease their treatment burden.
Looking at slide four, which shows the OTX TKI US-based study trial design. This is a multi-center, randomized, double-masked study. We enrolled patients who had subpoveal neovascularization due to a neovascular AMD. These patients had control fluid, so they could have some fluid at entry or no fluid at entry, but they had to show a response in the past to anti-VEGF, and we needed control patients for this trial.
In terms of randomization, patients were randomized three to one to either receive OTX TKI or versus aflibercept. Patients at baseline received OTX TKI or a sham injection, and then a month after, both treatment groups received aflibercept injection.
After that, patients in the OTX TKI were evaluated for disease activity using the criteria listed at the bottom or at investigator discretion to receive a supplemental injection of aflibercept.
In the aflibercept arm, patients received on-label aflibercept, which is Q8 weeks. As I said, today I'll be sharing the results of the 12-month analysis.
Looking at the baseline characteristics, these appear to be well-balanced. Slight differences in terms of mean BCVA and CSFT. If you look at OTX TKI, these patients had slightly lower BCVA at 70.9 letters compared to 73.8 letters with aflibercept.
And looking at CSFT, 273.8 versus 240.6. So patients with aflibercept had better CST at baseline. As you can see, 16 patients in the OTX TKI and 5 in aflibercept.
I think this slide really highlights the results today. When you look at patients with neovascular AMD, you need to look at prior treatment history. Criticism in the past with many trials that they are enrolling patients who don't have any disease. I enrolled most of these patients and they all had disease.
So here you can see patients were receiving injections anywhere from every month in most cases to every two or three months with a variety of anti-VEGF in the past. After receiving a single in-clinic injection of OTX TKI, you can see on the right that there's an 89% reduction in treatment burden when you look at the data at 12 months.
Really highlighting that this technology is really helping patients control their disease. Obviously this is a treatment burden slide, but we need to look at visual acuity as well as anatomy to prove that. But just want to again highlight that these were patients who were receiving frequent injections in the past.
And after receiving OTX TKI, we see an 89% reduction. And also when you look at the rescue injection, in this study, investigative discretion was allowed. So you can see those purple boxes. Those are injections that were given at investigators discretion. And I like that because as an investigator, my hope and goal is to control disease for my patients so they can do well. And sometimes if I feel like that the disease is active and patients still don't meet the rescue criteria, we were allowed to give supplemental treatment. And that's why I respect the company for doing that so that we can better take care of our patients.
Looking at slide seven, you can see the rescue fee rate over time. OTX TKI demonstrated extended duration of action. 60% of patients were rescue free up to 12 months with four additional subjects rescued at 12 months.
So you can see that there is great durability here where majority of the patients can go without treatment for eight to nine months or even longer. So here we are taking patients who are receiving treatment very frequently and we are able to extend majority of them past six to eight to nine months, which again highlights that this technology is really providing sustained delivery to control disease.
Looking at slide eight, here what we are seeing is vision and CSFT. So you see on top, we are showing mean change in BCVA. And what these graphs show that looking at BCVA, this was comparable to a aflibercept when you look at patients with OTX TKI. We are also showing the light blue dotted line, which is sensing rescued subjects.
So patients with OTX TKI had mean BCV of minus one letters at week 52 compared to gold standard of aflibercept, which was plus two. And this was comparable to OTX TKI. So again, BCVA is stable.
As a reminder, these are patients who were previously treated. So we don't expect these patients to have improvement in visual acuity. As I said earlier, these were prior treated with essentially controlled disease when they were enrolled in the trial. So stable BCVA actually is the goal of this trial.
When you look at CSFT, we have to look at a few things. With a aflibercept every eight weeks, we have seen sawtooth or fluctuations in CSFT in essentially all trials. So a sustained delivery platform should be able to stabilize anatomy and we should not see fluctuations.
