Good day and welcome to the BioCryst Second Quarter 2024 Earnings Call. All participants will be in listen-only mode. [Operator Instructions] After today's presentation there will be an opportunity to ask questions. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to John Bluth at BioCryst. Please go ahead.

Thanks, Dave. Good morning and welcome to BioCryst second quarter 2024 corporate and financial results conference call. Today's press release and accompanying slides which we'll be referring to, are available on our website. Participating with me today are CEO, Jon Stonehouse; CFO, Anthony Doyle; Chief Commercial Officer, Charlie Gayer; and Chief R&D Officer, Dr. Helen Thackray. Following our remarks, we'll answer your questions. Today's conference call will contain forward-looking statements including those statements regarding future results, unaudited and forward-looking financial information as well as the company's future performance and/or achievements. These statements are subject to known and unknown risks and uncertainties which may cause our actual results, performance or achievements to be materially different from any future results or performance expressed or implied in this presentation. You should not place undue reliance on these forward-looking statements. For additional information, including a detailed discussion of our risk factors, please refer to the company's documents filed with the Securities and Exchange Commission, which can be accessed on our website. In addition, today's conference call includes non-GAAP pro forma financial measures. For reconciliation of these non-GAAP measures against the most directly comparable GAAP financial measure, please refer to the earnings press release posted in the press releases section of our investor relations website at www.biocryst.com. I'd now like to turn the call over to Jon Stonehouse.

Thanks, John. Our second quarter performance with ORLADEYO is nothing short of amazing, especially when you recall the great start we had in the first quarter. This performance is due to the confidence we are seeing from our customers since late last year and it continues to build. Physicians who treat HAE in many of their patients are experiencing firsthand how well ORLADEYO works and that they can achieve this control with an oral once-daily therapy, efficacy and convenience. Many patients are experiencing efficacy similar to what they had on injectable therapy. As a result, halfway through the fourth year since approval, we are experiencing demand as strong as the start of the launch. Amazing. This confidence has also led us to increase our guidance for the year to between $420 million and $435 million. Charlie will provide more details on the quarter and share why the evidence is increasingly clear we are on a path to $1 million at peak. I'd also like to give you an update on our pipeline. Remember, our goal with this assessment is to bring to market our next meaningful therapy to patients living with rare diseases like we did with ORLADEYO. We continue to make great progress overall advancing our programs. First, we remain on track to file for approval in younger children down to two years of age with the oral-granule formulation of ORLADEYO next year. This is a very important patient population whose parents have been waiting for this therapy. Think about it. If your child is having HAE attacks, the only current treatment is injecting them. Any parent knows how traumatic that is. So, to bring a therapy they can sprinkle in a glass of water or on soft food is a game changer for these families. We are wrapping…

Thanks, Jon. It was an absolutely great quarter with over $108 million in global revenue against our expectation of $97 million. Demand remains strong and was the key driver of our 34% year-over-year revenue growth. New patient prescriptions for the past three quarters continue to equal the high demand we experienced in the very first three quarters of the launch three years ago. But operational improvements made the immediate difference that drove our performance in the quarter. The investments in our team that we have described previously are paying off significantly. The percentage of patients on paid therapy, for example, is up nearly 3% since the end of 2023, from 71.5% to 74.4%. This is ahead of our expectations. Of note, we are up to a paid patient rate of 82% among commercially insured patients. Recall that about 60% of our patients are commercial, and the paid rate in this segment is up from 79% at the end of 2023 and 72% at the end of 2022. This progress makes our long-term expectation to reach 85% paid even more clear. Other aspects such as increased patient compliance and retention against our Q2 expectations added to the great result and we see these improvements being sustainable. With that base of improving operations, let's move to the long-term demand and overall market opportunity. Patients have long told us that they want a convenient oral route of administration to prevent attacks, but they won't compromise on efficacy and nor will their physicians. Our long-term data and real-world evidence are convincing patients and their physicians that both are possible with ORLADEYO, efficacy and convenience. The cornerstones to this motivating message, 91% reduction in attacks versus baseline in our pivotal trial and the growing and consistent body of real-world evidence that reflects the favorable experiences…

