BioCryst Pharmaceuticals, Inc. (BCRX) Earnings Call Transcript & Summary

Good morning, everyone. My name is Gena Wang. I'm SMID cap biotech analyst at Barclays. It is my great pleasure to have our next presenting company, BioCryst Pharmaceuticals, on stage. On stage with me, we have John Bluth, Chief Communication Officer; we also have Helen Thackray, Chief Research and Development Officer. Giving Helen here, we will discuss a lot about the pipeline assets, and then we'll dive into the science and the preclinical data and the clinical development.

Thanks for having us very much. And Helen and I will both be making some forward-looking statements. So please review those forward-looking statements in our SEC filings.

Good. So before I dive in and ask Helen a lot of question, I wanted to ask John first the -- regarding the recent -- I mean if you wanted to give a quick overview, and then we can dive into the questions or we can start.

Yes. So just at a high level, for those of you who don't know BioCryst well, we are a company focused on developing medicines for rare diseases. Our lead product is a commercial program, ORLADEYO, for hereditary angioedema. It's the first oral treatment to prevent attacks of hereditary angioedema. It's been on the market for 5 years now, and our guidance this year is $535 million to $550 million in revenue, expecting peak sales of $1 billion. So we've got a thriving commercial product in ORLADEYO. We've got an exciting pipeline, which I know we'll talk a lot about today. We've got -- by the end of the year, we'll have 2 programs in the clinic and our first data coming from those programs. And then from a financial perspective, the company is right on the cusp of profitability. We achieved an operating profit last year and expect by the end of this year, we'll be EPS profitable and on a full year basis, EPS profitable next year. And that profitability really starts to expand over the coming years. So the company is in a fantastic position financially, commercially and from an R&D point of view.

Great. Since you brought up the financial goal of reaching profitability, so you do have a pipeline assets pretty active compared to the maybe past. We have 2 could be potentially very interesting, exciting assets there. So how do you -- regarding the strategy, how do you balance these 2 out regarding maintaining profitability?

So I'll answer that. So we think we can do both. ORLADEYO has put us in a great position with strong performance. We're on a path to profitability next year, full year EPS positive for the year. And that is together with bringing forward our pipeline. And so we intend to be continuing to do that. We have 2 molecules in the clinic, as John mentioned, both with data expected this year. And so that's included. And so we expect to be doing both move to profitability and bringing pipeline forward so that we can bring a second product forward. Our goal is to have a second commercially successful product after ORLADEYO.

Great. Okay. I will start with the Netherton syndrome, the BCX17725. So maybe first, can you lay out the scientific rationale targeting the KLK5? So we understand some parts, the mutation regarding the SPINK5 genes. And then maybe walk us through like why you're picking this target and what kind of preclinical data to support this approach?

Sure. So we're targeting treatment for Netherton syndrome, which is an ultra-rare genetic disease. It's one for which there's no disease-modifying therapy available. And as a genetic disease, it's known to have a mutation that leads to abnormal protein function and, therefore, KLK5 overactivity or unregulated activity. Our goal is to replace the missing protein function. So we're developing a KLK5 inhibitor. It's potent and very -- has potency specificity and high affinity. And our goal with that is to improve, as I said, the disease by replacing the missing functional protein. KLK5 as a target is important in this disease because that is the driver of all of the downstream effects of the disease. It's a driver of dysfunctional keratinization of the skin and early separation of the skin, which leads to a poor skin barrier and poor skin function to a very severe degree. It's also a driver of inflammation in the skin and the cascade of cytokines downstream from KLK5 as well. So there's both the KLK cascade, which improves -- affects skin and cytokines, which affect inflammation in an atopic-like picture to the disease. So our approach is to deliver KLK5 inhibition to replace that normal inhibition and to do it with a therapy then that is delivered as a subcutaneous therapy. So it's very potent. So small volume necessary to give the effect and to do so in a way that we expect to be able to look at and hopefully completely change patients' skin looking for healing of the skin.

So maybe highlight some of the preclinical data.

Yes. So the preclinical data as a genetic disease has a sort of single pathway, gene to protein to disease outcome, it means that the preclinical data is actually fairly simple. There are models preclinically that show what happens when you don't have the gene and that show what happens then when you correct with KLK5 activity. So there's a model that shows -- a knockout mouse model that shows missing of the gene and you see the disease. Then you can further knock out KLK5, which demonstrates control of KLK5, and you see a return to normal. So that is the most important preclinical data because it tells us that if we can correct for that gene mutation and the missing protein function, we can correct for the disease.

And so you mentioned the knockout mice. What other preclinical animal model you tested? And then how would that help you translate to the, say, the Phase I understanding regarding the dosing and the dosing frequency.

