All right, good morning, everyone, and welcome to Oppenheimer's 35th Annual Healthcare Life Science Conference. My name is Andreas Argyrides. I'm one of the Senior Biotech Analysts at Oppenheimer, and today I have the pleasure to be joined by the management team from Opthea Limited, ticker OPT, and I have CEO Fred Guerard here. I'll give a quick introduction of the company overview, and then I'll have Fred dive into his presentation here. So Opthea is advancing Sozinibercept, a VEGF-C/D trap inhibitor for the treatment of wet AMD, and they're currently in Phase 3. Sozinibercept's product profile has been getting favorable reception by the retinal community and payers, as seen with the recent survey work from Opthea. It's the only emerging agent in wet AMD focused on improving vision, the highest unmet need, which is designed to complement any anti-VEGF agent.
Top-line Phase 3 results from the COAST trial with aflibercept and Sozinibercept combination are expected in early Q2, followed by the ShORe readout with ranibizumab and Sozinibercept combination mid-year. Again, thanks for being with us today, Fred. Let's dive into the presentation, and we'll have some Q&A at the end.
Thanks, Andreas, for welcoming me to this conference and for Oppenheimer for inviting me to present the story. So we're publicly listed in two different stock exchanges, and I will be making some forward-looking statements. So, as Andreas kindly said in his intro, we are the only company working on the drug that potentially could deliver better vision outcomes for patients suffering from wet age-related macular degeneration. And this is a disease that, left untreated, could lead to permanent visual impairment or legal blindness. A class of drug developed 20 years ago in anti-VEGF-A has really changed the trajectory of these patients. The patients today get injected in the eye on a regular basis and can hope to regain some vision, or at least not to progress towards legal blindness over time.
The visual outcomes are clearly not perfect, and the majority of patients cannot go back to driving level of vision. We developed a first-in-class VEGF-C/D trap that is intended to be used in combination with anti-VEGF-A to deliver better visual outcomes. This is a new molecule. We have composition of matter IP until 2034. In the U.S., we're going to get longer extension of that protection. We have demonstrated already superiority in a very large, well-designed Phase 2b trial, comparing Lucentis alone to Lucentis combined with Sozinibercept. We've shown that we delivered better visual outcomes for the patients with a very good safety profile. We are now just about to read out our first pivotal trial, which is called COAST. It's around 1,000 patients, and we expect the data early second quarter of this year.
ShORe is a twin trial, looks very similar, and we'll read out in the middle of 2025. We have enough cash until the third quarter of the year. So this is our team. We are very blessed with a team that has worked in ophthalmology or retina companies before, and we are advised by a group of various teams, retina experts known around the world. Our lead asset is in wet AMD. We're also working on preparing for a diabetic macular edema indication, which is a natural lifecycle management of all the drugs on the market today. This is the second largest indication in these diseases. We're also working on a fixed-dose co-formulation of Sozinibercept and anti-VEGF-A, which could allow a faster administration in the clinics.
Vision remains and actually increasingly becoming a concern around the world and is the number one medical need according to the retina specialists attending this American Society of Retina Specialists during the summer of 2024, and this is in a context where all the drugs are basically the same, all of them being non-inferior to each other all the way back to Lucentis, which was approved 20 years ago. These drugs are amazing, and they really help the patients, but you can see that despite having been used for all these years and optimized over the time with new drugs coming to the market, the majority of patients do not go back to driving level of vision, which is 20/40, at least in one eye in the US.
60% of patients still have accumulation of fluid in the back of the eye, which is one of the presentations of the disease, and 25% of patients, despite getting these drugs, will have further vision loss one year after they are diagnosed, so clearly not perfect therapies available now. We are the only company working on superior outcomes. All the other companies are trying to be non-inferior to the original benchmark, which is ranibizumab or Lucentis injected every four weeks. We are first in class, as I said before, so we are not inventing new biology here. This has been very well documented for many years. We have IP on the targeting of VEGF-C, and we are the only company being able to do so.
All the drugs on the market today are anti-VEGF-A or A, B, and PLGF, but basically they leave wide open VEGF-C and D to bind to receptor two and three of the vascular endothelial growth pathway, and when it's left by itself, this pathway basically will promote angiogenesis, so abnormal blood vessels growing in the back of the eye and vascular permeability, so these vessels leak fluid in the back of the eye, which, of course, if left alone, will result in photoreceptor death. In animals, that's been very well documented. VEGF-C promotes angiogenesis. VEGF-C also opens the vascular walls and promotes vascular leakage or vascular permeability. When patients have the disease, they have a natural upregulation of the production of VEGF-C, but when they get treated with anti-VEGF-A, there is also that upregulation, so you block some part of the VEGF pathway, the other part will upregulate.
