I'm Jennifer Kim, a biotech analyst at Cantor. I'm happy to introduce Fred Guerard, the CEO of Opthea, for this formal presentation. Fred, you can take it away.
Thank you very much, Jennifer, for your warm welcome and giving me the opportunity to present the story of Opthea. We're a publicly listed company on NASDAQ and ASX, and you can find our forward-looking statements on our website under the Investor section. Our molecule is called sozinibercept, and it has the potential to be the first product in the last 20 years to improve vision outcomes of patients suffering from retinal diseases. These diseases are today treated with a very good class of drug called anti-VEGF-A, but despite these good therapies, patients are still experiencing vision loss, or at least not a vision benefit aligned with what they expect to get to be able to live their normal lives. We know now, with a number of studies, that every letter of vision counts, not only for quality but also quantity of life. Sozinibercept is the first-in-class anti-VEGF-C and D.
It is a trap molecule intended to be used in combination with a standard of care anti-VEGF therapy. This is a new molecule. We have a good composition of matter IP running at least into 2034, and our phase II-B trial demonstrated statistically significant superiority in terms of vision benefit at week 24 with a good safety profile. I'll come back to this data later. We are currently in the middle of our pivotal program. We have two large phase III trials ongoing. COAST is the first one, almost 1,000 patients in each of these trials. COAST will read out in the early second quarter of 2025, and ShORe will read out in the middle of 2025. We currently have a cash balance that we expect will extend the runway beyond these two readouts. No need to mention how big the market is.
This class is now around a $10 billion a year market opportunity around the world for wet AMD only. So this is what the market looks like. These drugs are approved for other diseases as well, like diabetic macular edema, all competing against each other, and we are the only asset working in combination, working to develop a superior drug in combination with these existing treatments. This is our team. We are very blessed with a team of retina experts, not only key opinion leaders but also internally working to bring this drug to market. So despite these amazing drugs that were developed over 20 years ago, the majority of patients still have persistent fluid in the back of the eye.
Almost half of them do not benefit from significant vision gains, and the majority of patients fail to achieve the 20/40 level of vision, which is the minimum required to be allowed to drive in the United States. You need that vision at least in one eye. We also know that these suboptimal visual outcomes are actually associated with a decrease in what's called IADL, and these IADLs are very simple tasks, like dressing, washing, cooking, looking at a bank statement that allows us to basically navigate life and operate.
It's now clearly established that vision loss not only impacts quality of life but also quantity of life, and you have here on the left of the slide a study showing that even when you reach 20/40 vision, which is not a lot of vision loss, it's three lines of vision loss compared to perfect vision, you already have a 29% increase in mortality, and that goes all the way up to a 90% increase in mortality if you reach legal blindness. One letter of vision loss a year has been associated with a 16% mortality increase. So not only do we make people live better, we also make people live longer when they see better. We are the only drug working to improve visual outcomes for patients. All the other drugs currently on the market or being developed are just non-inferior to each other in terms of visual benefits.
Our molecule and our mechanism of action is the following. All existing agents and agents being developed these days, late stage, are all blocking VEGF-A or A and B and PlGF, basically leaving wide open the third receptor of the VEGF pathway for stimulation, as well as some of the receptor 2, and the main stimulators of these pathways are VEGF-C and D. Sozinibercept traps VEGF-C and D in a very powerful manner, and this is why the drug is being developed in combination to be allowed to maximize efficacy, and you can see here in these animal models, VEGF-C stimulates angiogenesis in the same way VEGF-A would do with this proliferation of abnormal blood vessels. It also promotes vascular permeability, also in the same way as VEGF-A, resulting in fluid accumulation in the back of the eye.
When you have the disease, you have a natural upregulation of VEGF-A and C, but it gets even further upregulated when you start blocking VEGF-A by using these existing drugs, and you get this further upregulation of VEGF-C. So our drugs would work as a standalone, as you can see on the right panel, but clearly the maximum benefit is when you use these drugs in combination. So sozinibercept combined with any anti-VEGF-A delivers a much better control of the disease than anti-VEGF-A alone. Our drug fits perfectly well in what the patients want to achieve when they get this treatment. I mean, they are very interested by only one thing, which is how well they can see, they can read, they can drive, they can see their family members. It fits very well in the way the clinical practices are organized.
