Great. Welcome, everyone. My name's Jess Fye. I'm a biotech analyst at J.P. Morgan, and we are continuing the 43rd Annual Healthcare Conference today with BioCryst. First, you're going to hear a presentation from the company, and then we're going to open it up for Q&A. If you're in the room and you want to ask a question, raise your hand and we'll bring you a mic, or you can submit questions to the portal. And yeah, with that, let me turn it over to the company's President and CEO, Jon Stonehouse, to present.
All right. Good afternoon. Thank you, Jess Fye, for that introduction, and thank you for inviting us to your healthcare conference this year. It's nice to be in sunny and warmer San Francisco this year, so thank you for the weather. With me today is Charlie Gayer, our Chief Commercial Officer, Helen Thackray, our Head of R&D, and Anthony Doyle, our Chief Financial Officer. We are all going to be making some forward-looking statements, and they have risks, and they can be found in our filings under the risk factors section. So we're coming off a fantastic year in 2024, and that has put us in a very different position as a company. And what it's led to is we are now building a company that has durable, profitable growth and a pipeline that gives investors optionality. And so let me explain that a little bit further.
So with the growth, we have a growing marketed product with ORLADEYO. We put up a number of $437 million last year in the fourth year since approval, and we have guided to over $500 million this year. So we are on a path growing at a steady rate towards $1 billion at peak. In addition, last year at this conference, we announced that we were accelerating profitability, and that would provide us financial independence. Well, what we found in the course of the year is not only were we accelerating it, but we were doing it at a pace and at a magnitude that really made a difference. And Anthony Doyle will talk to us a little bit more about that. And then lastly, we were in very early stages with our pipeline.
We are now moving into the clinic with our KLK5 inhibitor BCX17725 for Netherton syndrome, and we are about to move into the clinic and patients with avoralstat and DME, and we're really excited about that as well. And so we can do all of that, make those investments, and at the same time accelerate our profitability and continue this durable, profitable growth. So with that, I'm going to go a little bit deeper with each of my colleagues, and I'm going to start with Charlie Gayer. And I'm going to, Charlie Gayer, have you explain to the group that we had this fantastic year in 2024 and what drove it.
Yeah, Jon Stonehouse, in 2024, we had 34% year-over-year revenue growth. To put that in context, as Jon Stonehouse said, that's in the fourth year. In the third year in 2023, it was 30% year-over-year. Really good progress in the fourth year. It was driven really by two things. The first is very strong patient demand and, in fact, increasing demand. Our U.S. new patient prescriptions were actually up 6% over 2023, and we had the exact number of new prescriptions in 2024 as in the first year of the launch in 2021. The other thing is that ex-U.S., our patient growth, was about 40%, and in the U.S., our patient growth was about 20%. Really strong. The other key piece of 2024 was in the U.S., we captured more of the potential paid prescriptions ahead of our expectations.
And so number one, we did really well in the first quarter during reauthorizations, getting patients reauthorized quickly. So we used less free product, and we also converted more patients from long-term free product to paid product. So you put both of those things together, and that led to the 34% growth.
Okay. Thank you. And then this year starts the first year of new competition coming into the marketplace. And can you describe to us how you see that market evolving both this year and in years to come?
Yeah, absolutely. So if you could go on to the next slide. Oops, sorry. Go back two slides. So real quick, we've generated a lot of real-world evidence. And so this is the first part heading into 2025. Physicians and patients are seeing that ORLADEYO is not just convenient, but highly effective. You can see from this Type 1 and Type 2 patients are getting down to a median attack rate of just 0.2 per month. That is very good efficacy. So they're getting efficacy and convenience. Next slide. We're also seeing this in patients with C1 normal inhibitor. This is a patient population that struggled for effective therapy in the past, and they're getting it with ORLADEYO. So on that base of really great efficacy, we expect continued patient growth.
