Thank you for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the Senior Biotech Analyst here, and, please join me and welcome, Ms. Megan Baldwin, MD, and, Founder, Chief Innovation Officer, from Opthea for this fireside chat session. Welcome, Megan. Maybe, to start off, before we get into specific pipeline questions, could you give us a brief overview of the company and, and why, you developed the company developed the drug OPT-302 in the wet AMD space? What are the unmet needs there?
Yeah. Good afternoon, everyone. It's a pleasure to be here. Thank you, Kelly, and thanks everyone for coming. A s Kelly said, we are an Australian and a U.S.-based company now. We're both listed on the ASX as well as on the NASDAQ, so a dual-listed company. W e're developing sozinibercept, which is formerly known as OPT-302. Y ou'll hear me referring it a lot to OPT-302 today. OPT-302 is a trap molecule, essentially, that we have in development for the treatment of wet age-related macular degeneration. A s a trap molecule, it's actually a very potent inhibitor of two novel members of the VEGF family, which are VEGF-C and D. Everyone in the room would be very much aware of the standard of care treatments in the retina space, particularly for wet AMD, which selectively target VEGF-A.
We are very much differentiated from the standard of care because we hit another part of the pathway. Our objective with OPT-302 is to use the drug as a combination therapy. W e are, at this point in time, a separate injection into the eye that's administered and almost immediately following, the administration of a VEGF-A inhibitor. A drug like Lucentis, Eylea, more recently, Vabysmo, for example. Our objective is to then have a second injection where VEGF-C and D can be inhibited together with VEGF-A. W hat that can achieve is then a broader blockade of the VEGF pathway, which we have shown in a phase II study, which I'll talk about in a moment in more detail, has visual acuity benefits.
Patients actually stand to have a much better visual acuity response, and which really speaks to the real point of difference for us. We want to improve outcomes, improve vision in patients, and actually address the number one unmet medical need for patients in retinal eye disease.
Okay, and you mentioned about targeting VEGF-C and VEGF-D will bring additional benefit, and you have observed the evidence from your phase II trials. Y ou have shown subgroup analysis to actually delineate the efficacy benefit. W hat do you think, which subgroup actually benefited the most from OPT-302, or it's actually more broadly benefit?
Yeah. Maybe if I can click through to a couple of slides here. Just to start really with our phase II-B clinical trial, it was a very large study, one of the largest phase II-B studies that's been conducted in wet AMD. We went very broad in terms of the patient population that we recruited into this study and recruited essentially patients with all types or subtypes of wet AMD into the study. Across that total patient population, what you can see on the screen here is that we saw a significantly superior gain in visual acuity when OPT-302 treatment was added on to Lucentis or ranibizumab treatment, compared to those patients that received ranibizumab or Lucentis on its own.
The overall benefit relative to the control group here of Lucentis on its own was a 3.4-letter superior gain in vision over and above standard of care, and this was highly statistically significant at 0.0107. J ust to put this data into context, we're the only company currently in clinical development that has demonstrated superiority in clinical benefit over and above an anti-VEGF treatment like, like Lucentis. What we also did in evaluating the outcomes from our phase II-B clinical trial was to dive into the data in a lot more detail. I n doing that, in a pre-specified analysis, we looked at the efficacy of our treatment in wet AMD lesion subtypes. There are three main types of wet AMD lesion subtypes: minimally classic, occult, and predominantly classic lesions.
The majority of patients actually have minimally classic or occult lesions, and this is really just a type of lesion that's really defined on the vascular patterning that you see within the lesion itself. T he most common forms of wet AMD have minimally classic and occult lesions, and this represented about 80% of the patients recruited into our phase II-B clinical trial. I t's these patients actually, that tend to do a little bit less well on standard of care treatment. W hen we looked at how well OPT-302 was increasing efficacy in these patients, these were the patients that were the highest responders. T his is 80% of the patient population, and we saw a 5.7 letter additional gain in visual acuity compared to the control group.
This is an over a line gain of visual acuity benefit over and above the standard of care treatment. As you can see there with the p-value, highly statistically significant, and it was a pre-specified analysis. This really does show us that perhaps when anti-VEGF-A treatment is not having an optimal benefit, that that's perhaps where these other parts of the pathways can be targeted and produce the best clinical response in our patients. This will be the primary analysis population in our phase III. As the primary analysis population, as the highest responding population, essentially, gives us the best opportunity to optimize for the outcomes in our phase III clinical trial. We believe that that will stand us in good stead for maximizing the probability of success in the outcomes of the phase III.