Thanks, Charlie. It's very encouraging to see yet another really strong quarter for ORLADEYO. It's great work by the whole team. You can find a detailed second quarter financials in today's earnings press release. I'd like to call your attention to a few items. Total revenue for the quarter was $109.3 million. And as Charlie said, $108.3 million of that came from ORLADEYO. That's a 34% increase in ORLADEYO revenue over the same quarter last year and ORLADEYO revenues in the past 12 months are over $373 million. Of the $108.3 million of global ORLADEYO revenue, $95.9 million came from US sales with the remaining $12.4 million or 11.4% coming from ex-US Sales. Operating expenses, not including non-cash stock compensation for the quarter, were $87.4 million, a decrease of $6.2 million from Q1 of this year, and a decrease of $3 million from Q2 of 2023. Full year 2024 guidance for OpEx remains unchanged at between $365 million and $375 million. We achieved an operating profit for the quarter of $21.9 million excluding non-cash stock comp and an operating profit of $8.8 million even when including non-cash stock comp which was $13.2 million for the quarter. Cash at the end of the quarter was at $338.1 million, and net cash utilization for the quarter was just $213,000. We had guided to net cash utilization of between $10 million to $12 million per quarter for the remainder of the year. The main driver for the improvement in cash flow for Q2 was the increase in revenue versus forecast of over $11 million. For the remaining two quarters of 2024, I expect net cash utilization to average out at single digit millions of dollars per quarter. We're even more confident in our guidance of having quarterly positive cash flow late next year…

[Operator Instructions] Our first question comes from Tazeen Ahmad. Please go ahead. Tazeen Ahmad with Bank of America, please go ahead. Is your line on mute? We're going to transition to Jessica Fye with JPMorgan. Please go ahead.

Hey, this is Nick on for Jessica. Congrats on the quarter and thanks for taking our questions. So, based on these results including the updated guidance for ORLADEYO and maintained expectations around operating expenses, can you discuss your level of feeling around if you could reach GAAP operating profits in 2024 and not just full-year operating profits excluding non-cash and stock compensation?

Yeah, Q2 as it relates to both revenue and our control on operating expenses, like we said, were terrific. And so what we have guided to previously was getting there not including non-cash stock compensation. We're still guiding to that. Is there a chance that we would get there even including the non-cash stock compensation? Absolutely. It just depends on, for the remainder of the year, revenue and then the offset between that and OpEx. But what I would guide to is our increased confidence of getting there excluding non-cash stock comp.

Okay. And then within that raised guidance for ORLADEYO, can you just discuss in a bit more detail your underlying assumptions around new patient starts, the percent of patients on paid drug, and maybe compliance retention for the remainder of the year, and how that changes -- could change versus 1Q and 2Q?

Sure. Yeah. Nick, as you know, we've reported very consistent new patient starts, and then the last three quarters have been even stronger, as strong as the first three quarters of the launch. So we would expect the consistent demand to keep coming based on all the metrics that I described today. As far as paid rate, like I said, we're ahead of our expectations. We are not expecting major increases for the rest of the year. The goal is to at least hold that consistent with the 74.4% that we were at the end of Q2. And compliance is just really strong. So, compliance at this point, if you measure it by the number of treatment days available to your overall patient population, and then the number of drug days basically delivered, we're in the mid-90s at this point, and we would expect that to continue.

Great. Thanks so much.

And our next question comes from Tazeen Ahmad with Bank of America. Please go ahead.

Hi guys, can you hear me?

Yep.

Okay, great. Thank you. Can I ask a question about the pipeline? You're focused now on Netherton disease. Maybe can you talk about the data that you've collected internally that gives you confidence in pursuing this particular molecule for this indication, and maybe the cadence of data to expect over the next year or so? Thanks.