And the other piece, if you could go on to the next slide, we have some new competition launching this year. So it's an exciting year for HAE patients. For us, that creates the opportunity. These new drugs are going to be talking about switching, and that creates more of an opportunity in 2025 for patients to try ORLADEYO before even trying another product. Longer term, every year we do a very comprehensive market research exercise where we do a conjoint analysis with 100 patients, 175 doctors, and over 50 payers. And then we run their results through a market simulation model to predict what's going to happen in the future. In this survey, we show every potential future product. We give them the best case, efficacy, timing of launch. And then this survey helps us figure out what's going to happen.
If you go on to the next slide, what it gives us is a prediction of market share. We've done this analysis four times launch to date, and it's been very predictive of our market share growth up to this point. What you can see is in a growing market over the next 10 years, today there are about 7,200 prophy patients in the U.S. We see that growing to 9,300. ORLADEYO is going to grow to about 25% market share and then hold that in a growing market even as new products are coming onto the market. This is the growth that's going to get us to $800 million in the United States and $1 billion in global revenue by 2029.
Okay. So now we're going to switch gears and we're going to move to the pipeline. And Helen Thackray, it's exciting to see real progress in the programs in 2024, but tell us a little bit about what you're most excited about in 2025?
So in 2025, we have three programs with high-impact milestones. That's what I'm excited about. So we'll go through all three. First, ORLADEYO, which you just heard about from Charlie Gayer, will be moving into pediatrics with an NDA for pediatrics. So this solves the parents' dilemma. For children under 12, there's no oral prophylaxis available to treat and prevent these HAE attacks. There's just injectable prophylaxis, which means they either have to inject their child at home several times a month or let their child be vulnerable to the potential of ongoing attacks. And we aim to change this with pediatric granules. Submitting NDA this year, this is easy oral formulations to sprinkle on food or drink, and that allows prophylaxis. So milestone one, NDA for pediatrics. Milestone two in Netherton syndrome, BCX17725 is our first protein therapeutic, and it's in the clinic.
That's a big milestone for the company. It's also a huge step forward to understanding this disease better and perhaps bringing a disease-modifying treatment. What you see here is an image on the right. This is a toddler with Netherton syndrome. I think every parent in the room can understand just how miserable that child is. That is how that child experiences Netherton syndrome, and that's what it's like throughout life. This toddler has scaling skin. You see large pieces of scaling skin. The skin is red. It's thick. It's itchy. He's really unhappy. His hair is thin and brittle, and you can't distinguish any eyebrows or eyelashes. Patients with Netherton syndrome have this condition, even when treated with the best sort of care, using ointments and creams multiple times a day. We aim to change that.
There's no targeted treatment, and we are delivering BCX17725 now to patients in clinical trials this year. And it's intended to be a functional cure, delivering a protein where one is missing. So the milestones, patient data this year, and including activity in the skin and some early clinical outcomes. Milestone three of avoralstat. This is our potent plasma kallikrein inhibitor that we're advancing for the treatment of diabetic macular edema. Patients with DME experience loss of visual acuity, and that leads to loss of independence. VEGF inhibitors are the standard treatment. They're injected intravitreally into the eye every month, so up to 12 times a year. The two unsolved issues there, one is that 40% of patients don't improve on VEGF inhibitors, and an alternative is needed. And two, the frequency of injections with VEGF inhibitors. avoralstat, we believe could give a significant step towards both of those.
Next slide. We have new data that we're sharing this week. This is preclinical data, but this is indicative of what we think we'll see in the clinic. This is an animal model. On the left is before dosing, and on the right, after dosing. This is a model that's well-established to test VEGF inhibitors that are in the clinic and on the market. On the left, you see retinal vessels, but you also see that white haze that's leaking the fluid into the edema. That is edema in the retina. On the right, six days later, after a single dose suprachoroidal of avoralstat, we see clearance of that leakage. That is what we're going to be looking for in the clinic, so milestone three, new data, going to patients this year and new data coming into the year early next year for avoralstat.
Thank you. Last but not least, Anthony Doyle. And so I mentioned that we'd made some commitments last year. Maybe talk about how we did last year and then we made commitments for this year and next year, and how do you see that falling?