At the moment, and also across the different regions, different study sites, is minimally classic and how enduring categorization is very well recognized by physicians ?
Yeah, it is a very well-recognized, I guess, classification of lesions. Prior to the approval of anti-VEGF treatments, actually, the typing or the classification, which is typically done by fluorescein angiography in this case, was very, very common. Anti-VEGF treatments have, of course, shown efficacy across all lesion types, but it is a very standard classification system. One point I will make, however, is that, while we're using this as a tool to classify patients for our phase III clinical trial, we would fully anticipate having a broad label once the drug's approved, and not actually necessarily specifying what type of patient would receive our therapy. T his is really a tool for our phase III analysis, and really to understand what AMD subtype responses.
In terms of the classifications, it is all done at the reading center. W e are seeing the proportion of patients that have these type of lesions track very similarly to what we saw in our phase II, which bodes very well. L ike I said, we're recruiting across all comers.
Can you also share the trial design details for the patients in the COAST and the ShORe study? Are they identical, or are they different too?
Yeah. T his is the overall trial design for our ShORe and COAST phase III pivotal registrational trials. The overall design of the two trials is essentially the same, but just has a different standard of care treatment in each of the studies. T hat was very intentional for us to want to do one study in combination with ranibizumab or Lucentis, which is the ShORe study, and intentional to do our second study in combination with aflibercept or Eylea, which is the COAST study. Why did we do that? We really wanted to position this drug, OPT-302, as being able to add on to any anti-VEGF treatment. When we first started our phase III clinical trial, these were the two approved therapies, and we knew at that time that there'd be new anti-VEGF treatments coming through the pipeline.
We've since seen the Beovu, we've seen the Vabysmo, and we believe that this design of doing one trial with one drug, one trial with the other drug, positions us well for a broad label that will enable us to add on to any anti-VEGF treatment in the long run. W hat is the design of the study? Each of the studies is designed to investigate the additional visual acuity benefit in patients when we add OPT-302 on top of standard of care treatment. T here is a control arm in each of the studies. In the ShORe study, we look at the control arm being Lucentis dosed according to label, which is every four weeks, with a sham injection. In the COAST study, the control arm is aflibercept or Eylea, dosed on an every eight-week dosing cycle after three initial loading doses.
There are two combination arms in each of the trials. One arm tests OPT-302 dosed every four weeks in combination with the standard of care. The other arm tests every 8-week dosing of OPT-302 together with the standard of care treatment. We compare to see if we can see a superiority in visual acuity benefit when we add the combination. T he primary endpoint of these trials is after all of the patients that have been enrolled in the study complete 12 months of dosing, whether that's on the every 4-week cycle or the every 8-week cycle. The primary endpoint is the mean change in best-corrected visual acuity at that 12-month time point. Patients do stay on study for a further 12-month safety follow-up, but that can be supplementally filed to the marketing authorization or the BLA.
R eally, the company is very much focused on top-line data readout. We expect to read out the top-line data in the first half of calendar year 2025. I think there's a lot of very good features about our phase III program. Most notably, it's to position us to be agnostic with respect to what patient treatment standard of care treatment they are receiving. A lso to give us information around efficacy on an every 4-week dosing cycle, but then on a more durable every 8-week dosing cycle as well. I think it's a very powerful study. The way that we're gonna analyze the outcomes from this study is to look at those high-responding subtypes first. Gives us the best opportunity of showing the most compelling visual acuity gain.
Then in a hierarchical fashion, we'll step down and ask: How well does our drug work across the total patient population that we have enrolled into the clinical trial? W e'll get a lot of information from the phase III program.
Okay. Are these two trials running at the same pace, so they're gonna be read out?
Look, we ideally, we'll read out both of the trials at the same point. At the moment, the COAST trial is running slightly ahead, but not really a lot between both of them. They're both recruiting very well at the moment. We've got over 200 clinical trial sites open and active around the world, across 30 countries worldwide. We do expect that COAST will likely complete patient recruitment in the first quarter, calendar year 2024. N ext, only in a couple of months' time, actually. T he ShORe study is not far behind that. T here's not really materially a lot of difference. I think that any difference that we're seeing is probably just due to some geographical and site-by-site variation in how quickly the sites can recruit.
Okay. I was just asking, is that the after your BLA, so if those trials works, then the combination with a similar drug, which will be also automatically approved, or you, you do some additional filings for this trial?
