Good afternoon, everybody. I'm Eva Forte Verdejo. I'm a biotech analyst here at Wells, and for our next session, we have the BioCryst team, so we have Charlie Geyer, Gayer, Chief Commercial Officer. Good to see you again, and for those that are unfamiliar with the story, perhaps we can start with, like, a brief overview of the company, and then we can dive into questions.
Sure, and great to be here, Eva. Thanks for having us, and I will be making some forward-looking statements, and those statements have risks. You can find out about those risks at biocryst.com. BioCryst is a small but growing biotech company. We're based in Durham, North Carolina, and we are well in the commercial stage with our product for hereditary angioedema, ORLADEYO. And then we have a growing and very exciting pipeline coming out of our Discovery Center of Excellence in Birmingham, Alabama.
Awesome. So, I mean, lots of stuff going on. So perhaps we can start off with the commercial side of the story, with ORLADEYO in hereditary angioedema. So can you start by providing a brief overview on, you know, the ORLADEYO launch and, like, the commercial progress so far?
Sure. ORLADEYO. Well, let me start with HAE. HAE is, as I mentioned, it's a rare disease characterized by unpredictable swelling based on a genetic defect that patients have. Until about fifteen years ago, there were no targeted therapies. Starting fifteen years ago, three different injectable therapies came to market, and that really helped prevent attacks and change lives for patients. ORLADEYO launched about four years ago as the first oral therapy to prevent these HAE attacks, and so it's been a really differentiated therapy that offers something that patients really want, which is convenience. But also, over time, what's become clear about the product is that the efficacy, when it works for patients, is really excellent, and so what patients get is efficacy and convenience.
Our launch has been really successful up to this point. Very consistent growth in patients on therapy, and we expect to sell between $420 million and $435 million in the U.S. and globally in 2024.
So, you know, diving a little bit deeper into the launch and kind of what are the main drivers of growth in, you know, the near term, medium term, and long term, and what are your expectations here?
So the big drivers of growth, like I mentioned a second ago, is that, as an oral therapy, what we learned actually before launch is that the idea of treating their disease with one pill once a day was really powerful to patients. And so the driver of growth right now is that both patients and physicians are discovering that ORLADEYO can really control attacks. Patients have very few breakthrough attacks when it works for them, and that level of efficacy, now that they're becoming aware of that, is driving more confidence in the drug, and it's leading to a real consistent growth in our patient new patient prescribing.
So, for example, the last three quarters of new patient prescriptions have been as strong as the very first three quarters of the launch back in 2021, and I think this is a real reflection of physicians and patients gaining confidence and understanding how well ORLADEYO works.
Do you expect this growth to continue, you know, kind of like at the same rates?
Actually, we do a lot of work at BioCryst to as best we can predict the future. We do a lot of market research with physicians, with patients, to find out what are their expectations. Both physicians consistently predict that ORLADEYO is going to be their most prescribed drug over the next 12 months. Patients consistently, even if they're not on ORLADEYO, express a desire and a willingness to switch to oral therapy. We expect this demand to continue for the next several years.
So you mentioned market research and switching to the oral therapy. So where are you seeing the most switches coming from, and how are you thinking about duration of therapy, and how should we expect this to, you know, variables to evolve with time?
In addition to the market research, we really dig in and measure where patients are coming from. At launch to date, 52% of the patients on ORLADEYO have switched from one of those injectable prophylaxis therapies that I mentioned. Another 32% have switched from treating their disease with on-demand therapy only, and they're moving over to prophylaxis therapy. And then about 17-18% are patients who were naive to HAE therapy and are beginning treating their disease with ORLADEYO. And we see opportunity for all of those segments to continue. There's opportunity in all of those spaces. And then once patients are on, this is a lifelong condition, and so if ORLADEYO works for a patient, that patient is likely to stay on essentially indefinitely.
So how are you managing, you know, retention rates, and, like, what are you seeing so far, and how do you expect it to change over time as both patients and physicians become more comfortable with the drug?
