BioCryst Pharmaceuticals, Inc. Price & Performance (BCRX)

Addition, today's conference call includes non GAAP financial measures, For a reconciliation of these non GAAP measures against the most directly comparable GAAP financial measure, please refer to the earnings release posted in the Press Releases section of our Investor Relations website www.biocris.com BioCryst, Now I'd like to turn the call over to John Stonehouse. Thank you, John. We ended 2024 with the strongest execution and performance in the company's history. What's even more exciting is it happened across the company. For the full year 2024, Ola deo revenue year over year grew by 34% and we added as many patients as we did in the first year of launch. Is an amazing result for a rare disease medicine. Especially considering it came in the fourth year on the market and reflects excellent execution by the commercial team. Next, on the clinical front, we now have the data from our pediatric clinical trial with Orlideo to put us in a position to file the NDA this year. We also advanced BCX1725 for Netherton syndrome into and made progress with the oralstat for DME that will enable us to put that program into the clinic this year. All of these advancing programs represent an opportunity to serve patients and provide them something meaningfully better than is currently available to them.

A chance to really change their life. Whether it's no longer having to inject your toddler finally having a treatment to change the underlying cause of Netherton syndrome or giving DME patients hope of a new therapy that may work for more patients and be given with fewer injections. The execution of our teams last year has put us in a great position to get data and answers on these programs later this year. [indiscernible] And finally, we executed so well last year we not only generated a non GAAP operating profit, but this profit was over $60,000,000 which is three times larger than what we had planned The magnitude of the free cash flow we now expect over the next three years will likely further transform our company. The place we find ourselves in today was intentional. As the execution by the employees at BioCryst has never been better the momentum we have is carrying over to this year and likely many years to come. I'll now turn it over to Charlie. Thanks, John. Orla Deo gained momentum in 2024 with over 34% growth in the fourth year on the market. And that increasing momentum is carrying into 2025.

Demand in early twenty twenty five has continued at the same strong pace we saw in 2024, but an even bigger source of early strength has been the impact of the Inflation Reduction Act for Medicare patients. We are seeing that a much higher percentage of Medicare patients on Orlideo can afford their co payments and this is happening at a rate ahead of our prior expectations. As a result, we are raising our Oral Lideo revenue guidance for the year to $535,000,000 to $550,000,000 The full reauthorization season will run for at least two more months. And most reoffs within our large commercially insured patient base are still in process. The outcome of those cases will dictate where the revenue ends up relative to the increased guidance range. Described previously how HAE treaters are gaining enthusiasm for Orla Dayo. And we have four new posters of real world evidence being presented this coming weekend at the Quad AI Conference in San Diego. That help explain why. Two of the posters stratify patient reported outcomes by baseline attack rate in Type one and two patients as well as HAE patient and then examine long term outcomes at 12 and 18.

These analyses include hundreds of patients each which we believe are much larger volumes of evidence than have been reported for any other HAE prophylactic medication. The poster show that Orlideo dramatic [indiscernible] and helps patients who are attack free maintain zero attacks while benefiting from oral administration. In other words, this is a treatment that works well for all types of HAE patients. Not just patients with so called mild disease. Our latest market tracking study completed in December underscored the momentum building among prescribers. Slide eight shows that ninety seven percent of the sixty USHAE treaters surveyed are considering prescribing Orlideo. Among those who have prescribed, fifty nine percent say they are extremely likely to prescribe Orlideo to more patients a metric that is up from just twenty six percent just eighteen months prior. That prescribing momentum showed up in 2024 as the number of new prescriptions was [indiscernible] the first year of the launch. Slide nine shows that HAE treaters expect to continue the momentum by prescribing Orlideo to seventeen percent more of their current patients in 2025 with an emphasis on prescribing to current inject Over the first four years of the launch, this forward view of the coming year from physicians has been very predictive of the Ora deo growth trajectory.

And physician intent is aligning with patient preference. Slide 10 shows that over half of injectable PROFI patients would prefer an oral route of administration. While only one in five preferred an injectable. Over 1,200 USHA treaters have prescribed Orlideo to over three thousand patients, through the end of twenty twenty four. And both patients and physicians are telling us to expect a lot more growth I'll turn it over to Helen to describe other exciting sources of future growth. Thanks, Charlie. In our pipeline, we're making great progress already this year advancing both BCX in Netherton syndrome and Evorostat in diabetic edema towards meaningful clinical data readouts and submitting our NDA this year to expand the range for Orlideo to kids ages two to 11. I'll start with Netherton syndrome. A severe disease that has no approved treatments and for which we will have initial clinical data later this year as we evaluate BCX-seven for the potential to deliver a functional cure. Patients with Netherton syndrome have a genetic mutation causing abnormal skin turnover and inflammation with premature separation and peeling of the outer layers of skin. They experience intense chronic itching and redness, along with severe atopic symptoms like asthma and food allergies, which which means that patients live with a disease that involves much more than red peeling skin.