Sure. So, let me take that last piece first. The cadence is that we, for [1775] (ph), we are proceeding into first in-human this year. And so that's an important milestone to keep in mind for this program. In terms of the data that we have to support that, we have all of the required data to be able to proceed to first human. Generally, that includes safety from a non-clinical toxicology perspective as well as data to support the importance of the mechanism for treating the disease and the potential to improve clinical symptoms in patients. So we have non-clinical data for both safety and efficacy that's supportive of proceeding to humans. We also have data around the likely exposure range, and we will be going to first in-human this year.

Yeah, and Helen and I were in Birmingham this week and we got to see the animal model work that the team is working on. It's an inflammation model and it was really impressive what we saw. The control animals have an inflammation and then the inflammation going down with each higher dose. So the key is that you not only have good drug levels, but the drug levels get to the target, which is the skin. And so far so good. So we're hoping we'll see that in humans as well.

Next question comes from Brian Abrahams with RBC Capital Markets. Please go ahead.

Hey, good morning. Thanks for taking my questions and congrats on the quarter. I'm wondering if you could maybe elaborate a little bit more on why we saw such a big uptick in the paid drug just on a quarter-over-quarter basis and maybe some of the seasonal trends underlying that versus kind of operational trends? And then, can you talk a little bit more about the inputs that went into your resizing of the HAE market and I guess just in terms -- with the additional 1,000 patients? And just kind of wondering if you can talk about the characteristics or anything you've learned about those additional patients who are out there, how accessible they are, what you might need to do to engage them. Thanks.

Hey, Brian. First off, on the uptick in the paid, as I mentioned in my comments and we've talked about this before, we've invested a lot in the team to really make sure that we are helping patients and healthcare providers do everything possible to not only put in kind of a complete start form upfront, all the information that payers want, but then to go through the appeals process when that's necessary. And since we made that investment last year, I think the team is really hitting stride, and that's what's making the difference. It's not a seasonal factor in Q2. Q1 is really the seasonal time with the reauthorizations. But now it's just really about every single patient and just the operational improvements that we've made. So I'm really pleased with their progress. As far as the resizing of the market, we've done this kind of work with claims data regularly and you'll recall that prior to launch we talked about 7,500 diagnosed and treated patients. We knew that there was a larger population of untreated patients, but we were conservative in those initial numbers that we put out. What we're seeing now with ORLADEYO attracting patients from all segments, from prophy switches, from on-demand only, and then also treatment-naive patients, we're attracting all three. And so we redid the numbers. We've seen that the market has grown. We think a good portion of that growth is due to our promotion with ORLADEYO. And so we thought it was time to update the overall [opportunity] (ph).

Got it. Thanks so much for the color, Charlie.

And the next question comes from Chris Raymond with Piper Sandler. Please go ahead.

Thanks for taking the question and congrats on the progress. Great to see. Just maybe one question on ORLADEYO, one on the pipeline. So, I was kind of struck by your patient activation slide with the market research showing that essentially three in four patients are willing to switch. Can you maybe give a little bit more color on, as you sort of distill those patients down, how do you activate those patients? That would seem to be a dynamic that would indicate -- certainly understand why your guidance has been raised here, but that there's maybe a little bit more opportunity if you can really convert all those patients. So maybe how many of those do you think are really candidates for activation? And then maybe just a pipeline question, with respect to the Netherton syndrome program, just maybe talk about why you think a KLK5 inhibitor would be effective in this population? And just looking at some of the other programs that are in this disease, talk about maybe how you look at the differentiation. Thanks.

I'll start with the question about the patient activation. Yeah, we're thrilled to see that so many patients are willing to switch and so many patients who are on injectable prophylaxis and that that's continued and actually grown throughout the launch. We have a number of ways that we try to activate them. We have extensive digital marketing, other kind of direct marketing programs to patients. But I'll say the number one way to activate them is to make them aware that ORLADEYO is out there and then to make sure that their healthcare providers are confident in the product. And what you can see from the data I've shown you today is physicians are increasingly confident. And I think when physicians have that conversation with their patient about all of their treatment options, you combine that with the strong patient desire for oral therapy and the willingness to switch, that is what is going to activate more patients to switch. That's going to be the strongest driver.