The last two years, the last couple of years, our retention rate has really stabilized and been very consistent. For patients starting on ORLADEYO, 60%, about 60% of them make it to 12 months. And that's the people who make it to 12 months is because the drug is really working, it's controlling their attacks, and then they're very sticky after that. They, the vast majority of them stay on. And it's interesting, we've started doing some work in claims data, looking at other HAE therapies, and we're seeing about the same one year of retention for patients starting on those injectable therapies.
The disease has really evolved so that, you know, patients and physicians really want to find what's the right treatment for each individual patient, and clearly, a lot are discovering that ORLADEYO is the right drug for them.
Are you seeing a lot of heterogeneity or, like, any, you know, clear reasons why some patients respond better than others or, like, for longer than others?
We looked at that very closely, and I wish we had the crystal ball to predict that. In our clinical trials and in our real-world evidence, there's been no correlation to things like background attack rates, sex, age, prior therapies. The likelihood to respond to ORLADEYO is kind of the same, regardless of all those factors, and so really it's about trying the drug, and like I mentioned earlier, physicians are gaining more confidence in having their patients try it, and I think that's what's gonna drive the continued growth.
Have you seen... You mentioned a small portion of patients that are naive and, like, go straight to ORLADEYO. Are you seeing this proportion increase with time, or where do you expect you will be, you know, in the medium to longer term?
There are a couple of dynamics in the HAE marketplace that I think offer that continued opportunity. The first one is the growth of prophylaxis. When I first joined the company nine years ago, we did some of our first market research, and at the time, about 40%, 35%-40% of U.S. HAE patients were taking a preventative therapy like ORLADEYO. That has grown today to more like 75%, and physicians see that growing to 85% in the future. In addition, we've done a lot of epidemiological work looking at claims data, and we see that there are about 11,000 patients diagnosed with HAE in the U.S.
About eighty-five hundred are treated with an HAE therapy, so there's that delta of two or three thousand patients that could be moving over to a therapy like ORLADEYO in the future, and certainly that's what we've seen launched to date. So our expectation is the disease has, as doctors become more familiar with it, more patients will be treated, more patients will be put onto prophylaxis, and with the only oral therapy on the market, we're really well positioned to gain a lot of that share.
Mm-hmm. And you mentioned only oral in the market. What's the current split between, you know, IV, subcu, and orals, and how do you expect this to evolve with time?
As far as prophylaxis therapy, the majority of patients are still on subcutaneous therapy. Interestingly, the first product in the market, CINRYZE, is IV, and there's still 6%-8% of patients who are on that as a twice-a-week IV infusion. It just kind of shows how sticky these patients are when they find something that works. It takes a lot to move them off. They're probably around about 15%-17% of the patients are on ORLADEYO, and what we see long term is it's really gonna be a balance between subcu and oral therapies, like ORLADEYO. That's what the future holds.
In terms of, you mentioned the IV, which there are still a few patients there. Do you expect that the newer patient starts are gonna go straight into, like, subcu and oral versus, you know, the older IV therapy?
In fact, that's what we're seeing, and that is a place where we think we have a real advantage as we do our market research. When a patient is first starting on prophylaxis therapy, we get about 50% market share, starting with ORLADEYO, which is a natural thing, start with the oral therapy first.
Mm.
And so we're pleased about that, but then I'm also really pleased that we continue to get people switching from the injectable therapies over to oral so that they can benefit from a lower-burden therapy.
And in terms of market research and reimbursement dynamics for ORLADEYO, what percentage of patients are paid versus, you know, non-reimbursed or compassionate or free use?
At the end of the second quarter, 74.5% of patients were on paid therapy, and the remainder we put on long-term free product. Giving away free product has been a part of our strategy because we want patients and physicians to gain experience with the drug, and then what we do is we work with them over time to get them over to paid therapy. Our long-term goal, and what I see happening, is getting to 85% paid across our patient base. An example of why I think we can get there is that amongst commercially insured patients, who are 60% of the patients on ORLADEYO, we ended the second quarter with an 82% paid rate. That was up from 79% at the end of last year.