In short, we are ahead of plan. We are at a point where we have additional confidence in achieving what we set out to do in terms of profitability. And to your earlier point, Jon Stonehouse, not just profitability as a goal and not just to eke out a profit, but to make substantial profits to the point where we can talk about from a capital allocation how we can meaningfully move that forward to generate a substantial amount of value for the company. So Charlie Gayer talked about percentages. I'll use absolute numbers to kind of set the table for it. In 2023, we had an operating loss, not including stock-based comp, of around $50 million. In 2024, that number turned into an operating profit of around $60 million.
And with the guidance that we just gave of revenue for 2025 at about $540-$560 million and OpEx of around $425-$435 million, that number goes up yet again. And not only did we give guidance for 2025, we gave guidance through 2027 in terms of the CAGRs that we expect for both revenue and operating expense. So through 2027, on a three-year basis, we're looking at a CAGR on revenue of around 20%. And on the operating expense side, a CAGR of around 5%. What does that mean when you look at 2027, for example? You're talking about a revenue that's north of $750 million and operating expense that's in and around $450 million, and thus an operating profit, not including stock-based comp, around $300 million. For a company like ours, that is a phenomenal number.
That is indicative of, again, not just getting to profitability, but it being meaningful in terms of what it allows us to do.
I talked at the beginning about how it's just put us, the company, in a completely different position than we've been in historically. Can you talk a little bit about this financial strength and then what flexibility it provides us in terms of capital allocation?
Sure. So take that same example of 2027. At that point where we're generating those types of margins, we're also generating EPS positivity, cash flow positivity at that point. Those numbers play out, and we'd be sitting on a cash on hand of north of $600 million. The following year, we have some debt that would come due. It gives us tremendous optionality as to how we handle that. Do we pay it down? Do we pay it down in advance? We don't need to necessarily wait. Do we start to utilize it for BD-related activities such that we can get a second product in-house with commercialization, either similar timeline or ahead of the timelines that Helen Thackray talked about for both BCX17725 and avoralstat?
At the same time, we could look at reducing the cost of capital that we have, and all while advancing this tremendously exciting pipeline that we have, both in the kind of three assets that Helen Thackray talked about and then the earlier phase pipeline that we shared this time last year, so optionality and confidence in terms of how we invest and what we invest in.
All right. So reminder of what we just covered. So growing product, $500 million plus this year on its way to $1 billion with IP, composition of matter that goes up to 2039. So that is durable growth. Profitability and not just a little bit of profit, but a lot of profit in just a couple of years. And then third, the option on the pipeline where we're going to be able to advance it and understand if we've got another product. And you're going to start to see some of that data towards the tail end of this year. So I said we're in a different position. We are now playing offense instead of defense at BioCryst, and we're really looking forward to sharing more of our updates over the course of this year. So Jess Fye, I guess we're ready for questions.
Great. We started out with ORLADEYO. So maybe we can talk about, in the context of the guidance you provided, what the key drivers are kind of underpinning that ORLADEYO growth.
Jess Fye, the number one key driver is just that continued patient demand that I described. The fact is that physicians in particular are really seeing this as a different kind of product than they did a few years ago, and that's led to the uptick in prescriptions that I talked about. We expect that to continue, and then the other piece is just continued improvement in the rate of paid patients. As I described, we made a big jump forward next year. We don't have as big a jump. We made so much progress last year. We don't have as big a jump. However, there's the situation with Medicare patients where affordability has been an issue in the past couple of years. With the full introduction of the IRA this year and the maximum $2,000 out of pocket, that could improve.
We haven't assumed it in our $515-$535 guidance, but if it does improve, that could push us into the upper end of guidance.
What's the right way to think about ORLADEYO's revenue mix? Geographically, U.S. versus ex-U.S. this year, and which are the international regions that are kind of driving additional growth?