Here we can see again, comparable results, but OTX TKI arm shows stable OCT as fluctuations are at minimum with OCT improving over time during the weeks 32, 36 and 40 time points. Again, showing that this sustained delivery is helping patients stabilize anatomy, stable vision, highlighting the biological activity of OTX TKI.
When you look at the subjects that are censoring, you know, the dotted line showing censoring rescued subjects, this also shows similar results.
Looking at slide nine, this is safety. Obviously it's an ocular implant. It bioabsorbs completely, but we still need to pay attention to safety. I am happy to report that there are no reports of drug related ocular or systemic SAEs in either arm. We did have one event of acute endophthalmitis in OTX TKI arm.
This is actually one of my patients, but this endophthalmitis happened at the mandated aflibercept injection at month one. So this is not related to OTX TKI, but rather the standard of care aflibercept injection that patients, all patients receive in this trial at one month.
This patient did well. We treated them with an individual antibiotics and over time, patient resolved and we have vision returning to baseline. Other than that, all events were mild and manageable. There really were no safety signals here that were concerning in terms of OTX TKI. We did not see any retinal vasculitis, retinal artery occlusion or anything else.
Looking at slide 10, here are some cases from the study. This is an 81 year old female with anti-VEGF injections given every eight weeks prior to study. And this patient has remained rescue free up to one year.
As you can see, the CSFT is very stable over time. There is increase at the end of the first year and patient receives supplemental treatment at that time. Looking at BCVA again, stable.
I want to point your attention to the OCTs on the right. You can see minus 16 weeks that before patient was enrolled in the trial, you can actually see fluid. You see the red area on the grid which shows thickening. You can see black circles inside the retina. This is intra retinal fluid.
This patient actually had a very active disease. The BCVA was not available because this is from standard of care clinic visit. And sometimes patients don't get BCVA or they get BCVA that doesn't get reported. So it's not available.
But when you look at baseline in blue, you can see patient had controlled disease with 83 letters of BCVA, which makes sense looking at the OCT. Patient got enrolled into the trial, received OTXT-KI week four. They got their aflibercept injection that was mandated. And then you can see the OCTs remained very stable until week 52 where you can see activity. You can see some intraretinal fluid and sub retinal fluid. And that time patient received a supplemental injection. Again, showing that this technology is really helping patients control disease with extended durability.
Looking at another patient, which is on slide 11, you can see this is a 65-year-old female with anti-VEGF given every four to eight weeks prior to study. And this patient has been rescue free through one year.
Looking at central subfield thickness, again, very stable central subfield thickness. You can see that patient had increased initially and with injections, it was stabilized. And then after OTX-TKI, the CSFT stayed stable.
In terms of visual acuity, some fluctuations, which we can see in real world from patient's effort and other parameter, but again, within range, and you can see we have stable visual acuity up to week 52. Again, looking at the OCTs on the right, you can see active disease with the red area on the grid all around the fovea.
When you look at OCT scans, you can see there is thickening the sub retinal fluid, the black line under the retina showing active disease. At baseline, patient was controlled with no fluid. They received OTXT-KI. Four weeks after, they received a mandatory aflibercept injection.
And you can see this patient has done really well over time up to week 52, really showing the benefit of OTXT-KI in patients with neovascular AMD to achieve stable vision, stable anatomy, and having good safety.
Going to slide 12, in conclusion, what we have seen at the 12-month data that OTX-TKI maintained vision and CSFT compared to a aflibercept every eight weeks with an 89% reduction in treatment burden over a 12-month period.
Safety showed OTX-TKI was generally well tolerated. The implant observed to bioabsorb over time completely at about eight to nine months, informing that potential redosing timeline.
What we have seen here that the data from this trial supports the characteristics of a potential treatment for neovascular AMD with durability between 9 to 12 months after a simple single injection of OTX-TKI implant which bioabsorbs completely in patients.
So with that, I'm going to pass it to Dr. Peter Kaiser to give you an overview of the program.