Yeah. W hen we were designing the study, and we submitted the protocol to the FDA as well as the EMA for review, we were very clear in describing our rationale for doing one trial with Lucentis and one trial with Eylea, and we explained that this is to position the drug to be able to be combined with any anti-VEGF treatment. We have a very pointed and very specific discussion on that very matter. T hat's why we ended up doing the designs that you see here today.
Now, to the extent that the FDA can comment and endorse your program, we certainly got very positive endorsement around our approach for this, and a positive feedback around that this would be the phase III program that would support a broad label, whereby OPT-302 is indicated for the treatment of neovascular AMD in combination with any anti-VEGF treatment. Of course, when you have data in hand and you submit your BLA, obviously the FDA reserves the right to evaluate it as it sees fit. W e have done everything that we can to get endorsement of this clinical trial, and we're very positive around the prospect of a very broad label for the outcomes.
Great. The data rather than anything that around you and this one have not had seen. What do you think about the bar for commercial success potential?
Yeah, yeah. Again, I think it's great that we're seeing new therapies enter into the landscape. It's great for patients to see more durable therapies coming through. I think the Vabysmo data and the high-dose Eylea data is very interesting. I think what we need to understand in terms of the movement in the landscape, however, is that all of those drugs that have been approved are really the same class of molecule. They are all anti-VEGF treatments, and they may have a durability benefit, but they actually haven't demonstrated an efficacy benefit over and above the drugs like Lucentis and Eylea that we've had for many, many years. T here really hasn't been a lot of innovation in the wet AMD space. We haven't seen a new therapy approved that's targeting a novel mechanism of action.
That's where we sit with our VEGF-C/D approach. A s Vabysmo and Beovu have come through, and potentially other drugs like biosimilars, as you said, Kelly, we would see that we would be able to be used on, in combination with those treatments, and that the treatment frequency would be optimized according to a treat and extend dosing regimen, which is exactly what goes on with the treat and extend regimen for standard of care treatment. W e fit into that moving landscape of more durable agents very, very well.
Of course, you know, if we look at the efficacy that we're seeing in some of those non-inferiority trials with the new therapies that are coming through, you know, as you extend out the durability or the interval between dosing, it does somewhat compromise on the efficacy. There's a little bit of a less efficacious kind of treatment because you're extending it out. As an example, the Vabysmo trials read out about a 6-letter gain in visual acuity from baseline to their endpoint. We're seeing about 16 letters from baseline to our 6-month endpoint in our phase II-B, and a delta of almost 6 letters. O ur data is stacking up very, very well to show that we can have a meaningful and very compelling visual acuity benefit on top of standard of care.
That if you look at it comparatively across all of the trials here, you can see that our efficacy in this 80% subtype group far outstrips and is very, very compelling compared to not only the results in the control arm of our trial, but also stacked against all of the other phase III registrational results that we've seen with Lucentis in the gray, Eylea in the blue, Beovu, and also some of the new data coming through from Vabysmo. C ombination therapy targeting a new mechanism of action can actually bring us up into visual acuity benefits that we just have not seen before for patients.
Great. Can you also walk us through the logistic perspective of how the second injection of OPT-302 is performed in clinical practice? What is the typical wait time after the first injection, and does this actually add more work to physicians? I f the second injection is associated with any risks of intraocular pressure increase?
Yeah. A few components to that question. O ur drug is administered as a sequential injection. P atients come in, they have their eye prepped for their first standard of care treatment. Could be Avastin, could be Lucentis, Eylea, could be Vabysmo nowadays. V ery soon after, they can be administered OPT-302 in the same clinical visit. In the context of our clinical trial, we record intraocular pressure. 50 μL injection, the standard of care treatment, is very well tolerated. In fact, intraocular pressure returns to normal almost immediately in the vast, absolute majority of patients. T hen the physician can administer our therapy almost immediately after. When we track the time between the standard of care treatment and the administration of OPT-302, what we found is that actually the physician is going from one patient to another.
They may be seeing five or six different wet AMD patients. They'll give them the first injection. By the time they come around again in the clinic, the patient's obviously ready for their second injection. T he actual time that lapses between the two injections is not dependent or triggered by intraocular increases in pressure. It's actually dictated by the availability of the physician, more so than anything. In the real world, after approval of the drug, we would fully anticipate that in many physicians' hands, our drug will be administered almost immediately. Because a 50 μL injection followed by another 50 μL injection, we would expect to be very well tolerated. That's what we're seeing in our phase III. The safety profile here is very well tolerated, almost, I mean, it's comparable to standard of care monotherapy.