These retina centers are very well organized now to inject intravitreal drugs, and our treatment would basically fit in the existing model. It also fits what the payers and the insurance companies are paying for. These drugs are being reimbursed based on the vision outcomes they deliver. We ran a survey during the summer on 125 retina specialists in the U.S., and we asked them, depending on the level of incremental vision benefits sozinibercept would bring to an underlying anti-VEGF-A treatment, how likely they were to prescribe to what percentage of their patients in their clinical practice, and you can see if we can deliver even under three letters of visual improvement over anti-VEGF-A, they declared they would put around 24% of their patients on sozinibercept, and it goes as high as 41% if we were to deliver an additional five letters of vision over anti-VEGF-A.
1% of market penetration is around $100 million a year. We are working on the first program is in wet AMD, but we are already developing a protocol for diabetic macular edema, which would be the next natural indication we would work on. We're also working on a co-formulation so that the drug is mixed already with an anti-VEGF-A in the same vial. These feasibility trials are ongoing. So this is the design of our phase II-B trial, which demonstrated statistical superiority of sozinibercept combined with ranibizumab over ranibizumab alone. And you can see the patients were naive, which is very standard in this disease. They had very standard inclusion-exclusion criteria, except one. I'll come back to it later.
And the patients were randomized into three arms, basically getting Lucentis every four weeks in all cases and getting either a sham injection every four weeks or getting a low-dose sozinibercept every four weeks or a high-dose sozinibercept every four weeks. The trial was around 360 patients, 120 patients per arm. The primary endpoint was mean a change from baseline in best-corrected visual acuity at week 24, which is the primary endpoint we have also in the pivotal program, except it's not at week 24. It's at week 52. The rest of the secondary endpoints were very typical for wet AMD trials. We pre-specified in the phase II-B the subgroups. We know depending on the lesion, the type of lesion you have in the back of the eye, you get different response to anti-VEGF-A. So these lesion types were pre-specified in the protocol.
Those are the baseline characteristics of the patients. This is very important because it shows that the groups were very well balanced. It also shows that patients had around 50 to 51 letters of vision at baseline, which is typically lower than what you see these days, and that was by design. The idea was to enroll patients that were more visually impaired to be able to see a separation between the arms. If you take patients with perfect vision and you give them an anti-VEGF-A, they're probably going to remain at good vision, and therefore the additive effect of a second drug would not be detected. So here, the idea of taking patients with 50 letters of vision was to be able to detect that separation of the arms, and you can see the rest of the statistics.
The patients clearly had disease activity with elevated central subfield thickness as well as presence of fluid intraretinally and subretinally. On the total patient population, the delta between sozinibercept high dose combination with Lucentis and Lucentis alone was 3.4 letters at week 24, and as you can see, the low dose did not deliver statistically significantly different visual outcomes compared to Lucentis alone, so the high dose is the dose we are taking into our pivotal program. On the occult and minimally classic lesions, which are the patients we are testing first in our phase III program, we are enrolling all comers except RAP patients, and the statistical analysis will be done on these occult and minimally classic lesion patients, which basically are patients harder to treat with anti-VEGF-A alone.
We demonstrated in phase II a 5.7-letter improvement for the combination arm over the Lucentis arm alone with a very strong p-value. These patients represent around 3/4 of the patients in real life in the clinical practices. So when you look at these patients, minimally classic and occult patients, and here it's a new visual representation of our data set. Every bar is a patient. We classify them per vision gain or vision loss. So everything above green or yellow is actually green, sorry, is vision gain. Everything below green, yellow, or orange, or red is actually vision loss. And what you can see for the combination arm with sozinibercept 2 mg is a complete shift of the patient population to the right, basically a shift to vision gain.