Peter Kaiser, Chief Advisor for Retina
Thank you very much, Dr. Khanani. The great presentation and thanks for all your work on the study.
I'll have everybody switch to slide 13, which really shows how we feel the US trial supports the use of OTX-TKI.
As a practicing retina specialist along with Dr. Khanani, we would look at using the OTX-TKI after we've maintained and gotten control of the fluid with any anti-VEGF agent of choice. And it has shown, especially in the cases where once the fluid is controlled, we then place OTX-TKI on board and that allows us to maintain the fluid status and vision.
In this study, we know that by doing this and using OTX-TKI, we found that the central subfield thickness and visual acuity comparable to using the gold standard of just Eylea every eight weeks.
As we mentioned at the 10-month data release, about 73% of patients were rescue free. We also knew that the drug would eventually wear off. And as we hoped, we would see that these were not patients who were simply dry and needed no treatment. As soon as the drug wore off, we would expect to see more rescues. And in fact, that's what we saw, especially at month 12 where there were four additional rescues.
This led to a rescue-free interval of about 60% up to 12 months. And at the 12-month period, accounting for the patients who were actually treated at that 12-month visit, we still had an 89% treatment burden reduction compared to the previous 12-month period.
We would need to supplement with anti-VEGF, but we would anticipate maintaining the fluid status with the OTX-TKI and then re-injecting as the patients needed treatment as the drug started to wear off.
If you looked at slide 14, we would hope based on the results of this 12-month study to continue our development in wet macular degeneration. We are prepared to initiate a pivotal Phase 3 study as early as the third quarter 2023. I would also note that we have completed enrollment in the HELIOS study.
And if you switch to slide 15, you can see that this study was a U.S.-based, double-masked, multi-center, randomized study in patients with moderate to severe non-proliferative diabetic retinopathy without diabetic macular edema.
This study was enrolled very quickly. The patients were randomized to receive a single OTX-TKI implant or a sham injection and then were followed over time. And the key outcome that we are looking at in this study is the improvement in diabetic retinopathy severity score.
As you know, this is an improvable endpoint used in other studies for diabetic retinopathy. We expect the six-month interim data presented in the early first quarter of 2024. We are very excited about the use of OTXT-KI in both age-related macular degeneration as well as diabetic retinopathy.
And I will turn it back over now to the operator so we can take some questions.
Question & Answer Session
Dane Leon -Raymond James
Great. Thank you for the update. Congratulations on the data. One question for me. When you look at the 12-month data and just the time course of fluid control with the OTX-TKI administration, is it plausible or something that the team should consider in future clinical work to perhaps try a second administration of OTX-TKI without a standard of care injection? Meaning that once you do the run-in shot, give OTX-TKI the first time, there's somewhere around the 9- to 12-month mark where you could administer the drug product again and actually omit the need for another standard of care injection. Thank you.
Antony Mattessich, Chief Executive Officer
Thanks, Dane. That actually is the product vision. The idea is that you would get dry or you would induce with antibiotic therapy. Once they're dry, put them on maintenance therapy, and they stay on maintenance therapy for the rest of their lives, with need for a supplement only on an as-needed basis.
So we’re looking at time horizons and dosing intervals of when we would, in future clinical trials, do re-dosing to obviate the need for continuous delivery of antibody therapy. So, yes, we're actually considering that. This gives us great information in the trial that we have now to look at what a re-dosing interval would look like. So we will definitely plan that moving forward.
John Wollinben - JMP
Hey, thanks for taking the questions, and congrats on the data. A couple for management and then one for Dr. Khanani, if I may.
The first, can you talk a little bit about the timing of the hydrogel resorption in the patients that needed these late rescues versus those who didn't? I'm just wondering if there's consistency in quicker hydrogel resorption in patients that had the return of fluid versus those who didn't. And then can you give any more color on the IOP elevations that are new here, the two new cases?