So that knockout model, as I said, is the most important model for this disease. What we've then done is looked at 17725 and assessed -- it's BCX17725, assessed potency for KLK5 inhibition, specificity and affinity for KLK5 inhibition. So we've assessed that also preclinically, and we've demonstrated that it has very high potency. It also has very high affinity, which is important because that means sticking to the target and staying on the target. So what we've been able to show is that it stays on the target. And what we expect then as it translates through to humans, we'll be looking for one dose and the effect of one dose over time as that target -- that KLK5 molecule rises through the skin and then that layer of skin is shed.

So when you say high specificity, can you give quantified numbers regarding the target tissue versus or like target versus others, the selectivity-wise?

So what we're -- I'm going to focus back on KLK5. We really are looking for KLK5 activity. And so we're looking for -- and we'll be looking for this in patients this year. We're looking for activity in KLK5 as a marker that the drug is actually getting to the skin and having the effect in the skin. And then ultimately, we'll be looking for the clinical outcome, which is healing of the skin.

What's the half-life of the drug?

So the half-life at the moment, we have preclinical data, and we're in a healthy volunteer study. So we're gathering data in humans as well. We anticipate the half-life to be such that we could dose about every 2 weeks in the clinic.

Okay. So maybe help us understand regarding the Phase I data, like say, the selecting of the dose and the dosing frequency and based on what data and why you're choosing certain dose range? And do you expect to already having the -- within the therapeutic window even with the first dose?

Yes. So this is an interesting program because we can assess first in healthy volunteers to get through some of the basic questions you have to ask us first in human, safety, the pharmacokinetics and the plasma exposure. But it's a disease where the missing function and what we're looking for, for biomarkers is not present in healthy volunteers. So in our Phase I study, we'll be including patients immediately early on, and that will be this year dosing in patients. And we'll be looking for the activity in the skin in this Phase I study. We're looking for this year, I'm going to give you a couple of things that we're looking for, safety and pharmacokinetics, which then leads us to the ability to dose in patients and to know that we're dosing in about the right range for the effect that we want in patients. That means that this year, we'll be then looking in patients with that range of dosing for the penetration in the skin, the activity on target in the skin, but -- and then ultimately, that clinical healing. And we think we'll get to the clinical outcome this year.

So then from the healthy volunteer, what are you looking for? You mentioned, [ LTPD ] and that will help you determine the dosing frequency? What about the dose, also the exposure?

We're really just looking for confirmation of what we saw preclinically. And then we see confirmation of what we saw preclinically in terms of the level of exposure and the ability to dose perhaps every 2 weeks, then we'll be moving straight to patients. And I want to emphasize this as well. So moving to patients is really important because that's where we'll have the opportunity to confirm that the drug is having the effect, but also to confirm in this disease, when you have that effect in the skin, you then see healing of the skin.

So for the patient data because KLK5 will upregulate and you try to knock down, right, reduce the KLK5 expression. So for the healthy volunteer because they are normal level, will you still be able to see some level of reduction? Or are you trying not to touch too much on that part?

So we don't expect to see -- the changes that we've been looking for in patients, we don't expect to see that in healthy volunteers. KLK5 activity is normal in healthy volunteers, and it's not actively binding in the layers of the skin that we're targeting. So we would not expect to see either drug sticking in the skin or drug having an activity on KLK5 in the skin. And that's part of the reason why it's so important then to have patients early in the study is because we've had the basic confirmation of our expectation for dose ranges and timing of the interval of dosing and move straight to patients so that we can get to this assessment sort of understanding is the drug having the effect that we want and seeing it potentially very few patients. We do expect this year to have a handful of patients in the study with data after several exposures with the drug, several sort of doses over an interval. And it doesn't take very many patients to be able to see an effect. This is one of the benefits of a genetic disease where gene protein disease outcome is that we could, in our first patient, even see improvement in the skin, and that will be very exciting to us.

Okay. Would that be classic 3+3 study design for the patient? And what kind of data we will be looking for? We would need to collect the biopsy and to look at the KLK5 level and try to see -- like what kind of data you will share with us, biomarker data and also the skin scaling data?

So this will be a simple dosing study [indiscernible] necessarily a 3+3 design. A 3+3 design is typically to look for safety signals, and that doesn't apply here. But we'll be looking for dosing the first few patients. We'll be looking at the skin -- the bioassay of skin levels, as I said. But then we're also looking for changes in the skin measured by things like the validated scales that are used for atopic dermatitis like the IgA or investigator-assigned score of skin healing.