The effect on their health and well-being is profound. One patient I spoke with described the constant battle she faces keep her skin in good condition. Everyday life for her means having itchy, fragile skin, and being unable to prevent it from peeling off in big pieces. Even with her best efforts, she's still been in the hospital as a child and also as an adult. There are no disease modifying options for patients like her, even though she has confirmed diagnosis and sees specialists for her care.

Our goal is to change this.

We've engineered BCX-seventeen seventy five to replace the missing protein function to deliver this with very high potency. For subcutaneous delivery potential and high affinity the ability to stick to the target for a long time and have a lasting effect. We are aiming for a long dosing interval. Every two weeks or longer, which we believe could deliver a differentiated therapy for Netherton syndrome. Today, BCX-seventeen seventy five is in a Phase one trial dose escalation underway in healthy volunteers. Next, we will start dosing patients. And we plan to have data this year to confirm that the drug gets to the skin in patients and that the drug has the intended biomarker activity on the target KLK5 in the skin. These patients will receive multiple doses of the drug so we can assess for healing of the skin using known endpoints for chronic skin disease. For physicians to offer patients believe Nethergen syndrome is underdiagnosed. We know today is that Nethergen syndrome is an ultra rare disease and our studies estimate about sixteen hundred patients in The U. S, based on the reporting of a known feature called bamboo hair. We also know that patients with a diagnosis of severe ichthyosis or inflamed scaly skin may not be tested for the genetic mutation many may in fact have it. [indiscernible] We've seen how diagnosis rates change once a disease targeting treatment becomes available for a rare disease.

Not too long ago, HAE was thought to affect only about two thousand patients in The U. S. But today, changes in therapy led to a known market more than five times the initial estimate, about eleven thousand patients in The U. S. It is possible Netherton syndrome will follow this pattern, making it an even more attractive opportunity for a drug like BCX-seventeen thousand seven hundred and twenty five. Next in the pipeline, Averolstat will be moving into the clinic in patients with diabetic macular edema this year. [indiscernible] had a lot of interest from physicians in pursuing an alternative mechanism to treat DME because VEGF inhibitors are effective only for a little over half of all patients. This gap in treatment leaves many with continuing loss of visual acuity making independent living more and more difficult. Earlier this year, we presented images from preclinical model that showed the cessation of vascular leakage after a suprachoroidal injection of Avorostat, a plasma caliquaryin inhibitor. The images, which you can see on Slide 19, are from an animal model of retinal vascular leakage and show the change in that vascular leakage in the retina before and six days after treatment with the vorrostat.

This effect lasted through twenty one days before leaking started to return by the next time point at day thirty six. This is a clear effect and we believe demonstrates the involvement of the palakryne beta radikinin pathway in retinal leakage and importantly provides strong evidence that Plaidma Cal inhibition may be an alternative pathway for reducing retinal vascular leakage. Of course, the real assessment of potential for both efficacy and durability in we look forward to moving the program into the clinic. This year, we plan to enroll patients with newly diagnosed DME and including patients who received a few injections of anti VEGF therapy. Our goal is that by the end of the year, we may be evaluating for activity such as measurable changes in edema in the first few patients on the trial.

And last, following Charlie's description of the robust real world evidence we're presenting this coming weekend [indiscernible] I'm really excited to report that the first data from our APAC P trial with the pediatric oral granule formulation of Olorideo in children 12 with HAE will be highlighted in a late breaking abstract on Sunday. This is the largest trial to date evaluating prophylactic therapy for HAE in this age group and we are thrilled with the results. Want to thank all the children and their families our investigators who made this trial possible. Both a pediatrician and a mom, I am truly excited that we are getting closer to making oral available for children with HAE.

In the APeX P trial, we saw that the granules were safe and well tolerated in this pediatric population and children achieved early and sustained reduction in monthly HAE attack rates. In fact, twenty five out of twenty nine children remain on the study. These results for safety and efficacy are consistent with the adolescent and adult [indiscernible] and we are on track to file our NDA this year. We also learned that children with HAE are experiencing severe swelling attack at a very young age with a median age of onset at two years. These findings support an earlier age of symptom onset and need for HAE prophylaxis than has generally been understood. And we've learned that the oral granule formulation for Orlideo Also allows simple prophylaxis with great attack control to be provided for the youngest children. These outstanding data will be included in our NDA submission which is on track for later this year. So we have a very exciting 2025 ahead. With the pediatric NDA for Orlidea and our initial clinical data coming from both our Netherton syndrome and DME programs. And now, turn the call over to Anthony.