Rabia Ozden, Chief Medical Officer
Hi, John. This is Rabia. The hydrogel bioresorption is not related to when the patients are rescued. What we have seen is that consistent resorption of the hydrogel is around eight to nine months. That's why the rescues and the hydrogel bioresorption is not related.
For your second question on IOPs, I'll just start and I'll just ask Dr. Khanani to continue. Those two patients were about a year after the implant was injected. And in one patient, it was importized and there are low levels of increase.
Arshad Khanani, KOL
Yeah, Rabia, absolutely. The little change in IOP in both of my patients was not concerning at all. This was unrelated to OTX-TKI. One patient had bilateral slight increase in IOP. Since this is my first experience with OTX-TKI, we actually looked for several things.
We did gonioscopy to look at the front of the eye, we did thickness of the cornea on both eyes. So we did things to make sure that we are not missing any safety signals and we didn't see anything. So patients can have some fluctuations in IOP, depending on the time of the day. And really, both of these patients had no issues and they're being followed after the 12 months. And they have not had any issues with IOP. So an unrelated happens sometimes with the patients and I'm not concerned.
John Wollinben - JMP
That's helpful. And Dr. Khanani, you mentioned that you've been involved in trials for all the TKI candidates. Can you talk a little bit about what you've seen from this class of drugs and how you think OTX-TKI compares?
Arshad Khanani, KOL
Absolutely. So I think there are a few things that I've seen. I was involved with the graybug study in the past with many patients in that trial also. I think the main thing is that we need to have a platform that's safe. We need to have an implant that bioabsorbs completely and we need to have a drug that actually works.
So as a class, I've seen that it does take some time for tyrosine kinase inhibitors to kick in because they have an effect intracellularly. They are pan-VEGF inhibitors. And so I think that's why we had that mandatory injection a month after. So that we give coverage for the first four to eight weeks before the TKI starts working.
So I've seen that as a class. And that's why Peter was eluding earlier that we will give injections in the acute phase. And then once the patient is stable, before or around that time, introduce OTX-TKI and you're able to control disease.
That's actually the paradigm that's being used for all sustained delivery. We did that for poor delivery system. We are doing that for gene therapy trials where we want to make sure that patients get stable before they start getting the benefit of sustained delivery with the technology.
As you remember, we saw particle dissipation all over the vitreous and in the front of the eye with the graybug program. That's not the case here. The implant bioabsorbs and the drug sometimes is still present after the implant is bioabsorbed. But it's stationary in the area of injection, which is great. That's why we have not seen any safety signals.
In terms of efficacy, you know, I can compare this to what I saw with the graybug study where we did see some efficacy, but it didn't last as long as what we have seen here. So I think also having Xtinib as the drug that has the highest affinity, when you look at the OTX-TKI class is helping the patient.
Those are my experiences from being an investigator in the OTX TKI versus gray bug.
Albert Lowe - Piper Sandler
Hi, everyone. Thanks for taking my questions. This is Albert on for Joe and congrats on this nice-looking data. Just for my first question, I was wondering for this additional follow-up for these patients past week 52 what your plans were to share any additional observations from this extended follow-up?
Rabia Ozden, Chief Medical Officer
Hi, Albert. Thank you. This is Rabia. We follow the TKI patients after week 52, and the reason is we have still some patients in the trial, still not rescued, just, you know, see the effect, the efficacy, how long it's going to persist. And the reason is that, you know, longer safety follow-up for the TKI.
That's why we're going to be seeing and reporting on the safety and also the further efficacy of the TKI.
Albert Lowe - Piper Sandler
Okay. Great. So I guess we can expect to hear from that at some point in the future?
Rabia Ozden, Chief Medical Officer
We will be able to do presentations depending on when we complete the follow-up on those patients.
Albert Lowe - Piper Sandler
Okay. Great. And I was wondering, how do you think the rescue free rate that was observed here under these clinical trial conditions would maybe compare and translate under real-world conditions?