I mentioned the ex-U.S. patient demand is going really well. Market access has also gone really well. So for example, Europe is the biggest driver right now. In Western Europe, we have now got market access and launched in every country except for the Netherlands. And we expect to get that at some point in 2025. So really good growth there. The same kind of dynamics of physicians seeing this product differently, so prescribing more. Things are also going great in Canada and Japan with our teams and with our partners in Eastern Europe, in the Middle East, and now with Latin America. Things are starting to pick up there as well. And so what we see is, and we would expect is, every year as we go forward, the percentage of ex-U.S.
Revenue will start to tick up to the point where at peak around the end of this decade, we'd expect it to be around 20% of the $1 billion.
Okay, so smaller base, but growing faster.
Growing faster and going really, really well. More and more, there's not just recognition of ORLADEYO, but recognition of modern prophylaxis as the growing standard of care.
Where does Persistence currently stand?
Persistence is really good and really stable. So we actually put out, presented a poster at the College of Allergy meeting in October where we looked at claims data of patients who were newly starting ORLADEYO, Takhzyro, or Haegarda. And what it showed is the one-year persistence was indistinguishable between all of them, but actually numerically, ORLADEYO was the highest with about 61% one-year retention. That's what we've long seen in our internal data. And once we have a patient to a year doing that well, the vast majority of them stay on because they're getting great attack control with just one pill once a day.
Has the mix of ORLADEYO patients coming from switches versus treatment-naive evolved over time, or do you expect it to change in 2025?
It really hasn't evolved. I'll tell you what, maybe we've started to talk about differently, so ever since launch, it's been roughly 50% patients switching from other prophylaxis, 30%-32% going to prophylaxis from acute only, so starting prophylaxis with ORLADEYO. The new thing we've started talking about is the remaining 17%-18% of the patients are naive to therapy. Back in 2021, we did not expect that segment to be as big. We thought that more of the patients were already found. What we're seeing is the market is growing, though, and starting prophylaxis with an oral makes a lot of sense. We get about 50% of those patients newly prescribed, and we see that as all three of those segments as durable. I would expect the same percentages this year and for the next few years.
What's the current proportion of patients on paid drug, and how could that evolve, and what can you do to impact that rate?
We ended 2024 about two percentage points better than the end of 2023. So it was about 73.5%. What I would point to is the commercial patients, who are about 60% of our patients, ended the year at about 80% of them paid. And that's up from about 70% just a year and a half before. So the things we're doing to make progress is overall, first, is getting a really complete prescription. So having the physician put in all the patient history, the lab tests, family history, everything else that has been done that the payers demand, we've gotten really a lot better at working with our customers to do that. That makes a difference. Number two, just all the evidence that I described. We get about a third of our patients are HAE with C1 normal inhibitor. Historically, those patients have not been reimbursed.
We get them reimbursed at a fairly comparable rate to classic type one and type two patients because we're providing more and more evidence. And then the last piece is the Medicare bit that I mentioned earlier.
So it sounds like you didn't dig into the guidance, but to the extent the IRA continued implementation this year is a tailwind in terms of kind of improving the proportion of paid Medicare patients, can you quantify that a little bit? How big could it be?
Sure. Yeah. Well, Medicare is about 20% of our patients. The Medicare plans themselves agree to pay for ORLADEYO at the highest rate of all of our segments, so it's over 80%. But at the end of last year, only about 55% were paid. And the difference, that 30% difference, is because patients couldn't afford their co-payments. If they're able to do more of that this year with the IRA, that reverting back to that 80%+ would be about a $30 million annual revenue at our current patient base. And of course, it would keep growing as our patient base grows. So it's a potentially significant tailwind that is not at all baked into this year.
It is baked in when we gave the CAGR from 2024 to 2027. We have included significant growth in that period because we think it might take us longer to do it. If we can accelerate, then it would most significantly be a positive impact to 2025, but we keep in line with that same growth through 2027.
Maybe the last one on commercial, but you mentioned competitive entrants. How are you thinking about the evolving competitive landscape in HAE prophylaxis, and what would you tell investors to watch out for this year?