Thanks, Alan. In the beginning of last year, we laid out our goals for strong commercial growth for Orladeo, advancing our early pipeline into the clinic, and moving towards sustainable and meaningful profitability in the short term. As we shared earlier, it's great to see that we've exceeded even our own expectations can find our detailed fourth quarter financials in today's earnings press release, and I'd like call your attention to a few items. Total revenue for the quarter came in at $131,500,000 $124,200,000 of which came from Orla Dayo. Full year 2024, total revenue was $450,700,000 with Orla Deo contributing $437,700,000 of that.

For quarter $417,200,000.0 or 13.9% of the $124,200,000 total for Orla Deo came from ex U. S. While for full year, it was $51,700,000 or 11.8% of the $437,700,000 total.

Operating expenses, not including non cash stock compensation for the quarter were approximately $115,000,000 Operating expenses not including non cash non stock based comp for full year 2024 came in at $388,000,000 an increase of just $8,000,000 versus 2023. With revenue increasing $119,000,000 year over year, and this small increase in OpEx, this resulted in an operating profit including stock based comp of $62,900,000 an increase of $111,000,000 versus the non GAAP operating loss of $48,100,000 from 2023. A remarkable achievement that sets us up for 2025 and beyond. Cash at the end of the year was approximately $343,000,000 and net cash utilization for the quarter was $8,400,000 Charlie shared the increasing guidance for Olorideo revenue for this year of between $535,000,000 and $550,000,000 based on the progress that we've seen thus far in Q1 around reauthorization and Medicare reimbursement. For total revenue, we're adjusting guidance upwards in line with the Orladeo increase between $560,000,000 and $575,000,000 there's some increased uncertainty around future government funding for Rapavab, we're also seeing strong commercial demand for the product given the prevalence of flu at the moment. For OpEx, the improved Orla deo commercial performance will result in increased expenses around COGS, distribution fees and incentive compensation, but should remain bound by the upper end of the $425,000,000 to $435,000,000 guidance that we provided previously.

That puts us in a great position to achieve our 2025 goals of positive and sustainable quarterly cash flow and EPS in the second half of the year. Longer term, Earlier in the year, we provided guidance for revenue with a three year CAGR of 20%. So north of $750,000,000 by 2027. Of getting to $1,000,000,000 in global revenue by 2029. We also provided a CAGR for OpEx not including stock based comp of 5%, closer to $450,000,000 by 2027. [indiscernible] With positive quarterly cash flow this year, [indiscernible] positive cash flow generation next year and the cash flow that we will generate in 2027 when revenue was greater than OpEx by more than $300,000,000 we expect to have more than $600,000,000 of cash on hand at that time. Allowing us to reduce our debt and our cost of capital and reinforcing our position that we are capital markets independent. Operator, we can open it up for Q and A. We will now begin the question and answer session. The first question comes from Tazeen Ahmad with Bank of America. Please go ahead.

Thanks, guys. Good morning. Thanks, Rolo. The color. I wanted to start maybe with a question on Netherton. You're expecting data from patients later this year. Can you potentially narrow down when this year those patients added to come in? And then secondly, can you talk about what would be positive data in your view? Do you think the the amount of patients that you've enrolled would allow for a sense of efficacy in a clinical setting beyond the biomarker data that you've talked about releasing And if that data is encouraging, what do you think the path forward could be for Netherton just given that there's nothing approved in patients right now? And it is an area of under met need.

Ellen, you want to take this?

Yes.

Thanks, Tazeen.

So first of all, we have we will have data this year and that's the guidance we're giving at the moment. In terms of what we expect to see, so how many patients One thing about this disease as a a genetically driven disease is that we really only need see data in a very small number of patients to have confidence that we're hitting the mechanism. We're looking to make a functional replacement of the missing protein and we may see that with single digit patients.

In terms of what we're looking for then, we're looking at the first of all, as I said, the activity in the skin. But with that specifically, we're looking for the drug's effect on KLK5 activity in in the skin, the suppression of KLK5 activity. What that will lead to then is healing in the skin. And so we're looking for a graded observation of the skin and is it actually demonstrating signs of healing. So that way, we would be able to see later this year possibly and early next year as well for healing of the skin.

In terms of the development path forward, the data we'll get this year is very important to us because that few patients' worth of data showing activity in the skin that drug is getting to the skin and having its activity, we would then expect to see some degree of healing following from there and we would move pretty quickly into assessing that in the next study. This is an ultra rare population with a serious outcome and a pretty clear response that we're looking for. So it could be a very short path to pivotal studies. As soon as we have a dose, I'd expect to have at some point next year, then we'll move into a pivotal program that would be the registration program. And it probably is a single pivotal trial program.

Supported by the data that we'll be collecting this year and next.

And Helen, the profile we're shooting for is functional cure. So the magnitude of effect will drive what the pivotal program looks like and the number of patients [indiscernible] we need. Is that a fair assessment? Yes.