Okay. When you say dosing interval, were you using like one dose and a different frequency or you will explore different doses?

So we really just need to know what happens in the first few patients to then confirm what the dosing frequency would be for a pivotal study. So we'll start with maybe once a week, maybe once every 2 weeks. But the outcome from those first few patients is do we get the exposure in the skin. And I know I'm sort of emphasizing this, but it really is important, and it's very easy to see in those first few patients.

Okay. And that dose selection is mainly based on the healthy volunteers. So you think that dose, whatever you select should be efficacious. And the differences you are doing Phase I is just different frequency of dosing. Is my understanding correct?

So we'll start with one dose level patients. If we don't see effect in the skin, we'll dose range from there. So if we don't see effect in the skin, we'd go up. If we have hit it and we're seeing effect in the skin, then we'll just proceed forward.

Okay. And that when you say hit it, you are looking at...

Healing.

Healing, okay. And how soon do you think that we should see that, the skin healing?

Skin turnover is pretty fast in Netherton syndrome. We'll be looking for outcomes within a matter of weeks and 4-week outcomes, 8-week outcomes 12-week outcomes. So we would expect to be looking pretty quickly, and we would expect -- and we're looking for a very large and dramatic effect. So we're looking for one that is easily visible, easily detectable and has a substantial change on that physician score.

Okay. Very helpful. So 2025 data update, maybe lay out under what -- how much data package you have you think it's ready to share with investors? And then realistically, how -- which part of the 2025 you will be able to share that data?

So towards the end of the year, we'll probably bundle it all together because the meaningful outcomes are going to be that skin healing in patients. So we'll just combine everything that we know and have something later this year. But it's likely to be one update, not sort of incremental information because what matters is that patient data.

So when you share the update, will you be able to also have some initial FDA feedback to share with investors regarding the next step, say, pivotal study or the path to approval?

So I don't expect that we'll have pivotal study plans to announce by the end of the year. I expect that we'll have information sort of confirming and confirming that the drug is effective and that there's clinical outcomes and that we're preparing to move into the next step, which would be pivotal trials. We'll, of course, need to be interacting with regulators along the way because in order to start a trial, you have to have some regulatory interactions. And you could expect that we'll be having typical interactions both for getting studies started and for sort of long-term planning for the program.

Okay. Great. Now switch gear to your DME program. So maybe a little bit background why selecting avoralstat? And then maybe first, why this target, kallikrein target is a good target and a second, and you do have -- we saw this failed in the HAE development in the past, you discontinued. So why selecting this asset for DME?

Yes, sure. So we think this is the right drug for this space. And in fact, we learned a lot in that HAE program. The reasons for avoralstat not being successful in HAE were related to poor exposure because it's poorly soluble. So as an oral drug, it was not the ideal drug. And we moved on to ORLADEYO, which has been a much better drug and is showing that in the market. But avoralstat is as poorly soluble, it is actually ideal to put it in a suspension in a closed space and let it slowly dissolve over time. So it's got ideal physical characteristics for instilling in the space. And then we're going to -- we plan to put in the suprachoroidal space sort of bathing the outside of the eye, bathing near the retina. And that means that as a suspension, it will slowly dissolve, it will slowly deliver and it will have sustained exposure over a long period of time. We have some animal data to show that the levels in the retina after one dose are sustained well above the effective target out to 180 days. So that suggests that this is something that in the clinic could be dosed perhaps once or twice a year. And that would be a really important change for patients with DME where VEGF inhibitors typically are dosed every month. In terms of plasma kallikrein, and this is a mechanism of action. So what we know in diabetic macular edema is that VEGF inhibitors have really changed the field. What we also know is that somewhere around 40% of patients are not well served by VEGF inhibitors. So there's clearly something else going on as a mechanism of diabetic macular edema. We know from data that has been published that in the eye of patients with DME, there is detectable VEGF and some patients who don't have detectable VEGF. And in those, there is detectable plasma kallikrein. So that suggests that it could be an alternative target and alternative mechanism for diabetic macular edema. Plasma kallikrein is involved in contact activation and in vascular leakage. And our more recent data -- preclinical data that we showed earlier this year is actually very helpful in confirming that, that vascular leakage can be influenced and specifically changed with plasma kallikrein. So we had an animal model. Looked at the rabbit, we looked at suprachoroidal dosing, so using avoralstat in the same way in the same location that we would use in the clinic. And in a model that's well established for assessing VEGF inhibitors, assessing whether they can reduce leakage in the retinal vasculature in the eye, we were able to show that using avoralstat plasma kallikrein inhibition only, no VEGF inhibitors, we saw a reduction in leakage to a very similar extent. So that confirms for us the plasma kallikrein inhibition is by itself able to reduce retinal vascular leakage in the eye. And so between those 2 pieces of data, we now have the confidence to go into the clinic and move straight to patients and be able to dose in patients. And we think with one dose, we could assess over a month, 2 months, 3 months and look for clinical outcomes with that dose. What we'll be looking for -- say a little bit more, what we'll be looking for is change in edema. And this is a known marker in this disease. It's known to be predictive of changes in visual acuity. It's used as a sort of an interim way of assessing likelihood of success in the drug. And so with our first patients enrolled with their first dose of avoralstat, we'll be following those patients without needing to dose other doses to be able to see then at 1 month, 2 months, 3 months, are we seeing a change in that level of edema in the eye? And then over a longer period of time, are we seeing changes in visual acuity? So we have our unique opportunity with one dose study assess outcomes in the eye as well.