In animal models, we've demonstrated that actually Sozinibercept or OPT-302 would probably be as effective as existing drugs like aflibercept or Eylea. But obviously, the magic is when you combine the two, you get a synergistic effect. And then in this animal model, you control a lot better the choroidal neovascularization area of these animals. So we are alone working on superior vision gains. We saw also in the Phase 2b consistent anatomical improvements, which drives the vision benefits. And our safety was very similar. And we had around 1,800 injections done with the drug all the way into Phase 2b. We now have tens of thousands of injections in the pivotal programs. But the safety was very similar to existing anti-VEGF-A therapies. On all comers in the Phase 2b, we demonstrated a statistical superiority versus standard of care for the combination with Sozinibercept.
You can see the benefit was appearing early after the treatment was initiated and was maintained all the way to week 24. The safety profile was unexceptional. You see the ocular and non-ocular adverse events. The rate of adverse events with Sozinibercept is what you would expect with anti-VEGF-A. Basically, with injections in the eye, nothing exceptional here. Nothing on inflammation, which is different from existing anti-VEGF-A. You see the rate and the type of inflammation was similar to what is experienced by patients today. This is our pivotal program. We have two large global pivotal trials ongoing in 33 countries. The first one is called COAST. COAST is testing aflibercept or Eylea in combination with Sozinibercept versus Eylea alone. ShORe is a redo of the Phase 2b.
Basically, it's with Lucentis as the Phase 2b and comparing Lucentis and Sozinibercept 2 MG versus Lucentis alone. We have three arms. So patients basically all get the standard of care as per label, and then they get randomized and get a sham injection, or they get a Sozinibercept injection every four weeks for two years, or Sozinibercept injection every eight weeks for two years after they get three loading injections, monthly injections at the beginning, which is the way Eylea is being used. The inclusion and exclusion criteria are identical to the Phase 2b, with one exception. We excluded the RAP lesion patients in Phase 3. This is a very small type of lesion in the back of the eye, and these patients did not benefit from the combination as much as other patients did.
So by doing so, we are maximizing the probability of success without reducing the commercial opportunity of the drug. Our primary endpoint will be mean change from Best Corrected Visual Acuity from baseline to week 52. And this is that week 52 data that we'll read out in a few weeks now. The secondary endpoints are a mix of functional and anatomical endpoints. As I said, the top line data is at week 52, but the patients will stay on the same regimen for another year. And the idea of the second year treatment is to collect more safety data. We can file and be approved with the one-year data, and we can do a supplementary filing of the second-year data whenever it's ready. We are doing two statistical testing in the trial for every endpoint.
We are first testing these occult and minimally classic lesion patients, which is a very large subsegment of the wet AMD population. It's around three quarters of the patients in clinical practice. These patients had almost a 60% improvement in their visual outcomes using Sozinibercept on top of Lucentis in the Phase 2b. And that's the first statistical analysis we do. The second one is on all-comers. And as you can see here on all-comers, RAP absence. So basically, the population we enrolled in the pivotal program, we had a 40% or so improvement of the combination versus standard of care. So we have multiple chances to win with this design. We published recently in January the baseline characteristics of the patients.
The good news is we enroll patients that have a very similar disease severity at baseline in the Phase 3 program compared to the Phase 2b. Very similar patient types. There are small differences, though, mainly positive for us. The first one is a higher proportion of occult lesions in Phase 3 than we had in Phase 2b. In Phase 3, we have around 55%-56% of patients having these lesions. We only had 44% of them in Phase 2b. Why is it good news? Because in Phase 2b, these patients gained 6.5 letters of vision at week 24. Having more of these high gainers really helped us in Phase 3. We also have more PCV lesion types in Phase 3. That's because we now have sites in Asia, which we did not have in Phase 2b.
These lesions are notoriously difficult to treat thanks to the combination in Phase 2b. These patients had an incremental 6.7 letter benefit in their visual outcomes at week 24. Now, we only had 17% of patients with these lesion types in Phase 2b because it was done on Caucasians only. Now in Phase 3, we have around 25% of patients have these lesions because of the sites we have in Asia. So the mix of patients is slightly the same disease severity, but the mix of lesion types is slightly more beneficial to us in Phase 3 as it was compared to as it was in Phase 2b.
Our clinical trial design, having ranibizumab as a comparator in one trial and Eylea as a comparator, ranibizumab or Lucentis and Eylea or aflibercept in the other trial, allows us to have potentially a very broad label if we get approved, supporting the use of Sozinibercept with any anti-VEGF-A. The pivotal trials are very large, extremely well-powered, and therefore we should be able to answer all the questions we're asking. And finally, we are answering a very high unmet medical need, vision being the number one medical need for patients and for physicians. The market has grown tremendously over the years. We estimate now the anti-VEGF-A market for wet AMD only, so that does not include the other indications like diabetic macular edema, retinal vein occlusion, to be around $12 billion worldwide.