Yes. Great.

Okay. Thank you.

The next question comes from Jessica Fye with JPMorgan. Please go ahead.

Hey, guys. Good morning. Thanks for taking my questions. One on Orladeo and one just following up on the prior question for Nutterton.

First on Orla Deo, where are you tracking towards for the proportion of paid patients overall and within Medicare specifically? And what is the current Orlydeo guidance embed there? And then second, [indiscernible] How quickly mechanism result in skin healing in Etherton Just thinking about the mechanism and the underlying disease pathology.

Charlie?

I'll take the Orla Daya question.

Thanks, Jess. As far as the proportion of paid patients, we ended last year at 73.5% paid across our whole patient base. I can't give you an exact number yet because we're literally right in the middle of the reauthorization season. So what that means is a lot of our patients are previously on long term free products, or even paid product have moved temporarily into Quickstart product. So any number that I would give you now would not be accurate. I have said though before that with a swing back in Medicare paid patients, that could push us toward 80%. And so by the end of the quarter, we'll be able to see where we are. So if I would expect to report [indiscernible] the reauthorization season, revenue for the first quarter is is still going to be flat to slightly down versus Q4. Just because of all the free products that we have to give away as well as the impact to gross to net from the co payment assistance that we provide to commercial patients. There is also a little bit of a a headwind as it relates to foreign exchange. So included in Charlie's increased guidance There is a headwind of probably around $5,000,000 give or take in the EU So it makes the number that we're achieving in terms of the increased guidance for here in The U. S. All the more impressive. [indiscernible] Our assumption prior to getting into the year was that it would that Medicare thing would happen over a couple year, two, three year period.

That's not what you're seeing. The pace of it is is significantly faster and that's the reason for the guidance. That's correct. We assume that we would get back to a high paid rate in Medicare by 2027. It's looking like we'll get much more of that back this year, but we won't know the final results until I the quarter.

Ellen, you want to take the Netherton? Yes. So, Jeff, on your question about Netherton syndrome and how quickly we'd expect to see healing in the skin, The short answer is we don't know. But what we do know is that we'll see the activity on target activity first and it could be just a very few months after that that we're seeing healing of the skin We'll be looking at four weeks, eight weeks, twelve weeks, etcetera. And once we see that on target activity, the biomarker we'll know that we're at the dose and then we'll just continue treating longer term and following for those first few months to assess for healing of the skin. And Helen, can you talk about skin turnover? And it's not like it's years to see it's been affected. Yes. Just talk a little bit about that. Yes. So skin turnover actually pretty fast.

And normal skin, we expect the skin layers to turn over about every two weeks or so. And so with this drug, when I talk about seeing activity on target, that KLK5 activity, then we would expect that activity to be there for the duration of that skin layer being present. So it's going to be two weeks and longer that we'd expect to see the effect of the drug for each dose and then we're looking to see what happens with that skin over time. So that's why I look back to it could be very few months, four weeks, say week follow-up.

And given what we see in terms of potency and affinity of this molecule, the treatment effect that we're expecting is pretty significant and it should come pretty quickly. In general in terms of the results that we see from this early study.

Yes. We're looking for a pretty big effect here.

And this is a very potent drug It is very sticky, that's a high affinity. And we're looking for a really obvious effect. So that's why we think it's something that we might see pretty quickly.

And is it safe to say that de risking event is drug getting to the skin in patients?

Yes. Okay.

Thanks. And was there a follow-up Ms. Fai, That's it. Thank you. The next question comes from Stacy Ku with TD Okay. Well, thanks so much for taking our questions and congratulations on the results. So first, Quick follow-up on Netherton's We might have missed this. Have you talked about specifically when you plan on dosing other patients? So just some specific timing on that. And then again on the So now to Orla Dayo, On the survey results, are you kind of finding that the attack free rates are similar to other prophylaxis therapies? Kind of curious your take away as it relates to kind of the patients that are well controlled on oral versus patients that are well controlled on injectable therapies. And then the last question is another follow-up on the guidance.

What exactly are you seeing kind of in the last month and a half that kind of gives you conviction in a new updated guidance? Is it kind of the charities, it really just that Medicare kind of update? And remind us kind of every one percent that you're converting, is that $5,000,000 in sales you so much. So on Netherton syndrome, in terms of when we'd be dosing. So we we haven't said exactly. However, what I can say is we are dosing healthy volunteers now and we're moving towards dosing patients with otherton syndrome soon. So it will be sometime around the middle of the year third quarter. That's what would give us then the opportunity to assess the activity in the skin and be looking at healing by the end of the year.