Okay. Good. We only have a few minutes. I do wanted to ask about ORLADEYO. John, you did mention the $800 million revenue guidance, right, in 2029. Maybe can highlight what are the key assumptions there? And then why you feel so confident that despite upcoming multiple potential competitor entrants, you still feel confident that, that guidance could be achievable.

Yes, I'll walk you through the components of $800 million, and Helen can share a little bit on the confidence that we've got. So to get to $800 million in peak sales in the U.S., we need to add about 200 net new patients on an annual basis. We did that last year. And again, 2 years ago, we're well on our pace with very strong demand for ORLADEYO. Most of those patients are switching from other prophylactic or acute therapies. We also need to continue to increase the rate of patients who are paying for ORLADEYO versus getting free drug. So to get to $800 million, we need a paid rate of 85%, and we made additional progress last year, getting the number at the end of the year up to 73.5%, and we see the path to 85% getting clearer and clearer as we make more and more progress there. We think we'll end this year around 80% paid. And then finally, there's a small component of price increase associated with that assumption. We've taken 5% price increases over the last couple of years. So that's how we get to $800 million and the trajectory we're on with the guidance increase that we just announced at the last quarter, we're extremely confident in achieving $800 million in peak U.S. sales and $1 billion in global sales. And Helen can talk to you about some of the reasons for that confidence.

Yes. So I'm going to talk a little bit about some of what data that we just brought out at Quad AI. It was at Quad AI in San Diego just a little -- just recently. And we had some of our largest real-world dataset there in 2 different abstracts presented at Quad AI. What's remarkable is we have data now on over 800 patients who've been on ORLADEYO. It was presented in 2 abstracts looking at the type 1 and 2 HAE as well as C1 normal HAE. And we see tremendous efficacy. We see it's -- for patients who do well on ORLADEYO, they do very well, and that's now reproduced in real-world evidence with longer-term follow-up in large numbers of patients. That gives us confidence that patients who are on ORLADEYO, who are doing well on ORLADEYO, they are continuing to do very well, and we're seeing that in such large numbers that it's really hard to argue with.

And maybe any thoughts on the potential competitors, for example, Pharvaris oral drug, I know they are still a little bit behind. Any concern there? And of course, there are other subcu, less frequent dosing and those also could potentially later will enter the market.

So maybe I can speak to Pharvaris and you can talk about the others. So Pharvaris, so we think oral clearly is differentiated for treatment for HAE. We're very pleased with how ORLADEYO has been doing as a result. ORLADEYO is in the fifth year on the market. And by the time another oral will be available, it will have been on the market for 8 years. So this is an opportunity for us to continue to build the real-world evidence dataset to continue to get patients on drug and doing well. And we think that's in a sticky market, it's going to be harder than for anyone else with another oral to come in and have patients do well.

Yes. And I think in terms of the injectables that are coming on to the market for patients who are doing well on ORLADEYO and doing well on ORLADEYO is 90-plus percent reduction in attack control and the real-world evidence that Helen was describing. So many, many attack-free patients or very few attacks. Those patients who are getting that kind of result with an oral capsule once a day, the injectables, we don't think are going to offer anything incremental that's going to motivate an ORLADEYO patient who's well controlled to switch. And we actually think that the discussions that are going to happen between physicians and patients as new entrants come into the market are going to be discussions about the options, the new options and do you want to switch? And we're going to be right there for those discussions with the relationships we've built over the 5-plus years of launch. And we think there's an opportunity for them to consider if they're not on ORLADEYO, but they're open to a switch to trying the oral medicine first. So we're looking forward to continued growth as these new entrants come on board.

Great. We are on time. Thank you very much, Helen and John, and we look forward to the data update later this year. Thank you, John.

Thanks, Gena.

Thank you. Thank you, everyone.