So we're making progress, and it's really about working with every individual patient and their healthcare provider to make sure all the proper information is provided to the insurance company so that the payer will agree to pay.
In terms of the pediatric population, can you provide updates on the pediatric study, and how are these patients currently managed? ... Kind of, what would you need to see to move forward in this patient population? Is it a more difficult population? How do you expect this to play out?
Oh, we're very excited about this opportunity because, you know, again, this is a genetic disease, and so kids can become symptomatic at, classically, it's around puberty, but what we've learned is that many kids actually become symptomatic earlier. And if there's one thing that I can guarantee is children, their parents, and their healthcare providers do not like giving kids injections. And so to have an oral therapy to prevent attacks is a huge opportunity. We're on pace to file our NDA to go for the age 2 to 11 indication in 2025. And we think that there's a lot of opportunity for patients in that marketplace.
So what are you hearing from KOL in the sense that is it like the earlier you start treating these patients, the better they're gonna respond, or like, are expectations a little bit different than with adults?
Yeah, it's a great question, and I think that this is something that's going to evolve. Until recently, there were no indicated therapies below age twelve for prophylaxis. And so I think what that caused healthcare providers to do is say, "Hey, let's watch and wait. Let's make sure the kids, we can treat them, minimize the risk, treat them with acute therapy if needed." But what we're hearing now from the experts is, "Hey, if we can treat these kids earlier, we can change the course of their life. And their parents, their grandparents may have grown up in a situation where they struggled with attacks for most of their lives. What if we can treat kids earlier, and they never really have to struggle with that?
It can change their whole perspective on living with HAE," and I think with an oral therapy as a possibility, I think ORLADEYO can really contribute to that.
How big is the pediatric opportunity here? Have you provided some numbers?
We have. We think that there are about 500 patients in the U.S. who are under age 12 and diagnosed with HAE. Not all of them will need prophylaxis. You know, maybe until they get a little bit older or maybe not at all, depending on their phenotype. But we expect to see an increasing number of those patients treated. Kind of like I mentioned, with patients moving from being treatment naive to first treating with a therapy, we expect to get kind of disproportionate share amongst those patients because we have an oral therapy once that's launched.
You said not all the patients might require prophylaxis. Who decides or, like, how is it decided which patient requires and which doesn't?
It's gonna be a decision between the healthcare provider and generally the parents. And it depends on when the kid becomes symptomatic. If they do, what's the frequency? What's the severity of their attacks? Again, historically, physicians would have waited longer to treat, but I think that's where there can be an evolution, which is as soon as a child starts having attacks, why wait for it to get worse? Why put the kid through that? Prevent them, you know, as soon as they start becoming symptomatic, and that can really change the course of how they grow up.
Makes sense. And in terms of, you know, the ramp, how should we be thinking about it, you know, upon potential approval? And do you believe you can reach a higher market penetration in this pediatric population versus the adult population?
Yeah, I do think that the ramp-up will be faster, again, because of the benefits of oral in the pediatric population that I mentioned earlier. I think also the fact that starting as a first therapy, it's just natural to start with an oral therapy. And then the other thing is that ORLADEYO is a much more known quantity right now, so there's that experience that I think will carry to how physicians think about the kids. The other thing about the pediatric indication that we're really excited about is that there may be a halo effect, too. So there's still some doctors who have not prescribed HAE, treaters who have not prescribed ORLADEYO. This may be a new way to introduce it to them because often it's the same physicians treating the kids as the adults.
Then it's genetic, so there's gonna be a family member, sometimes more, who may be treated with other therapies. This may be their first introduction to oral therapy with ORLADEYO. If they treat some of the younger children in their household, it may be a way for others to become introduced to the benefits of the product.
How big is the overall opportunity for ORLADEYO? We just discussed, like, the pediatric one, but, like, have you provided numbers? And also, do you think the market might grow, you know, due to the availability of this new oral therapy?