I think the number one thing that we've learned, well, a couple of things that we've learned, is when patients are doing well on a therapy, it's a really sticky market. Once they've solved for their HAE, preventing of attacks, they don't look as much in the future. So you need something really significant, really differentiating to get the patient to think differently, to get their physician to think differently. We have that now as the only targeted oral therapy. Other new injectable therapies that are coming look like very good products, and they provide incremental benefits to patients with going to once-a-month dosing, for example, maybe every three months dosing. That could be great, but what our research tells us is it's not enough to move most of those patients once they're already well satisfied on a drug like ORLADEYO.
Yeah. I think one other thing is we had these abstract conversations with investors about, "Well, there's a competitor coming. It has this kind of reduction in attacks in phase II, and why wouldn't it take share from you?" And so what we've tried to do with the data that we've shown you with the market research methodology, and I don't know if any company's ever shown the results of their market research forecasts out 10 years, is instead of having this abstract conversation, this is what the data says that we've generated with the robustness of the methodology that we've used. So let's have a conversation around that. If you have that kind of robust data and you get a different outcome, well, let's talk about that. And what we're trying to do is remove bias from the conversation.
We all have our past experiences with new competitors coming to the marketplace, but if you spend some time with us trying to understand the market like we have, and you have, Jess Fye, and so you get it. I think investors will have a different view of the competition.
Question in the audience?
Yeah. So you talked about the one-year persistence rate.
You talked of the one-year persistence rate of 61%. Could that go up? And if it were to, would that inform your market share projection model in any way? I mean, is that meaningful, or is it just around the edge?
Certainly, if we can, then we're always trying to improve that. As I described, we're doing well relative to the competition. So we're happy with the stability that we've seen. But sure, if we could move up even 1% or 2%, that would make a difference to our long-term revenue. So we're constantly trying. What we find is the number one thing to do is to educate healthcare providers to set expectations for their patients. So a breakthrough attack can happen early in therapy. You could get a GI adverse event. The attacks will tend to stabilize over time. One does not make a pattern. The GI tends to go away. So if you react too quickly, you're not going to get the experience. So it's really about setting expectations, giving it a good three- to six-month try.
As we do that with more and more customers, it's conceivable that could get better. We're going to try to make it happen.
I think one other thing is we are about to start a trial phase IV study we call APEX-T, which is apex transition. And the whole goal of that study is to talk about what's a good switch look like. And I think with that data, we're going to start. Stress is a trigger in HAE. You have to have low C1 inhibitor level and then some sort of trigger, and stress is the number one trigger. And so if somebody's really worried about, "Oh my God, I'm controlled on my previous therapy. What if this doesn't work?" You start to have thoughts that can trigger stress, that could trigger an attack. We've actually had people overlap Takhzyro and ORLADEYO in a period and have a breakthrough attack. So that tells you what stress can do in terms of the swelling.
And so we think we're going to learn a lot from this, and we're going to be able, through this data, to help physicians have a better chance of a good transition switch.
Maybe switching to the pipeline, can you highlight the aspects of BCX17725's early profile that you think make it a good candidate to treat Netherton syndrome? And maybe talk about how the mechanism is different from other development efforts in Netherton.
Sure. BCX17725 just rolls off the tongue. So this is a fusion protein. It is very potent. It has a million-fold potency over the native ligand. It also has very high affinity, which is a physical characteristic of the molecule, which means that it sticks to the KLK5 molecule that it's seeking, and it doesn't come off. And that gives it a high potency potential for a small dose, subcutaneous dosing. It also gives it a chance to have a long dosing interval. So we think this drug could have subcutaneous dosing, dosing maybe every two weeks or longer. And what was the other question?
Oh.
Differentiating.
Yeah, differentiating.