Antony Mattessich, Chief Executive Officer
Well, first of all, I think we need to think of rescue rates differently with continuous therapy than we do with antibody therapy. And I think rescue rates are an obsession with antibody therapy in part because when you rescue a patient, you truly are rescuing them because there is no drug-continued delivery within the target tissue.
From our standpoint, when you're giving a continuous drug delivery for 9 to 12 months and you do need a top-up or a supplement of a rescue medication in that period. It is a clean rescue in the same way as you have in an antibody approach.
So we had a patient, for example, that was supplemented around month 3 or 4 and then continued through week 52 without the need for additional supplements. With the background of continuous therapy, the way you react to fluid, to increases in fluid, may be different because you know you have drugs on board.
So we use rescue rates because that's what the industry is used to. You look at the revised model and the hydrophilia treatments, they really obsess on this idea of how many patients can get to a certain time period. And that's really about gaming the time to disease reactivation after the drug has already left the vitreous.
So we'll continue to look at those rescue rates, but really the more important thing is injection burden. And that's where we really think that we'll try and move the goalposts. So look at injection burden and also look at retinal variability.
As you look at the central subfield thickness line in the OTX-PKI arm, as Dr. Khanani mentioned, you don't get that sawtooth pattern. Now that sawtooth pattern is a mean. You look at the individual responses that drive that sawtooth pattern, you actually get quite a lot of variability in the retina when you use immediate release pulse dosing in antibody therapy. You don't get that with that individual variability with a continuous dose product.
We'd like to move the goalposts in the future to injection burden and to work on some form of metrics that really looks at the variability of the variable thickness of the retina over time. Because we do think that that variability has good data to show us that the greater the variability, the worse the vision outcomes.
Colleen Cusi - Baird
Good morning. Congrats on the data and thanks for taking our questions. So on BCVA, it looks like a three-letter difference at 12 months. If you do go the non-inferiority route for the pivotal, what do you understand to be the margin for BCVA? How many letters worse than Eylea can you be and still be non-inferior?
Rabia Ozden, Chief Medical Officer
This is Rabia. Those are the non-inferiority routes, it is very clear in the recently established guidelines. If you use the aflibercept, that is four and a half letters. And if you use Eylea in your comparator, that's four letters.
That's why currently what we are seeing in our trial, the BCVA report, we cannot comment on non-inferiority. We don't have the numbers to make that claim. What we can say is that those numbers are very comparable.
Antony Mattessich, Chief Executive Officer
I would like to add that I think it's pretty clear that getting out to a 52-week time point that we would need to consider redosing. I mean, what you do get is the central subfield thickness, you really start to see a separation by week 52. And fluid is a precursor to vision loss.
If we kept running this trial out for another four weeks, you would start to see, I believe, a difference in BCVA start to open up. But when we look at this from the pharmacodynamic data of this trial, which matches the pharmacokinetics that we expect in the target tissues, is that we would need to consider redosing for a 12-month time point.
Colleen Cusi - Baird
And then those three patients that were rescued for the first time at 12 months, that they didn't meet the criteria, but they were rescued based on a physician's discretion.
Do you have a sense of what was going on with those patients? And do you think that that was like true disease kind of recurrence in those patients, even though they didn't meet the criteria?
Arshad Khanani, KOL
Yes. So what happens is, you know, we are watching these patients in extension, but it's standard of care extension, essentially. When a patient finishes the study, the option is, we know these patients have neovascular AMD. Should we just give a treatment now so they don't have to come back as often as they were in the clinical trial?
I have one patient actually who's in this trial that moved six hours away and flies in and again, and gets seen. So it depends on multiple things. Why we treat the patients once they finish the study, you know, it's more like the paradigm we have in the real world where we treat and extend to kind of decrease treatment burden. That's why these patients were treated, even if they did not meet the criteria for treatment because in the extension phase is standard of care and the study finished at month 12 in a controlled setting.