And, maybe I'll start and then pass it to you. So it's a great question because we're really excited to bring something forward that actually treats the underlying disease rather than the inflammation and the system, the inflammation due to the disease. But I'll let Helen talk a bit more about it.

Yeah, thanks, Jon. So, KLK5 is dysregulated in Netherton syndrome. That's the cause of the disease. So, the KLK5 inhibitor is a way to place the function that's missing and improve the cause of the disease. It’s -- so we believe we have a differentiated product for this for two different reasons. One, we've achieved very, very high potency with our drug and that means that we could potentially deliver a subcutaneous dose and also deliver it on a less frequent basis than is typical for this type of therapy. And so, two, in terms of the mechanism of the disease, it's important to go back to that KLK5 dysregulation of the cause of the disease. Approaching this target means that you don't just affect the cause of the disease in the skin, you're also affecting the downstream inflammation, whereas some other programs that are in the pipeline for this disease are affecting just the downstream inflammation. So we expect to see healing of the skin and improvement of the disease from that perspective, as well as preventing then the downstream inflammation that causes other effects in the disease.

And one of the things you see in rare diseases like this where there's nothing to treat it is there are way more patients than you originally estimated and that's really exciting as well.

Thank you.

The next question comes from Gena Wang with Barclays. Please go ahead.

Thank you for taking my questions. I also want to add my congrats on the strong quarter. So, with revised guidance, just wondering where do you see the main increase? Would that be mainly from on-demand patient, untreated patient or continue to be from the switch over patient? And then for the pipeline assets, just wondering, were you at some point, sharing the preclinical data?

On which program, Gena?

The lead asset, the pipeline asset, the 17725.

Okay, got it, got it. So, Gina, I think what I showed today, we're thrilled that we are getting over 50% of patients from prophylaxis switches, and then, we're also getting the on-demand patients and even treatment naive. We expect that to continue and the market research that I showed on Slide 12 is specific to patients on injectable prophylaxis and you can see from that that 50% of the patients have -- of those patients have a preference specifically for oral prophylaxis therapy and three out of four of those patients are willing to switch. And so, what I would expect is the same dynamics to continue, about half the patients coming from prophy and then the other half coming from on-demand and treatment-naive.

While it's great to see that, you know, growth this year and growth next year is going to come from that growth in patient demand, the increase in the guidance for this year, a lot of that's driven by the operational activity that Charlie explained. So it's great to see both things happening simultaneously.

Helen, you want to take the…

Pipeline? Yeah. So in terms of sharing preclinical data, we would of course publish data in the future as we have excellent results for our pipeline programs. In terms of the Netherton syndrome program, Jon mentioned earlier the data that we have in an animal model showing changes in the skin. We also have animal model information showing the extreme potency with this molecule. So we would expect to share data supporting both potency and effect. But for the purposes of today, I think it's important to know that we have sufficient information to be ready to proceed to first in-human and we're very excited about this program's potential.

Yeah, and we're going to have human data by the end of next year. So you're going to start to get a sense of activity and dose by the end of next year, both in this program and the DME avoralstat program, which is super exciting.

Thank you.

[Operator Instructions] Our next question comes from Maury Raycroft with Jefferies. Please go ahead.

Hi, good morning. I'll add my congrats on the quarter and thanks for taking my question. Just to follow up on the paid patients improvement this quarter, you said you could potentially get to 85% paid patients over the next few years, but it sounds like you're doing better than expected on this front. At this point, are you able to provide more clarity into when you could achieve the 85% of patients on pay track?

Hey, Maury, I think the real key with the 85% is, that's part of our growth to the $800 million in the US as we achieve $1 billion in peak sales. We previously mapped out a path to that by 2029. We'll try to get there as quickly as we can, but if we get there by 2029, we will achieve that billion dollars. And based on what we've talked about today, it's increasingly clear that we're going to get there. What I'm particularly excited about, and I noted this in my comments, is the fact that we're at 82% paid already for the commercial segment, which is our biggest segment. And that just shows that we're going to get there. It's just a matter of time.

And, Charlie, is it fair to say that next year could be a really interesting year with Medicare patients in particular? And we don't want to project what we think will happen, but there's a possibility that we could make real progress there as well.