We've been talking for a couple of years about how we see ORLADEYO being a $1 billion-dollar product. When we launched back in late 2020, we said no less than $500 million. The uptake we've seen, the confidence of our customers, the forward-looking market research has given us confidence that it's more likely to be a $1 billion. The math to get there is actually pretty simple. If we in the United States average a net patient growth of 200 patients per year between 2024 and 2028, that's the first piece. We did well more than that last year, and we expect in the first few years to be above that number.
We get to the 85% paid rate that we talked about, and then a modest price increase of just a few percentage points gets us to $800 million in 2029 in the United States. The other $200 million we expect to come from our global market, Europe and beyond, where we're commercializing the product.
So perhaps moving on to the ex-US market, like, kind of like, can you just discuss, you know, how the launch is going there and kind of, you know, the approach that you've taken for this global commercialization?
The launches ex-US are going really well, just as it is in the US. There are a couple of differences. Number one, the prices ex-US are lower, so it takes more like five ex-US patients to add up to one US patient. So that's a big reason that the at peak, we expect it to be more like 20% of sales. The other big difference is that the market access process tends to be at a national level, and that can take, in some markets, it can take a year or more to get in. And so the pace of the launch will be spread out more over time. We built our own team in Europe, Western Europe, and they've been really successful. So the Big Five are all launched now. We...
In fact, by the end of this year, we should be about launched in every country in Western Europe, and the uptake and kind of the same dynamics that I described in terms of physicians and patients becoming more familiar, having more confidence in the drug, we're seeing that same thing outside of the U.S.
Are you planning to spread into other countries besides, you know, the European market?
We are. So we've actually. We have a team that's launching the product in Canada. We're in the final stages of market access there. We actually have built our own BioCryst team in Japan. We started there with a partner. We've changed that up a little bit to put our own rare disease team in there in Japan. That's going very well. And then beyond that, we are working with commercial distributor partners in other regions, like Latin America, like Eastern Europe, the Middle East, where we think in those cases, they already have the infrastructure and the local expertise, and so we work with them to do the regulatory filing, the market access, and ultimately commercialization. So our goal, right, as of now, ORLADEYO is commercialized in over 20 countries.
I think over the next two years, that will at least double.
Wow! Okay. So, I don't know if you have any further remarks on ORLADEYO and the commercial aspect before we move on to the pipeline?
Yeah, I think one other thing I'd add about ORLADEYO is, you know, as I've been describing, when patients find the right drug for them, this is a really sticky marketplace. Once a patient is well controlled, finds something that fits into their lifestyle, they are likely to stay on this drug for a long term. And ORLADEYO has composition of matter, IP protection out to late 2039. So our goal and our expectation is to reach peak sales around the turn of the decade, so around 2030, and then we're gonna be able to maintain that for a long time. We may not gain as many new patients, but the patients who are on therapy are likely to stay on. And so we've got a long runway for this product, and we're very excited about that.
Are there any emerging therapies that, you know, you're watching out for?
We watch for everything. We watch for everything, and we plan for... We assume the best case for all potential future competitors, and we bake that into our plans for the $1 billion. We do a lot of market research with physicians and patients, and what we hear from them is what I just described, which is, if I'm doing well as a patient on one pill once a day, I'm glad there are other therapies coming out, but why would I switch? Why would I switch my patients? And so we're excited for the HAE community, that they'll have more options, but we're also really excited about the patients who are doing great on ORLADEYO.
I mean, the more different mechanisms, the more potential to grow the market, too, so.
That's right. As I mentioned, there's still two or three thousand patients just in the US alone who may move into the treatment over the next, you know, several years. Then globally, there's still a lot of opportunity to help patients everywhere.
Great. So, this is very helpful. We can move on to the pipeline. Perhaps we can start with your Netherton syndrome program. Perhaps you can just introduce it for us and kind of, like, give us, you know, the quick overview.