Peter Kaiser Chief Advisor for Retina
And if I could add, you know, we showed you one of the patients who on slide 10, I believe it was, that, you know, basically was rescued at the 12-month interval. And this is a really great patient. The reason it's great is the patient had a lot of treatment burden prior to the enrollment in the study, did very well. And then at that month 12 visit, you can see obvious fluid coming back.
Now, most companies, when they have polymerase, or other types of things, where they're trying to sort of limit rescue will require both a loss of vision and an increase in OCT. In our case, we allowed the investigator discretion to treat. In this case, they still had a gain in vision, so they didn't really meet any criteria, but there's obvious fluid.
The investigator correctly injected at that point where you could see that the drug is really wearing off in this case, probably somewhere at the 11- to 12-month time point. You can see at 11 months they were doing fine and then the fluid started to come back, indicating the sustained nature of the anti-VEGF TKI. And as that wears off, the patient needs treatment.
And as Anthony mentioned earlier, you know, probably in clinical practice we would be reconsidering re-injecting with some sort of TKI at that point, at that 12-month time point. And in the future, we'll have home OCT to help us guide this. We'll actually be able to see these sort of changes in fluid fluctuations without even really having a patient come in for that. They'll do it at home, so it'll be nice in the future.
Tara Bancroft - TD Cohen
Good morning, and congrats on the data, and thanks for taking the questions. So my first question is, what is the biggest factor after these data now that a partner would need more information on? Is it CMC or something else? Curious to get your thoughts there.
Antony Mattessich, Chief Executive Officer
Well, I mean, obviously this data from a drug developer's standpoint is much more exciting than the month 10 data. Because what you want to see when you're developing a drug is when the pharmacodynamics line up.
As we've been telling the market and showing our people investigating this compound that our insert viral desorbs at around eight-nine months, we have a release of Axitinib into the vitreous, which lasts for another couple of months, and then begins to clear by month 12.
So the difference is the increase in rescue rates is one thing, but really the separation is the thickness that demonstrates that these people really are having disease reactivation when the Axitinib clears from the vitreous.
That is very exciting for a drug developer because you want to have those things match more if you're excited about what the future looks like. Now, we just got this data about a week ago and just dropped it into the data room.
So the response from the people that are in that data room at the moment is yet to be seen. They're looking at the data now and they're absorbing it. But we feel, obviously, that it's a key piece of information that they would need in order to really feel confident in being able to enter physical programs in diabetic retinopathy and wet AMD.
Chaitanya Galakota - HC Wainwright
Congratulations on the data and thanks for the questions. The first question is regarding the ideal target patient population. I know you mentioned extensively about OTX-TKI as a potential maintenance therapy. Is that where you would ideally like the product to be used upon commercialization? Essentially, patients with controlled fluid and perhaps without active disease. And then I also have a couple of quick follow-ups.
Thank you.
Antony Mattessich, Chief Executive Officer
I think this goes back to the vision of what we see in this product and what continuous delivery of anti-VEGF therapy and how it would work in practice. I think it would be good for maybe Dr. Kaiser can start and sort of suggest how this would work and what type of patients you would use it on.
Peter Kaiser Chief Advisor for Retina
As a retina specialist, to me, it's sort of intuitively obvious where I would use this product. Which is control my patients with anti-VEGF, but as any patient or a caregiver of a patient will tell you, is there any way to reduce these injections, but keep the same efficacy?
That's the most important part, keep the same efficacy. All our real-world studies of anti-VEGF, the patients do really well at the beginning, but then there's patient burnout, there's caregiver burnout, there's the people that are taking a day off and giving them rides to the appointment burnout and the number of injections go down.