We had a lot less vision loss with only 2% of patients losing some vision as opposed to 13% of patients losing vision, some patients as much as three lines of vision in the Lucentis arm. On the other side, we had 10% of patients with extreme vision gain, six lines or more of vision, 30 letters or more, as opposed to very few patients reaching that level of vision gain on Lucentis alone, so you can see here very graphically the benefit of combining sozinibercept to a standard of care. When you look at the percentage of patients reaching 20/40, which is this kind of artificial threshold for driving in the USA, you can see that in that patient population, we had a 42% increase of the number of patients being able to reach driving level of visions for the combination compared to Lucentis alone.
Anatomically, the combination with the 2 mg did also provide some benefits. We had a further reduction of CST. We had a reduction of presence of subretinal fluid, intraretinal fluid, as well as the total lesion area and the CNV area in the back of the eye, so all of that contributes to a better vision for patients. Finally, on this especially hard-to-treat patient population called PCV patients, these patients still sometimes receive laser treatment with anti-VEGF-A or laser alone. These benefits on these 20 patients per arm was around 6.7 letters, additional incremental vision over Lucentis alone. These lesions are extremely prevalent in Asia, also not rare in Caucasian patients. We only had Caucasian patients in this trial, and you can see we had around 20 patients per arm with these lesions. On the safety side, nothing really to mention.
Whether it was ocular or non-ocular safety signals were very much in line with what was observed with anti-VEGF-As, and if you zoom on ocular inflammation, which is always a concern in retina, you can see here that the rates were very similar across the arms, whether it was for anti-VEGF-A alone or for the combination with sozinibercept, so the phase III design is informed by the phase II data. We've enriched the patient population by running the primary statistical analysis on this high-responding group to the combination of sozinibercept and ranibizumab, which is the minimally classic and occult patient, and of course, we are enrolling all comers, and these patients would be tested as a second statistical analysis. These trials are very robust. One is being conducted comparing sozinibercept with Lucentis. The other one is being run comparing sozinibercept with Eylea.
The idea of running these trials using two different comparators is to get a broad label when we get approved to be potentially combined with any anti-VEGF-A, not necessarily specifying which molecule. The design is very classical. It's multi-centered. Those are global programs. Double mask, randomized one-to-one-to-one. There are three-arm trials, and they are conducted on the same patient population as in phase II-B. The inclusion criteria are extremely similar, and they are naive patients. As you would expect, cost is around 1,000 patients each. The primary endpoint will be the same as in phase II-B, except it's at week 52, not week 24, and we test also a number of very classical secondary endpoints such as percentage of patients gaining three lines of vision or 15 letters. This is the trial design.
We use the comparator, whether it's Eylea in COAST or Lucentis in ShORe, as per labels, so monthly injections for the loading phase, and then Eylea is given every eight weeks for two years to all patients. Lucentis keeps on being given every four weeks for two years for all patients, and then patients get on top a sham injection or they get a low dose, sorry, they get a 2 mg sozinibercept every four-week injection or 2 mg sozinibercept every eight-week injection, so we're going to get two answers in these trials. We're going to get the answer of the statistical superiority of the combination over monotherapy, and we are going to get the answer of ease injecting every four weeks similar to injecting every eight weeks.
The primary endpoint is at week 52, as I already mentioned, so we're going to get the data for COAST early second quarter of next year and the data for ShORe in the middle of next year. The patients will continue on whatever regimen they had in the first year for a second year, and this data is collected for safety purposes for the BLA filing. So the milestones, the big ones are clearly the readout next year now that the trials are fully enrolled. We are in the process of finishing our manufacturing scale-up. As you know, for a BLA filing, we need to demonstrate three PPQ batches that basically demonstrate our process is good enough to manufacture at commercial scale for the BLA filing. We are preparing, obviously, the dossier for the FDA.