Sure. Well, Netherton syndrome, I would describe as a classic ultra-rare disease. It is characterized, it's a genetic deficiency, where the protein that regulates skin turnover, so the natural sloughing of skin, is missing or defective. And so what that means is these patients, their skin is turning over way too fast, and that causes two main problems. Number one, their skin barrier just doesn't work as well as it would in a healthy individual, and so they're more susceptible to infection, temperature control, and other symptoms such as inflammatory symptoms, such that it's like they have eczema over their entire body, which is obviously uncomfortable and can really affect patients' lives. It also starts...
The patients typically become symptomatic as infants, and that is particularly severe and can lead to a pretty significant mortality rate. So what our goal here is to replace that protein that is missing that regulates that inhibits KLK5. It's a tissue kallikrein, and KLK5 is at the top of the chain that regulates the skin turnover, and then that inflammatory process that I just described.
So it's basically like a protein therapy replacement?
It's like a protein replacement therapy.
Okay.
And so our product is a fusion protein, BCX17725, and we're about to start into human trials by the end of this year, and we'll get into some patient proof of concept by later next year.
So, have we seen any data on this, the replacement of this specific protein that had kind of like the risks, your program, or have you shown any preclinical data that supports your hypothesis?
We have shown some preclinical data, and then there's other that's out in the literature and animal models showing that KLK5 really is the protein that regulates this cascade, and then the SPINK9 protein, which is what we're replacing, is the inhibitor of KLK5. What we've shown preclinically in mice is that seventeen seven two five, when injected in mice, it is getting to the skin, which is where the KLK5 is. And so that's, you know, that's good in mice. So that's what we need to see in humans, is that the... When you inject this, that it gets to the skin and then inhibits KLK5 in the epidermis.
What are the gatekeeping steps that you still have to go through to, like, get the program into the clinic? And also, are there any safety concerns or any AEs that we should watch out for, specifically for this phase 1?
So the next key steps really is kind of to get into the typical single ascending dose, multiple ascending dose in healthy volunteers. But as I mentioned, we're building on in a third phase of our phase 1 program, which is going to be enrolling actual Netherton’s patients. And so with them, what we're hoping to do is get some early signs of clinical activity that can become very informative for the pivotal program later on. I'm sorry, the second, there was a second part of your question?
Oh, if there were any safety concerns.
Safety, safety concerns. As far as safety, we think this is a protein therapy, so the main thing you worry about is just drug antibodies developing, but we think that when you inhibit KLK5, it's really doing one thing, so there shouldn't be any on-target safety effects, and as a protein therapy, we think also the off-target therapy or risk of adverse events is likely to be fairly low as well, but that's why we do the phase 1 clinical trials to figure these things out.
Are you gonna include any patients with the syndrome in this phase 1 trial, kind of like a phase 1b?
We will, and that... Yeah, that's what I was mentioning, and we could have early results from those patients in terms of dosing frequency. Is the drug getting into the skin? Is it inhibiting KLK5? And are we seeing those early signs of clinical impact, which, as you could imagine, could be things like, is there atopic dermatitis-type symptoms? Is the itchiness, is that starting to clear up? Are we noticing visual signs that the disease is being modified?
In terms of the regulatory path, is this a very, like, active, you know, with lots of innovation indication, or, like, are you conversations with the FDA to kind of, like, trying to figure out how to get to pivotal studies and stuff like that?
It's an ultra-rare disease, but there is some activity. So, Daiichi Sankyo has a similar program that's in the clinic right now in proof of concept, and so of course, we watch that. Of course, our regulatory team is in conversation with the FDA and other agencies. We'll learn more as we go along. I think one thing that we are learning is that this clinical endpoints of measuring using kind of global scales of response like physician measurement of response, assessment of response, is likely to be the type of pivotal endpoint. But we'll learn more as we get into the clinic and have further conversations with the regulators.
Regarding your conversations with KOLs, where's the big unmet need, and kind of like, how big of an opportunity do you think this is for the company?