Any time that happens with anti-VEGF, the visual acuity results get worse. The hope is to use something like OTX-TKI after the patient has done really well on anti-VEGF, they're controlled, give them the TKI, watch them theoretically with home OCT and then as we start to see the fluid return, bring them in for another injection of the OTX-TKI.
By doing that, maintain the vision gains that we had achieved early for an extended period of time, but dramatically reduce the number of injections. If you told a patient, look, I need to do this every nine to 12 months, they're like, yeah, sign me up. This is fine. But when you tell a patient I need to do this every two to three months, that's when burnout occurs.
So the hope is to have just better outcomes long-term using a product such as this.
Arshad Khanani, KOL
Yeah, and if I can add to what Peter just said, I agree with Peter completely.
When people are looking at the uptake, I think this is an injection that's going be available essentially for all patients with neovascular AMD. We have the poor delivery system, now obviously it's recalled, but that was a surgical treatment so it was difficult to justify in patients who were going three or four months already with anti-VEGF and so that is a small subset of patient population that could be treated.
Here we have a simple in-clinic injection. The hydrogel bioabsorbs completely. So this should be given in my opinion as Peter said, the burden is high even with every two or three or four month injections. This can be a therapy that can be treated that can be given to essentially all patients to extend their durability and decrease their treatment burden and then give supplemental injections as needed.
So patients are variable in terms of their disease and if we can have a baseline level of control in all patients and then we supplement them as needed based on their individual disease activity. That’s how I would think about this platform. To decrease treatment burden, to have better control and anatomy and hopefully have better outcomes in terms of visual acuity for our patients with neovascular AMD.
Chaitanya Galakota - HC Wainwright
Thank you so much. That was very clear. And lastly, one quick one for the management. Could you comment on the expected cost for those pivotal studies please?
Antony Mattessich, Chief Executive Officer
Yeah, we've laid that out. There are three approaches moving forward that are viable approaches that we believe have a high probability of success and we believe that they would be acceptable to the FDA, given the new draft guidance.
There are two approaches in wet AMD. One is a non-inferiority trial that would look very much, the two treatment arms would look very much like the trial that we're discussing today. With an additional arm for masking purposes because sham is no longer recommended by the FDA.
We would expect two trials, so it would be about 900 patients per trial. That looks upwards of probably $300 million to full NDA applications.
There is another possibility of a superiority trial that we believe would be far less expensive because we think that we could see bigger differences between a single dose of an on-market, currently marketed product, versus a single dose of OTX-TKI. Clearly, we know that we've delivered drugs continuously for nine to 12 months. We know that any comparator antibody drug would be out of the eye by about two months, that we could see a separation, a superiority in a relatively short period of time. That difference would be fairly profound.
That trial has issues that make it difficult to execute, but we do believe that that is an executable trial. Whether we choose to take that path is another question, but that would be significantly less expensive because it would actually have far fewer patients necessary to execute that trial. That would be more along the lines of $50 million per pivotal or $100 million all NDA.
The final pathway that we're considering is a diabetic retinopathy approval, which would be fairly similar in size and actually in structure to the superiority trial in wet AMD. That would be a trial that we could, I believe, easily execute. That we would get a lot of support from local key opinion leaders around in an area that we believe we could open up a market environment that does not exist today because when you look at diabetic retinopathy, well, the end point is about the improvement of the severity score.
In fact, the reason why you would treat diabetic retinopathy would really be to prevent disease progression, to prevent proliferative disease. And when we have current therapies which are pulse dosed antibodies, the one thing you really would not want to use is pulse dosing where you have very high concentrations and then the drug leaves the eye and then you dose again. Would be in a prevention paradigm.
Continuous dosing of an intracellular drug like TKI on a nine to 12 monthly basis, we believe could open up that market in a very substantial way. I remind you that there are a very, very high number of patients suffering from NVGR, about 8.5 million in the US and about 3 million of those are on the more sort of severe end of that spectrum.