Thank you. Right. Okay. So there are several things going on in Netherton syndrome. There's the kallikrein sort of KLK5 to KLK7 to KLK14 cascade, which affects the skin and sloughing of the skin. There's also a cytokine cascade downstream. We think it's important to target the top of the stream, KLK5, rather than one pathway or the other. So that way, with KLK5 inhibition, you get both the skin activity from the kallikrein cascade and the anti-inflammatory activity, which may affect itching and scaling, the thickness and redness of the skin, as well as atopic symptoms that come with the disease. So it's a matter of which target you pick, and we want to go for the top of the pathway.
Hey, Helen Thackray, it might be helpful too. I'm sorry, Jess Fye, to just dig a little bit more on what are we shooting for with this drug?
Yeah, and as I said earlier, this is intended to be a functional cure. What we mean is that it replaces the activity of the missing protein, so we expect to see then the result of the protein being replaced and control of what's happening in the skin. In Netherton syndrome, the skin is separated too early. We aim to change that, so the skin will be normal, healed and normal. It'll be as close to it as you can get with this disease. So we will be looking for this year activity in the skin. So does it get to the skin? Does it have activity on the target in the skin? And then towards the end of this year and next year, we're looking for, do you see the outcomes healing of the skin?
Yeah. So we're looking for a whopping treatment effect if we're going to restore normal skin turnover, and in rare disease, historically, if there's nothing to treat patients and you show that even in a small number of patients, the regulatory path can be much faster. So we're really excited about this program.
You mentioned maybe patient data around the end of this year. How should we think about the development timelines, kind of thinking towards the next step and the step after that?
It's too early to talk about development timelines, but following the comment that Jon Stonehouse just made, this is not a traditional program in an ultra-rare disease with what could be a disease-modifying treatment. We want to get experience in patients this year. That's critical. That will be part of how we define our development pathway. I do expect we'll need a pivotal program of some sort, probably a single trial, but whether it's the next trial after this or whether it's something further, we have yet to figure that out.
What about kind of the market opportunity for a product like this? What's the right way to think about that?
I think the potential that you should think about this as a classic ultra-rare disease where there are no therapies today in a really high-need patient population. So we've already identified about 1,600 patients in the United States who have this condition based on not ICD-10. There's not an ICD-10 code, but some of the unique characteristics of the disease, specifically the hair, bamboo hair that patients get. What we know from HAE, those who've been around HAE and were there 15 years ago, it was thought that maybe there were 2,000 or 3,000 patients in the U.S. Now we're talking about 10,000 patients or more. And so if that same kind of pattern happens, it could be not 1,600, it could be 3,000. It plausibly could be 5,000. And the need is so high here.
Ultra-rare disease, rare disease pricing, it's a large opportunity based in that incredibly high patient need.
Yeah. One of the things we've been talking a lot about and are going to do a lot of investigation as the program evolves is in a dermatology practice, there's a big population, a `big ichthyosis patients. Is there a subset of those patients that are actually Netherton syndrome patients, and can we have a genetic test to be able to identify those? That could really grow the overall population because these patients are great copers, right? I mean, if there's no therapy, they're like, "What can my physician do for me?" If there's a therapy, we may be able to find a lot more.
What about overall status in DME? Can you take us through the mechanism as it relates to the pathology of DME?
So the pathology is leakage of blood vessels leaking into the retina, causing edema and loss of visual acuity. What we know from what's happened with VEGF inhibitors is that that's part of the pathway. What we also know is that where VEGF inhibitors don't work, there's got to be something else going on. And so plasma kallikrein is part of the contact activation system. It's part of the downstream you get leakiness of vessels. And with the data that we're showing today, we feel pretty confident that this is demonstrating plasma kallikrein is an alternative mechanism of action, but also sort of contributing to the disease.
Hey, Helen Thackray, one slide I think I skipped over was the characteristics and properties of the drug that could affect dosing frequency.