And then, Stacy, as far as the attacks free or sorry, the attack rate reduction that we're seeing, in the real world. Yes, I think we see that patients on Ora Lideo are getting to really low rates of attacks. If they don't, they move on. And so what we've said before is no drug is perfect for every patient, but this is related to our really strong retention rate for Oloridea patients of sixty percent in a year. Patients are staying on because they're doing really well.

That's what you'll see in the posters that we present at Quad AI this this coming weekend that patients whether they started at a baseline attack rate that was really high over five attacks a month or whether they started at zero attacks at baseline. They're doing really well over time. So we think they're getting a a very competitive efficacy rate And the things that give us confidence so far in the year the number one thing is the Medicare patients moving to pay therapy. We think that this is really because the IRA is is making it more affordable. Probably make it more affordable for the charities. But what we're just seeing is patients are getting approved by their plans. They're able to afford their co payments. And so they're staying on unpaid therapy. So that gives us confidence. And then the continued demand that we're seeing in the first half of the first quarter is very consistent to what we saw last year. And so those two things together give us confidence to raise guidance at this point. Charlie, just one more piece on the control. With the real world data that we see, do you really see it when you're controlled on Orladeo, is there a difference in the control versus the therapies on the market or the ones that coming in the data that we see in the future?

Not Not based on what we've seen in our market research. So the patients, very few patients across the board regardless of what product you're on are truly attack free. The goal for patients is to have very infrequent attacks have those attacks be very manageable, so they tend to be more mild on prophylaxis. That's what we're seeing on Orla Dayo. That's what we're seeing on injector we we'll see with future products that reach the market as well.

And as physicians see that data or they have that experience with their own patients, that's what's driving that excitement about prescribing more of it in the future. Yes. That's what's exactly. So not only are they saying physicians telling us as of December that they will prescribe to 17% more of their patients, They expect over 60% of those prescriptions to come from injectable prophylaxis switches. It's because they have confidence in what they're seeing with Oildale.

So Stacy, I think the bottom line is [indiscernible] any incremental anybody that's saying that there's incremental control with a future product or a current product really isn't true. It either works or it doesn't work.

Okay. Understood. You so much. You're welcome.

The next question comes from Brian Abrahams with RBC Capital Markets. And congrats on all the progress. Two from me. I guess first on the pediatric study, can you talk about how tolerability compared to the adult experience? And maybe just remind us your expectations for the regulatory bar in The U. S. As you prepare the NDA filing there? And then you're planning for the international approvals and filings? And then secondly, I guess speaking of international, for OlorDAO commercially fourth quarter, it looks like you saw an uptick in the contribution from Europe. But I know that can be variable and sometimes higher in fourth quarter. Course, we'll need to think about the FX headwind for next year, but where do you see that demand outside The U. S. Tracking in 2025? So on pediatrics, So this is the new formulation for pediatrics is oral granules. They are what we know from the study is that those are delivering well patients are able to use them easily. We're seeing good exposure levels, which means that they're compliant with receiving them and we're seeing very good tolerability with the oral granules as well. It's very similar to what we'd expect in terms of efficacy and safety for the adults in the adolescents.

And so this is a formulation that we're very very pleased with how it's doing in pediatric patients. In terms of the regulatory bar for approval, this is actually pediatric extrapolation is what it's called. It means we're matching safety and exposure for the pediatric population to extend labeling from adults and adolescents down to the younger children. That means that primary outcomes are safety and pharmacokinetics and we have that data and we've already discussed that with regulators. In The U. S, this is a fairly straightforward approach with something called written request with FDA. In Europe, it's under a pediatric investigative plan with EMA.

Both of those predefined the path to approval in The U. S. And Europe and we're on track to submit the data that meets those requirements. So we think we're in a really great place with this data set and looking forward to bringing this to children. Agreement on what the path forward for that is as well. So we expect that filings will occur in multiple countries either all this year or into the early part of next year. And then maybe as far as ex U. S. Demand, I'll cover the demand then Anthony can talk about kind of the cadence of the revenue. What we're seeing in Europe, in Canada and Japan is the same type of growing confidence in Orlando that we're seeing in The U. S. Different markets are at a different place depending on where the launch was. So for example, we're seeing really transformative confidence with Orla Deo The United Kingdom, which has been on the market for several years now. We're seeing great early confidence in Italy that just launched last year as as examples. But what they're seeing is Orlideo is a really effective drug. And we're also very excited in Europe that countries that historically have used more androgen steroids are going away from that.