So all of these pathways we see are viable and we're working extremely hard now to kind of decide which one we think is preferable in a go it alone scenario because clearly we have partnership discussions ongoing, but you cannot plan on a future with a partner because you can't say yes to a deal you don't have. And right now we don't have a deal so we are plotting our future to do this without partnership.
If we're lucky enough to receive a term sheet that makes us reconsider that pathway then we will do that and make a decision that's in the shareholder interest.
But we're blazing ahead with those three options moving forward and thinking about how we would do it if we were to go alone and then speaking with partners about how they would do it if they were to join us in the development of this project.
Caroline Palamecki - with Ladenburg
Hi, good morning, thanks for taking the question and congrats on the data. So my question is just when you're thinking about pretreatment, the patients that come in having been pretreated with Lucentis or Eylea, I'm just wondering, are there any trends that you're seeing as to how that pretreatment affected being treated with LTX, TKI?
I mean, just looking at the data, it seems like many of the patients with Eylea and Lucentis did not need rescue but then some of them had several different products that they were pretreated with. Just wondering if you could just talk about how that has affected results.
Peter Kaiser Chief Advisor for Retina
Yeah, so we didn't really, obviously the study doesn't have a lot of patients to be able to make any determinations if there's a variability in the response rate depending on what patients were treated previously. However, the way Eylea, Lucentis, Avastin work is mainly by blocking VEGF-A.
And for the most part, the response rates are similar. So if you look at any of the clinical studies with anti-VEGF, not one is any better than any of the others. So to us, we don't anticipate that there'll be any variability in response. I mean, this is blocked to all the VEGF receptors, in particular receptor two. And so because of that, we would expect to have a similar result irrespective of what anti-VEGF the patient was on previously.
I'd also point out that the Australia study shows, to me, really shows the benefit of this. The US study showed that we can use this as maintenance, but the ability of this drug to treat treatment-naive patients which was in the Australia study with no anti-VEGF at all is actually very exciting.
Now, I'm not saying that that's how we would use it. I maintain that we will use it the way I mentioned earlier. But the fact that even with anti-VEGF we can eliminate that with just the TKI in OTX-TKI is actually very exciting from a physician standpoint.
Caroline Palamecki - with Ladenburg
And then just a quick follow-up. I'm just wondering if there were any updates from the FDA conversations that you're having.
Antony Mattessich, Chief Executive Officer
There are really no updates. We've been pretty clear for a while now about what the FDA would accept.
And those three pathways that I just mentioned we're highly, highly confident that we have protocols that the FDA has seen and that they would accept if we decided to move in those, in any one of those three directions.
So there are no updates. I don't think there are any updates necessary. I mean, we're hoping that maybe some of the endpoints can be adjusted moving forward, particularly and we'd love to be able to work toward a fluid endpoint rather than a BCVA endpoint because that's more in keeping with the way current practice works in the, particularly in the US where doctors really treat to minimize or eradicate fluid rather than wait for vision loss.
But I don't expect there'll be many changes within the FDA or the feedback that we've gotten from the FDA. And then we really have enough at this point to understand how to move forward.
Antony Mattessich, Chief Executive Officer
Thanks, everyone, for attending the conference and certainly thanks everyone who spoke and was able to answer questions. We are extremely excited about OTX-TKI. I assume that comes through our voices.
I’ve been involved in drug development for 35 years now. And when you see that the pharmacokinetics and the pharmacodynamics match on a product, it is both tremendously exciting and feels also a tremendous sense of burden because you know that there's a drug in here somewhere.
It’s a question of how you unearth the potential of that drug within the framework of how physicians practice, what patients expect and what the agency allows you in terms of a pathway to approval. So as we work through those issues to try and please all of those groups, not to mention our investors along the way, we are very excited to have such a level of interest and enthusiasm among the investment community and scientific community. We're asking them to help us think through this as well. But we're very excited in this very important moment for our therapeutics and patients suffering from wet AMD.
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