We have a fast-track designation from the FDA, so the review could be a bit faster than usual. And we're also, obviously, building the team to be in a position where we can prepare for the launch when the time comes. Finally, we had a recent financing in June and July of this year. We currently have pro forma as of end of June, over $200 million of cash, which allows us to get to the two top-line readout of our phase III programs. And as you know, we have a partnership with Carlyle Abingworth, who funded our clinical development. So as a recap, we are addressing a very large patient population with a round market estimate in wet AMD at around $10 billion a year worldwide.
We would be the first drug to ever demonstrate superiority to anti-VEGF-A treatment, which has not been done in the last 20 years. We are developing the drug in a way that could make it indicated in combination with any anti-VEGF-A on the market. And this is a very elegant business model where we're very concentrated in a few retina clinics or retina networks in the United States, which allows a small biotech to actually execute a commercial launch in the U.S. So this is the Opthea story, and I thank you very much for your time.
If I could ask a couple more questions. If the clinical data are positive, I know you said that this drug won't be competing against the biologics, but what's your confidence that this would support your baseline therapy with some of the newer therapies alongside your product?
Yeah, no, it's a very good question. So the new therapies, whether it's faricimab or high-dose aflibercept, have not demonstrated superiority in terms of vision outcomes compared to Lucentis, which was launched, as you know, 20 years ago. So we don't think our drug would necessarily be used differently with these molecules. In real life, we know they extend their injection intervals probably by a week to 10 days compared to Eylea or Lucentis, which were in the U.S. injected around every seven weeks. So these drugs certainly last a little bit longer, but maybe not as long as their clinical trials tend to indicate. And therefore, we don't think it would make a difference for us whether these drugs are used as a baseline therapy or biosimilars of ranibizumab, bevacizumab, or aflibercept are used as baseline therapy.
Can you remind us the dialogue you've had with the FDA and what supports your confidence that your goalposts are aligned with the FDA given some of the recent leadership changes as well?
Yeah, so our protocol is very classical in some ways. We are looking at mean change of BCVA from baseline, which is a very well-documented and approved endpoint. We are not looking at any sort of exotic design by not using the comparator as per label. We are using all the drugs as per label and adding sozinibercept on top. So it's actually pretty straightforward as a design, I would say, and now, obviously, nobody has been successfully running superiority trials in phase III. We would be the first drug to be demonstrated that superiority trial. So there is no superiority threshold defined by the FDA, as opposed to non-inferiority thresholds which are well-defined for all the other drugs which are being developed as non-inferior to each other.
Now, the FDA will certainly look at the p-value we would generate on the difference between the control arm and the combination arm, and the rest of the data. They will look at how well do we correct the anatomy, the proportion of patients gaining three lines, the proportion of patients losing three lines of vision. All these other parameters enter into account when the FDA would review our data. But as I said, the design is pretty classic.
Maybe one more question. Just on those parameters that you touched on, what are the goalposts in your mind based on looking at the primary analysis, but also the all-comer population?
Yeah, so as you know, there is no correlation between anatomy and vision. There is not a single anatomical endpoint that correlates to better vision. So it's very much about looking at the totality of the data. Otherwise, most trials would have moved from measuring vision to measuring anatomy, and that's never been approved by the FDA because that correlation does not exist. We actually do not have a goalpost on anatomy. We'd like to see some sort of correction of further correction of anatomical endpoints such as lesion area, area of CNV, potentially CST drying a bit more. But we know it doesn't really matter for patients. What matters for patients is vision. And all around the world, payers are not paying on anatomical correction. They are paying on vision improvement. So insurance companies actually want to see better vision.
Should I sneak in one more question since you touched on pricing and what payers want to see? How are you thinking about potential pricing and then reimbursement for this type of product?
Right, so if we demonstrate superiority in vision improvement, that's what payers pay for around the world in the U.S. and outside of the U.S. So we would be having discussion with all these different payers based on the data we see in phase III. But so far, payers are actually even paying for drugs that do not improve vision currently in retina, but they certainly always paid for drugs that were improving vision in retina. So we're not really worried about reimbursement.
I think that gets to the end of our time. Fred, thank you again for the informative presentation, and looking forward to an exciting year ahead.