There are several drugs that have been approved that have a much larger dosing volume, and they're very well tolerated. If we look at the GA drugs, for example, 100 μL in a single injection. The Kodiak molecule was 100 μL. There's a lot of examples out there where a much larger injection volume is also well-tolerated, and remember, we're at 50 μL on top of a 50 μL standard of care. W e don't anticipate issues with the volume.
Super helpful. Could you also help us understand how you make most of the second injection once in the U.S.?
Yeah. A t the moment, if you have a second injection into the same eye, there isn't a reimbursement for that second injection. However, if you have bilateral eye disease, so you have wet AMD in both eyes, the reimbursement on the injection fee for the second eye is at about 50% of the total injection fee. I think over time, as we start to see the ophthalmology space evolve into a landscape where combination treatment becomes much more common, we're seeing that with the GA drugs now approved, with new mechanisms of action like OPT-302. I think there's very much room for negotiation around getting coverage for that second injection. T hat's certainly work that we'll be interested in doing as we move forward. I would say that will likely change over time for some reimbursement on the second injection.
Do you have time to develop a co-formulation on this combination, and how does it work?
Yeah, absolutely. O bviously, at the moment, our drug is formulated as its own drug in its own vial, and there's a lot of advantages to that because we can tap into the entire market, and we're kind of agnostic with respect to whatever the physician may choose in terms of standard of care treatment, enables us to tap into the entire market. Longer term, as a lifecycle management approach, we would be very interested in developing a co-formulation where there's a standard of care anti-VEGF treatment in the one vial, and then we put OPT-302 into that vial as well, and then we can inject in a single injection and achieve the broad blockade of our therapy. As a company, that is a priority.
We see it as a follow-on program to our sequential injection approach that I've talked about mainly today. You can imagine if you have both drugs available in a single injection, all of a sudden, that's a market-leading product, differentiated on the basis of improved efficacy. You would imagine that would be the preferred choice for physicians. They know to select that drug, administer it, and know that they're going to give the best chance for the benefit of the patient in improving their vision. I think that could be potentially a complete market disruptor and a complete game changer for the field. As I think the sequential injection as well enables us to tap in and give patients the best opportunity for the most compelling and improved visual acuity gains.
Can you also share with me the capitalization and if you need additional capital to finish it?
Yeah. W e run on the fiscal year in terms of our financial reporting. A t our June 30 financial position, we had $89 million cash in bank. Almost immediately after we put that number out, we did a financing in September, which was a $57 million financing. We also have a structured financing deal in place with Abingworth and Carlyle, where we expect a $35 million tranche to come in before the end of this calendar year. T hen there's a further potential for an additional $50 million tranche to come in under the same Abingworth and Carlyle agreement as well.
Factoring those tranches and the financing that we've done since our last reporting, we have a cash runway through to August of next year. W e don't quite get to the top-line data, and obviously, we'll be looking at financings or other ways of funding the company that may be less dilutive in the long run, but we get through to about August of next year.
Terrific. Then one last question. Are you planning to find a commercial partner for this big market? If so, who is the best fit, given that you have Lucentis and Eylea combination?
Yeah, I think, I think we are in an enviable position that there are a number of really good fits for us in terms of our program. I think as any biotech company will tell you, you need to be in a position to be able to take the molecule forward yourself. We've done a lot of work in understanding what that commercial organization looks like in the United States. I think it's fair to say that the, the ability to do that in Europe, where there's lots of different countries, is perhaps more challenging for a small company, and I think partnership, therefore, makes a lot of sense. A longside, you know, being ready to do it ourselves, we would also be exploring partnership opportunities. W e're very interested in, in doing that. T he third part of your question was?
Who would be the best fit?
Oh, then who is the best partner? Sorry. Look, I think that there's multiple. I think that, you know, a number of companies have really promising drugs. You know, there's, there's the Vabysmo drug, which would be well suited for combination. There's the Eylea, standard or high dose, that would be well, well suited for combination. There's all of the biosimilars that are really battling it out for market share in a competitive anti-VEGF space. Not necessarily a competitive wet AMD space, a competitive anti-VEGF space. Opportunity for us to combine with a biosimilar. T hen there's a lot of companies, I think, also that are looking to get into ophthalmology and bring in new novel assets, particularly ones that show benefit for patients. M ultiple partnership opportunities for us with larger pharmaceutical companies.
Terrific. Thanks again, Megan, for joining us and for a very insightful discussion.
Thank you, everyone.
Thanks, everyone for-