We are not competing with anyone because we are the only company working on a combination drug that could be added to all anti-VEGF-As. Basically, we have this entire market at our disposal without having to face the competition of any other company or any other drug. For patients, when you ask them what is it that you care about when you get diagnosed, not surprisingly, the number one factor for them is preserving as much vision as possible. This is a disease of the elderly patient. In our trials, the average age at entry is around 77 years of age. These patients want to maintain autonomy. They don't want to trip and fall at home. Vision is very important for them. And indeed, for them being able to keep this autonomy by being able to drive a bit longer would be something absolutely beneficial for them.
In our Phase 2b, we allowed 42% more patients in the combination arm to keep driving than patients on the Lucentis arm, so that is a massive improvement in the quality of life of patients that we can hope to achieve again in Phase 3. When we asked the retina specialist how many additional letters of vision do we need to deliver for them to be using the drug, and we tested under three additional letters, which is far below what we delivered in Phase 2b, to over five letters, which is the full line of the vision chart. You can see here the rates ranged between 24% of their patients for the lower end all the way to 41% for the higher end.
So if you think of every point of market share being over $100 million of sales, 24% is actually a very good floor for us for our forecast. And of course, those are yearly sales. Obviously, this market is also growing year on year by a single digit. Our drug is used in a buy-and-bill model in the U.S. in Medicare Part B. So the clinics basically buy the drugs from manufacturing companies, store it, inject it in the clinics, and then bill the insurance companies with a markup of 4.3%. So this system has worked extremely well over the last 20 years to ensure access to the majority of patients in the United States. When we asked the payers what it is you would want to see to support reimbursing Sozinibercept on top of VEGF-A therapies, their feedback was around a 20% incremental improvement in visual outcomes.
You can see on the right-hand side here, in whichever patient population you look into in the Phase 2b, whether it was all-comers or the more difficult patients like PCV patients, we had anywhere between 40%-96% improvement versus standard of care. We seem to be falling right within what they want to see for us to be covered very broadly in the Medicare system. When we asked the payers to which drug would you see us being combined, the answer was basically all of them. Assuming we are successful with both our pivotal programs, we would be used in combination with any drug out there, including biosimilars. Finally, price. What can we expect in terms of price range?
The answer from the payers we surveyed in the U.S., and this is a very extensive market research we've done with payers covering over 200 million lives in the U.S. So basically, the vast majority of Medicare patients would be covered by the payers we surveyed. They said that they were okay with the price in the range of existing branded anti-VEGF-As. And you can see here on the screen, the cost per injection of these drugs today ranged anywhere from $1,800-$2,600 per injection. So they were comfortable with the price in that range. Finally, can we execute a launch in the U.S. market? And the answer is yes. The market is extremely concentrated, held by a very small number of retina practices. You can see 500 retina specialists in the U.S. inject 50% of the volume in the U.S. market.
1,400 retina specialists inject 80% of the volume. For a biotech company, it's actually a very easy, it's a big word, but it's a very manageable number of customers to cover. We do not need hundreds of medical reps and spend hundreds of millions of dollars in promotion to cover this system. It's very much business to business. It's also becoming incredibly concentrated in private equity-owned retina networks, with now four private equity firms owning more than 25% of the market in volume. Very easy to access for a smaller company like ours. Finally, financially, we are in a very sound position. We reported at the end of December $130 million of cash, which is around three quarters of cash burn. We have a development agreement with Carlyle and Abingworth, which is basically a risk share.
We drew $170 million from that agreement, and the payback is capped at 4x and starts being paid only after we get approved in a major jurisdiction, which would be the U.S. market. We do not owe any money until that point. Finally, just to recap the timelines, so we are in the final steps of finalizing our manufacturing module for the FDA. We are just waiting for the drug product release. The drug substance has been put in vials. The vials are being tested as we speak, and we're going to press release that when it's done. Then the next milestone is the COAST top line data, which would be early second quarter of this year, then ShORe in the middle of the year.
We are now guiding everybody to a final module submission for the BLA early 2026, and it could potentially be approved by the FDA by the end of 2026 because we have a Fast Track designation, which one allows us to submit the modules as they are ready and could accelerate the review of the dossier by the FDA. So that's in a nutshell what I wanted to cover with you today.
Yeah, that was great, Fred. Thank you. And very exciting, to be honest. As you said it, there are not many drugs in wet AMD development that can improve vision. I think you covered a lot of what I was going to ask, but maybe we can just revisit a couple of questions and points here. So I think investors do wonder about the second injection.
And maybe you can give us, and I think you alluded to this already in your slides, but how physicians think about the minimum bar of success for visual acuity improvement that would allow them to feel comfortable with a second injection. So yeah, maybe that was the slide. There we go.