I mean, the unmet need is, as I was describing earlier, this is a really serious disease. It's genetic. It's lifelong. It can really affect patients' lives. So the way patients treat today is on a daily basis, they're applying ointment, nonspecific ointment, to try to aid their skin barrier as best they can and control their symptoms. So the real need is disease modification, and by inhibiting KLK5, we believe we have the opportunity to do that, and that's what we hear from the KOLs as well. The overall opportunity, we think, we've done some work in claims data in the US. About 1,600 patients, we believe, have already been diagnosed with this disease.
But like a lot of ultra-rare diseases, once a therapy is actually on the market, we expect that to expand, and this could be a, you know, several-hundred-million-dollar-a-year product, maybe, maybe more, depending on the disease awareness and patient identification.
You mentioned disease modification. Are these well-established endpoints, or do you need to kind of, like, talk with the FDA and kind of, like, figure out with KOLs what's the best measurement for this?
Because there's never been a therapy approved for this disease, we can't say anything has been established. Similar kind of global assessments have been used in dermatology and other diseases, so we're confident, but of course, we'll have to keep working with investigators and with the regulators to figure out the path forward.
Okay, makes sense. So perhaps moving on to avoralstat, how is it different from Eylea, and what's the rationale for developing it in diabetic macular edema or DME?
Avoralstat is also a kallikrein inhibitor like ORLADEYO, and interestingly, for those not familiar, it was our first attempt at an oral therapy for HAE. It's a very potent kallikrein inhibitor. The drawback is its bioavailability is very poor, so it turned out not to be a good oral therapy, but what made it not great for oral therapy makes it potentially perfect for DME. And so the hypothesis here is that a good portion of the swelling and the increase in retinal thickness that is caused by DME is driven by kallikrein. And so avoralstat is our...
Our kind of therapeutic hypothesis is, if we can get this drug to the back of the eye, the back of the retina, it can then stay there for a long time and inhibit kallikrein and hopefully improve the symptoms and progressions of DME. So we'll be getting into human trials, actually starting with patients in DME with suprachoroidal injections into the back of the eye, starting early next year.
If you start the trial early next year, should we expect an update towards the end? Have you guided on that?
We could have as soon as later next year or early 2026, we could again have some early proof of concept data that will both give us an indication of activity and then also inform what a longer-term pivotal program would be.
Okay, interesting and in terms of your complement pathway, pipeline, you have a few molecules that are targeting different aspects of the pathway. Can you just provide an overview of which... What are these programs, and kind of like, what's the strategy behind targeting the different parts of the pathway?
Yeah. So our overall strategy is for any of this goes for our complement program, but also the rest of our discovery portfolio, which is we wanna do things that meet an unmet patient need and can either be first or best in class. So just like we've done with Eylea, we want to duplicate that in other diseases. The programs that we've announced, we've got three that we're looking at. So we've got an oral C5 inhibitor program that has the potential to be like Eylea in larger rare diseases like myasthenia gravis, where current standard of care is injected or infused. But if patients could have an effective oral therapy, many of them would much prefer to treat their disease with oral therapy. We also have an oral C2 inhibitor. Same kind of concept.
If I could treat my disease with one pill once a day and control that could be really life-changing for patients. And then the final one is a really novel program. It's a bifunctional inhibitor, so a protein therapy that inhibits both the C2 pathway, so the classical and lectin pathway of the complement system, as well as the alternative pathway. And we think that this could really be applicable to a growing number of diseases where patients need full inhibition of the complement system, potentially on a long-term basis or potentially more on a short-term basis to really get control of diseases. And so we're excited about the opportunity for all of these and potentially more in the future.
So perhaps last question: When do you expect to get into the clinic with these programs?
The next step would be, where we're at with all of these programs, is starting to get towards lead identification, particularly for C5 and the bifunctional program. So once we do that, you know, going through the IND-enabling studies usually takes you about a year. We could start getting into the clinic as soon as 2026 for some of these programs.
Okay, well, this is all today. Thank you so much for being with us.
Great. Thanks a lot, Eva.