And patients are being switched over. New patients are not being prescribed to androgenase anymore. And so I think we're still seeing a a transformation of how prophylaxis is understood around the world and Oral Dave was playing a big part of that. Specifically as it relates to Q4, yes, so the percentage for Q4 ex U. S. Was higher than the total for the year. So thirteen point nine versus what 11.8 for full year. Some of the drivers are, yes. Europe, it helps in that regard, but also some of the Q4 dynamics distributors that we have whether it's in Latin America, whether it's in Eastern Europe, whether it's in The Middle East, annual distribution shipments go out in Q4 time period. So that can be a small driver. The other one is we renegotiated and kind of refocused on the Japan side of the house in the year and we were able to renegotiate a revised term around flipping the economics for performance over a certain number. We achieved that number in Q4. And we're able to get a higher share therefore the licensing revenue for that territory. In terms of how that plays out into 2025, Listen, for Q1, we'll probably get to the point where flat to lower on the total revenue for the rest of the year, same dynamic would play out including this Q4 dynamic that I just described.

Terms of the percentage [indiscernible] ex U. S. Compared to the total for Orladeo, This year might be a little bit different. We'd normally say that you'd get about a percentage increase or uptick on your way to that 20%, with the significant increase that we're seeing here in The U. S. That might be slightly deflated, but that has nothing to do with the [indiscernible] it's just a counterpoint of the significant strength that we'll see on The U. S. Side. That's super helpful. Thanks so much. Hey, Brian, just one more. At best of the tolerability, the retention rate in the pediatric study, I can't remember the exact numbers, but it was pretty high. So it was twenty five patients out of twenty nine who paid on drug as opposed to using that formulation and having the effect that they A lot of times that can reflect some of the tolerability, Brian.

So Got it. That's really helpful. Thank you. The next question comes from Geno Wang with Barclays.

Thank you for taking my questions. I have one also regarding OLED Olaudeo. So maybe like you did mention the Medicare patient benefit from the low copay. Can you share with us what percentage of patient or Medicare patients And I assume those Medicare patient in 2024 or 4Q 'twenty four paid percentage is 73.5% and you are expecting this will go up, right? And the second question regarding the Netherton syndrome, and you did mention that it will start with healthy volunteer and then switch to patient. So maybe can you give us a little bit more color regarding what kind of how many dose escalation you were tested in a healthy volunteer and what KOLK5 activity you'll be looking for to switch to patient And then can you give us the benchmark and what are you looking for? Regarding the KLK5 activity?

Hey, Gina. I'll take the question about Medic Medicare is about twenty percent of the patients on Orlideo. Are covered by Medicare. The seventy three point five percent paid rate was across our entire book of business. In Medicare, it was actually lower. So we finished last year at about a 55%, 56% paid rate. Historically, the Medicare plans tend to say yes, that they will cover Orlideo at 80% or more. The problem has just been the affordability. And so what we're seeing in Q1 is the plans are still saying yes. The affordability seems to be there for the patients. And so they're able to move to pay therapy. And this is a big part getting that proportion of our Medicare patients over to paid therapy is a big part of our path to eighty five percent paid over the long term. Which is represents by 2029, that that will represent about $100,000,000 in increased revenue towards our $800,000,000 future view of revenue in The U. S. So what we're seeing is this year that may be accelerating a bit and we'll know the final answer after reauthorization season is complete.

And Helen, maybe just describe the design of going from SAD to MAD to then patients and the differences between what you can see in healthy versus what you can see in patients. Yes. So in Netherland syndrome, Gina, we are in a Phase one study. That Phase one is in healthy volunteers and will include patients. In healthy volunteers, we're doing single ascending dose We will proceed also with multiple ascending dose. And what we're looking for there is simple safety and pharmacokinetics exposure levels so that we can identify a dose that is likely to have activity and goes to patients from there. We would expect to include patients in the study while continuing with the dose escalation in healthy volunteers. So it's not in series and dependent on that. And there's an interesting aspect of this disease, which is that KOK5 activity is normal in healthy volunteers, which which means we can't really look for activity there and we want to get to patients as quickly as possible. That's why we've built the patient portion straight into the Phase one study. That's why we're dose escalating quickly and healthy volunteers to get to the likely effective dose range.

And then we're moving to patients within that study so that we can look at the activity of the drug in the skin where KLK5 activity is abnormal and look at whether the drug is inhibiting KLK5 inhibit activity at the dose levels there. So we'll be looking at a range of doses, but we're expecting to be in an effective range in patients. And we'll be looking for that suppression. Of KLK5 activity to give us confidence that the drug is having the effect and to extend dosing then in those patients to assess for the healing we were talking about earlier in the call.

What percentage of the suppression you were thinking KLK5 suppression that will lead to the clinical benefit?

Yes. So short answer, that's that's not known. But what we're looking for is this drug is very potent. And as we're talking about, it has this stickiness, it's high affinity. What we're looking for is suppression. So that's nearly complete suppression of KLK5. And as we learn more about what's whether that's actually required for healing activity, we'll learn more later on the program. But in in the near term, we're looking for complete suppression of KOK5.

Okay. Thank you.

The next question comes from John Walden with Citizens JMP. Please go ahead.