Thank you. Jon Stonehouse, this is an important one. Again, a preclinical model, so not yet human data. However, what we know is that levels in the retina after a single dose of avoralstat given by suprachoroidal injection in the model, those levels are sustained out to 180 days. Six months of durability of exposure above the critical activity level for the target in the retina. That suggests that we may be able to dose this on an every three or six-month basis in humans. So suprachoroidal injections a few times a year compared to VEGF inhibitor injections, which could be up to 12 a year. So we think that's another aspect with this drug and the characteristics of avoralstat that could be really transformative.
Is it possible that it would be synergistic with VEGF?
I don't know. Short answer. It's possible, but we also know that plasma kallikrein is detectable in the vitreous and eyes in patients who don't have VEGF inhibition and in patients—I'm sorry, don't have VEGF detectable and in patients who do. So it may be overlapping. It may be synergistic. We just don't know, and we have to treat to find out. What's important for us in terms of the patients that we go after is that we now know that it is an independent mechanism with this data. And that means that we can enroll patients who are naive to prior therapy, have not had VEGF inhibitors as some of our first patients in the program. So when we go into patients this year, it will be in patients who have not had VEGF inhibitors as well as potentially those who have.
Hey, Jess, it might be good. Don Fong, our Chief Medical Officer, is in the audience, and to give him the mic just to quickly introduce himself because we brought a real DME expert into the company and just talk about what you see in this rabbit data, the animal data, and what it could mean for the program.
Thank you, Jon Stonehouse. It's an honor to join this company. I'm super excited with this asset. I've been in this diabetic retinopathy space now for 25 + years. Worked on ETDRS, DRCR. I started. Protocol A was mine, and what I see here is really not just an effect, but a VEGF-independent effect that is really very close to VEGF, and what Helen talked about, the durability of it, is a durability that we don't see in any other product, so I'm really excited about this product, and I've shared this with a number of KOLs, and they share equal enthusiasm for this.
And one of the things you were saying earlier today is this independence that it's a mechanism independent of the VEGF pathway and what that could mean in terms of what patients we go after and the potential here.
Yeah. There's a potential to treat all patients with DME, and it is a first-line therapy looking at the results you see in our clinical model.
Thank you.
How well does the rabbit data tend to translate?
This model has been tried with Avastin and Eylea, and the results look just the same.
It's preclinical data, but we were able to use the suprachoroidal device to inject our drug into it. You see after six days, you see the remarkable transformation of the leakage. It's got characteristics that look very similar to VEGF in this model.
Is this a product where you could go straight into patients? Do you have to inject any healthy volunteers?
Yes. So that's not an appetizing prospect. So, avoralstat, we actually have significant experience with this drug given systemically. Oral dosing was used. This was taken through a phase three program for HAE. It failed on efficacy for all the reasons that it's a great molecule to use this way. And we were able to demonstrate in a randomized trial systemic safety. So we have that background as we go into the clinic for DME. We don't know local tolerability in humans. And so our first step is to go into patients and then assess for local tolerability and then proceed from there.
Can we just spend a moment walking through the reasons when you said avoralstat didn't work back in HAE, but that actually those characteristics are positive in this setting?
Yeah, absolutely. So this was our first molecule of avoralstat with an A prior to berotralstat with a B for plasma kallikrein inhibition in HAE. It was not very poorly bioavailable, poorly soluble, and therefore poor exposure for systemic delivery. Here, we don't need systemic delivery. We are going to put this into the suprachoroidal space, directly into that space, which it's right around the retina. And as a poorly soluble molecule, it then slowly dissolves over months, which is why we get this long exposure. So we expected to deliver a suspension by injection to this space and let it dissolve over time, giving steady sort of depot-like exposure to the eye.
I think one other thing is this is pretty hot off the press data that we have, and Don Fong has been able to share it with about a dozen KOLs, and I think at the end of the day, we need human data. We need visual acuity improvement to really have a drug, but I think what's great about this is from what Don Fong hearing from these KOLs who are involved in all the trials that have been done in DME is that they're really excited about doing a study here in frontline treatment-naive patients with DME, and they're excited about this mechanism where in other trials, they were less excited about this, so I think it gives us a chance to get some real momentum around this product.