That's right. There's an opportunity to hopefully get a lot of the Medicare patients who have not been able to afford their co-payments and that's led them to be on free product with the full introduction of the IRA next year and the max out of pocket for patients going to $2,000. That could be an opportunity that creates more affordability and thus more paid patients.

Got it, that's helpful. And just to clarify, for the 74.4% for this quarter, you expect that to be consistent for the rest of this year, or could that potentially improve some as well?

We will always try to improve it. The time where we can make the biggest progress is during the big reauthorization season in Q1. And we did a great job in Q1 and then some of that great job bled into the early part of Q2. The rest of the year will be driven more by new patient prescriptions coming in, the opportunity to convert long-term free product over to paid will be less than it was in the first part of the year, kind of the seasonal cycle that we should expect going forward.

Got it. Okay. Thanks for taking my questions.

Next question comes from Stacy Ku with TD Cowen. Please go ahead.

Wonderful. Thanks so much for taking our questions, and congratulations on the progress. So we have a few follow-ups. First, appreciate your detailed market research. Our KOLs and survey also tell us that additional injectable entrance are very unlikely to impact oral prophylactic options in HAE. So, curious if Charlie or Jon, can discuss long-term where they expect the oral share to stabilize versus the injectable share. That's the first question. And then the second question is a question on clinician outreach. So, Charlie, can you talk about the progress this year? How many new prescribers are adopting ORLADEYO? And what percentage are still in the early days of a prescribing? Just remind us our goals for this year and what target you might have for next year. And then last, a quick follow-up. Just, can you elaborate a little bit more on the ex-US versus US split in Q2? Thanks so much.

Sure. So, on the long-term oral share, I mean, ORLADEYO obviously is the only oral drug on the market in once a day. You really, you can't get better than that. So -- and we talked about our path to $1 billion and 2,000 paid patients in the US. And so, 2,000 out of over 11,000 total patients, you can imagine ORLADEYO is going to get to at least about 20% share. We'll see what happens with other products in the future, but we're very confident in our overall growth. As far as prescribers, we continue to see new prescribers coming on board, And we've talked before about our Tier 1 doctors that cover about 50% of the market, sort of 500 to 600 doctors there. And then the bigger Tier 2 group. In Q2, we got equal number of prescriptions from both of those groups. So, very -- continues to be very balanced. And we had a very similar number of new prescribers to what we've seen in recent quarters. And as far as kind of adopters in the Tier 1 group, we're now to the point where over 70% of them have prescribed and we keep chipping away at that number. We may never get to 100% with them, but we're going to get close. And all the metrics we see is doctors across the board intend to do more.

Hey, Charlie, and on that 30%, can you talk about how things like more prophy medicines come into the market, and the noise of prophy going up can be an opportunity and [ped] (ph) opportunity as well?

Yeah, it's a great point Jon brings up. So we have two big opportunities. One, we do expect other competitive injectable products to launch. One may come as soon as the end of this year. And with that, there's just going to be more conversation around switching patients, more treatment options, maybe lower burden treatment injectable products. And so we're going to take advantage of that because we have the product that patients want with an oral once-daily therapy. And then [peds] (ph) that we intend to file next year, that is an opportunity in itself, but also there's the halo effect from that. It's a genetic disease. There are families. And then there are doctors where this may become their first real experience with ORLADEYO, and starting with the kids, and then they maybe move on to the rest of the family. So both of these are opportunities over the next couple of years for us.

Yeah. So these KOLs that tell us, if it’s not broke don't fix it, if they've got a pediatric patient on injectable it's going to be pretty hard for them to not want to switch to an oral. So we think that's a real opportunity to have that conversation with them. And then, ex-US, Charlie?

Yeah, ex-US, what we see is the same consistent pattern of demands. We see many of the ex-US countries moving increasingly towards prophylaxis. For market access reasons, they may never get to quite the same levels of the US. But we're seeing prophy become the standard of care for patients and ORLADEYO to be growing very strongly. And patient retention, too, has been very consistent with what we're seeing in the US. So, Europe, Japan, Canada, Eastern Europe, we're starting to launch now with our partners in Latin America, a lot of opportunity and a lot of excitement about ORLADEYO coming to the market.