Hey, good morning. Thanks for taking the questions. Just a couple for me. Charlie, wondering if you could talk a little bit about the historical reauthorization rates and what you guys have seen prior first quarters and how it's tracking so far this year? And then for pediatric opportunity, wondering if you guys have thrown that in your market model what we should think about that opportunity if that's included in kind of your projection that you have on Slide 12 in your deck?

Sure. Thanks, John. As far as the reauth across all payers go through reauthorization in the first quarter.

And it but it's really more than just the first quarter. It tends to drift into the early part of the second quarter. That's what we saw last year. And so when I said earlier, we're right in the middle of it. It's because we are we're right in the middle of it now. The last as I've talked about previously, the last few years, our team has done a tremendous amount of work to be ready for this reauthorization. Every year we think we get better at it based on what we learned from the previous year. And so I'm I'm pleased with what we see so far, but we won't know the final results until we get everything. As far as the PEASE opportunity, it is not baked into our our $1,000,000,000 peak global revenue forecast. At some point, particularly obviously when we get the probably build that in. But what we have said is in The United States, there are about 500 patients that we believe are 12 and diagnosed with HAE. Historically, we thought maybe forty percent of them, two hundred or so were appropriate for prophylaxis therapy. Based on what Helen was describing earlier, and the young age that we saw the patients in our trial, the young age when they first had their attacks we're rethinking this.

We think that there may be more of an within that within that 12 population. And again, we think Orlidea as an oral drug is going to be transformative for these kids. So we expect a lot of changes in how kids with HAE are treated in the future.

Is it safe to say that even with the increase in guidance and the tailwind that we're getting with free drug to pay drug that the first quarter dynamics still exists. And there's still free drug that we're giving to people going through re auth and there's still, as you said before, gross to net issue. So flat [indiscernible] how well we do, that is a dynamic that we cannot defeat.

And Charlie, maybe just one quick follow-up. How do you categorize a pediatric patient as appropriate for prophylactic therapy?

Well, that's John, I think that it's a great question and I think that's what we're going see changing over time. I think historically, treaters have not seen as many kids with [indiscernible] because they really didn't have options for treating them. Now they have some injector going coping, physicians coping with this and treating kids acutely, but that puts a huge burden on the kids and the families. And so with an available oral therapy, we think it's going to have physicians parents, obviously the kids rethink how to treat HAE. And it could create an opportunity where kids grow up rarely having attacks. Which could really change the trajectory of their whole childhood, their their whole life, their whole relationship with HAE.

So we're really excited about working with the community to make that happen for kids. I think too when we saw this data, I think we've many of us were surprised at how sick and how early kids got sick. With this disease. That changes our view of the market a bit. That there are younger kids that really need this drug and so that could increase the Thanks for the color guys. The next question comes from Lisa Beyko with Evercore ISI.

Please go ahead. Hi. This is Seema on for Lisa. I have a question on Aurisbet.

What's the target product profile for this drug? And what should we be looking for in patients data to start to de risk by asset? Towards this target product. Problem. Thank you.

Charlie, you want to take that?

Sure. And then maybe Helen can comment on some of this too. The TPP we're looking at for a VoraltaTep for patients with DME physicians are looking for other options. They're looking for other therapies because over over fifty percent or close to fifty percent of patients don't respond fully to VEGF inhibitors. So what we're looking for is an infrequent injection that helps prevent leakage. So this could be every three months, it could be every six months. Which could greatly reduce the burden of injections and improve efficacy for many patients.

Was there a follow-up?

Just wanted to, can you speak about the Phase one what's the design, what should we look for and then moving into patients.

So we're going directly into patients and all that Helen direct? Described that?

Yes. So this is a program that will actually go straight to patients So Phase one will be in patients, and it'll be using the injection suprachoroidal injection and peripheral stat in the suspension in order to observe safety in patients, tolerability locally in the eye, but also with that injection to observe in individual patients. Right from the first patient we dose to see if there is a change in the edema in the eye and then longer term a change in visual acuity. So the first study will be exploratory looking at using that injection and then assess just one injection, assessing over time, again sort of over four weeks, eight weeks, twelve weeks, sixteen weeks with this to to observe for the edema in the eye and observe for any changes in the edema. Once we have confidence that we've got a dose, we're seeing the changes that we want to see, then we would move to a randomized program, probably randomized Phase two to assess this in a controlled manner for the pivotal program planning. Helen, is it fair to say that this is an unusual setting where a SAD and MAD study could tell you a lot?

Because you're in patients?

Yes, right. So the oral stat, we know we already know a lot about the systemic safety of the drug because we tested it in a Phase three with our oral program some time ago. Now we're at a point where we're just looking at the from a safety perspective, the local tolerability. And because this drug is potent and the suspension has a depot like effect. We think one dose could be sufficient to see that effect in each patient. That puts us in a position to have first, second, third patients and the very first patients we put on the trials, the ones who we observed with that one dose observe over a number of months to see how they do.