No, but it's a very good question because obviously it's newish. Now, I want to highlight the fact that in the U.S. today, two injections are routinely done on the same day in the same eye for patients. Some patients that suffer from dry AMD also have wet AMD. Or sometimes the wet AMD is triggered by the treatment against dry AMD. So it is not unusual today in the U.S. to get two drugs on the same day in the same eye. So that's already happening.
When you ask patients, and you can see on the graph here, as much as they care immensely about vision, when they are told that they have this disease that can lead to blindness over a number of months, the concern about being injected in the eye, which is not a very appealing thing. I mean, if you think about injecting in the eye, it's not something people look forward to. But when you look at how it ranks on their thinking, it's actually pretty low. Going blind is a lot worse than being injected in the eye. For physicians, I think the answer to your question is here when we ask them what would be the penetration in your patient population based on visual improvement. You can see here anywhere from 24%-41% of their patients would be benefiting from the drug depending on different vision benefits.
Less than three letters on the right, all the way to more than five letters on the left. The floor is pretty high, and the reason for that is, and we've seen that actually in our Phase 2b data. We had a beautiful graph in the previous deck where we showed a heat map of the patient benefits in the Phase 2b of the combination patients versus monotherapy patients, and you could see that we had not only a lot more extreme vision gainers in the combination with Sozinibercept arm as opposed to Lucentis alone, but we also had a lot less vision losers in the combination arm, so basically, we moved in that trial in the Phase 2b the entire patient population toward vision gain, and that is what physicians want to see. It's not always all about vision gain.
Patients on Lucentis or Eylea today, despite getting injected as per label, still have vision loss, so any improvement, any hope of improvement for these patients will be used and will be the anchor for the physicians to offer the drug to their patients and the drug being used.
Okay. I'm going to ask this question first about the ex-U.S. opportunity, then we can go back to maybe some of the U.S. conversations here, so how should we think about the ex-U.S. opportunity, Europe, Japan, you also have IP in China. Are you engaging actively with potential partners?
So we have worldwide rights. So we did not out-license any rights so far. Think about the opportunity in the ex-U.S. being a little bit smaller than the U.S. opportunity, so it's around 50%-60% of the business worldwide is U.S. The rest is other markets.
And there are probably 10 markets that really count outside of the U.S. China and Japan being two of them. We are obviously discussing with everybody. We have not made a decision yet to sell the rights ex-U.S. There may be a time where it makes sense. As much as we can easily operationalize the launch in the U.S., I think getting in countries like China or Japan is a lot more complicated for a biotech. So there may be an opportunity for us post-top line data to engage into some discussions with companies for these territories.
Okay, great. Very exciting here. And we have data coming up very, very shortly here. Maybe you can discuss which patients would be best candidates for Sozinibercept when first approved. I mean, you've gone through this, but I think your trial has also enriched for success with a certain population that you've mentioned.
And then I think what's also important to tie in is the idea of this broad label and how important it is to have the one to four-month dosing.
Yeah, good question. So we are enrolling all comers, basically. So our label should reflect all comers. We excluded RAP, but RAP is a very small subsegment. So we don't expect the FDA would restrict use in these patients. So that's for us very clear. Every four weeks, we have a parallel testing of the two arms, every four-week injection of Sozinibercept or every eight-week administration of Sozinibercept. So we can win in both. We can win in one over the other. The flexibility that physicians need to use our drug is actually more driven by the every four-week label than by the every eight-week label.
And the reason for it is patients have very various needs in terms of anti-VEGF injections. So as of today on the market in the U.S., despite all the different labels we have from every four weeks, every eight weeks, all the way to every 16 weeks, patients get injected anywhere, on average, between every 50 days to every 60 days. The average injection frequency has not been increased very much over the last 20 years. 50 days is with Lucentis and Eylea. 60 days is with Eylea high dose and Vabysmo. So it hasn't really changed, and 60 days is around the eight-week mark. It's not very different.
So the challenge for retina specialists and driven by the insurance companies is if they need to use a drug every four weeks, but the label only says that the drug can be used every eight weeks, then they run into reimbursement issues. So for us, actually, what matters the most for reimbursement is the every four-week indication. Now, every eight weeks would be interesting to get a sense of duration and do we deliver non-inferior visual outcomes every eight weeks, but we do not need that to win because every patient is individualized anyway in real practice. So every patient is on a different calendar of injection.
Right. We are close to time. I'll also remind our listeners that what makes Sozinibercept so unique is that it doesn't really compete with the other products, but is in combination with all. And I think Fred has walked us through that.
There's some great slides that are available on the website to go through. I think you've done a fantastic job, Fred. Thank you for the comprehensive overview. We're looking forward to the updates very shortly, and again, thanks for joining us, and with that, we'll conclude.
Thank you, Andreas.
Yeah, looking forward to the results.