Wonderful. Thank you.

And the next question comes from Jon Wolleben with JMP Securities. Please go ahead.

Hey, good morning. Congrats and thanks for taking the question. Just a couple more for me on the market sizing updates. I'm assuming in that 8,500 you guys gave us, that's including acute and prophylactic patients, but wondering if you had any sense of reasons why that other 2,600 or so are not being treated? And then do you have any sense today of what percentage of treatment naive patients are going to ORLADEYO first?

Sure, Jon. Of the 8,500, that includes patients that are in HAE-specific medicine. So when we do this analysis, we look at all the prophy products. We also look at all the acute, the modern prophy products, I should say. So, ORLADEYO plus the injectables, and then the acute therapies. So, that's what's included there. You saw the data where we're attracting 17% of ORLADEYO patients launched to date have come from the treatment naive. What that tells us is that that treatment naive group is going to increasingly become a treated group. Some of those patients are probably just becoming aware of their disease or their physicians are starting to become more aware about HAE. And so again, it may never reach 100% of those patients treated, but we expect more and more of them will be treated, and it's a great opportunity to help more patients.

Okay, but you don't have a sense from market research or what you're seeing in claims, like, a new patient coming into the system is preferring ORLADEYO or TAKHZYRO?

Yeah, I knew I was missing one part of your question. We do. ORLADEYO gets -- we have at least 50% of those patients in our market research get ORLADEYO first before other prophylaxis products.

That's helpful. Thanks, Charlie.

The next question comes from Serge Belanger with Needham & Company. Please go ahead.

Hi, good morning and congrats on another solid ORLADEYO quarter. First one, given the nice growth we've seen over the first half of 2024, can you tell us a little bit about where you are in terms of market share in the market? And then maybe for Charlie, regarding the prescribers survey, we've seen a pretty drastic increase in the likelihood of prescribing year-over-year. Just curious, what do you think drove that increase over such a short period of time? And if I'm not mistaken, you've conducted a survey, I think, every year. Just curious how it is -- how predictive it is for future use and uptake of ORLADEYO? Thanks.

Sure. As far as share goes, Serge, I'll point you back to the 2,500 prescriptions we had at the end of last year. Some of those, of course, are repeat, patients who had dropped off and come back, but I think that's a pretty good marker roughly of where we are. So, depending on how you want to do the math, either of treated patients or of the total market, we're probably nearing 20% market share, roughly, a little bit below that, but growing very strongly. And then as far as kind of the indicators of increased prescribing and the physician confidence, I think it's what I said in my remarks. They're just -- they're experiencing -- they're learning more about the data and they're seeing it in their patients. So I think the best way for a physician to learn about this drug is to try it in their patients and see how well the patients respond. And that's why, of current prescribers, now 52% of them say they are extremely likely to prescribe more because they are seeing the response in their patients. And we do these surveys every quarter and we always ask physicians, what are you going to treat your patients with over the next 12 months? And what we've seen over the last year is that the drug they see to grow over the next 12 months is ORLADEYO. That is where they see the most growth in the marketplace, and I think it's because of what they're seeing with results in their patients.

This concludes our question-and-answer session. I would like to turn the conference back over to [Jim] (ph) Stonehouse for any closing remarks.

Yeah, I'd just like to wrap it up by saying, again, what I said before. It was an absolutely amazing quarter. It's two in a row now. The momentum we have, we see no signs of it slowing down. We're now having revenue over $100 million per quarter. And you should ask yourself, why is this happening? It's because this drug really works, right? When a patient sees control, they have the same kind of control they had with any other prophy medicine they were on before, and they get it with a once-daily oral medicine. And that is why we're seeing this great success. And then the last thing I'd say is, thanks to the commercial team for just having an outstanding performance and continuing to build the momentum in this company. Thank you.

This concludes our question-and-answer session. I would like to thank everybody for joining today's presentation. You may now disconnect.