That's very helpful. Thank you. The next question comes from Serge Belanger with Needham and Company.

Please go ahead. Hi, good morning. A couple of questions for Charlie on Orlikdale.

First one, can you tell us how many patients were on drugs at year end and how that number compares to year end 2023.

And then secondly, regarding the positive impacts you've seen from the from IRA so far, [indiscernible] expected improvements in paid rates, but do you also expect it could help improve volumes in the form of new patient adds. Thanks.

Thanks Serge. I haven't commented able to is that in that path to $1,000,000,000 the path to $800,000,000 in The U. S, we need to average 200 patients through 2029. We were well above that in 2023. We said in the early years, we would expect to be above that. We were well above that number again in 2024. So we are well on our path to what we laid out in that $800,000,000 to The U. S. And then the demand that I just there's no sign that the opportunity is slowing down or running out in any way. As far as I think the other part of your question was on the Medicare paid rate and whether that could have a positive impact in prescribing. I think it's a possibility. It's a good question. I don't think we've seen that yet, but but for patients and for physicians getting to paid therapy gives them confidence. Knowing that their payer will pay for this drug gives them more confidence about prescribing. And we've known that since before the launch. We've always done everything that we can to remove that that paid rate paid therapy insurance approval, remove that as a fear for patients and doctors, but it's always there.

And so seeing more patients get to pay their impact over time. And I think something that's really important that maybe isn't obvious is the the machinery that Charlie has built and the team that Charlie has built to make that go smoothly is a real competitive advantage. I think in in terms of just it's taken stress away from doctors. I mean, Charlie and I heard from a doctor recently about how our Empower patient services is like a model for other drugs even outside of HAE and that took time to build, that took investment and I think his team is really good at it. No, I agree and a shout out to the team because again they are right in the middle of what we call the Blizzard season, a, because it's cold and B, because there's a lot of work to do. So they're working super hard to help as many patients as possible.

Was there a follow-up?

No, all set. Thanks.

Your final question comes from Maury Raycroft with Jefferies.

Please go ahead.

Hi, good morning. Congrats on the progress and thanks for taking my questions.

Talked about Netherton being underdiagnosed.

Is BioCryst doing or planning to do to help these patients and get them on the radar for your clinical study program and to help set up commercial opportunity? Shirley, you want to start how we're thinking about how we identify patients and what we plan to put in place.

Yes.

And Maury, Helen alluded some of this in her comments as bamboo hair is a that that patients with Netherton's have. There is no diagnosis code for Netherton's syndrome. But most of these patients do have this bamboo hair. We did a claim study that helped us identify about sixteen hundred patients with this bamboo hair feature. And so part of our plan is to to expand on that. And as we're getting into the clinical trials here, make sure we're working to find more sites where these patients are treated. There's some a small handful of real expert centers at this point. But most of these patients, as Helen was saying, are probably lost a little bit in the broader dermatology practice potentially misdiagnosed with general ichthyosis. And so as we move into this next phase of trials, we expect to start doing more to educate the market about the need for this and the differential diagnosis for these patients.

And there's some great playbooks on rare diseases where there was no drug and no diagnostic code and how did you find the patients. And I think one of the beauties here is the genetic test. And what we do with that genetic test and how do we implement that playbook to start and when you have a therapy that has we're hoping for a real significant treatment effect. Those two things in combination you start to really be able to find patients. So we'll I don't think we have to recreate anything here. There are playbooks for this stuff that follow that will help us build that over time. And I'll add, let's just one piece, one part of that playbook is to engage very closely with patient community and we've we've started doing that with the Netherton's community and the patient voice in all of this is in rare diseases becomes really important. And so we'll do what we can to work with them and our early interactions with them has been very positive.

Got it. That's helpful. And maybe one quick second question. Just for the Orla deo pediatric formulation, do you plan to price that differently than the adult version We haven't made any final decisions on that, but but in most markets probably not. It would probably be be comparable, but that will be a decision that we we make as we get closer to launch Got it. Okay. Thanks for taking my questions. Thanks, Mark.

This concludes our question and answer session. I would like to turn the conference back over to John Stonehouse for any closing remarks.

Thank you. So as I said at the beginning, 2024 was one of the best years in the company's history terms of performance and execution and the evidence for that is [indiscernible] path to $1,000,000,000 programs now advancing and getting the point where they're going into the clinic. And then our path to profitability. So there's no letting up going into this year. We've got a lot of momentum We're off to a strong start as you can see by the raising of our guidance and we're really excited to continue to update you over the course of this year. Thank you.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect. [indiscernible] [indiscernible] [indiscernible] [indiscernible]