Thank you for standing by, and welcome to the BioCryst's Second Quarter 2021 Earnings Call. Please note that all participants would be in listen-only mode until the question and answer session of today's conference. Please also note that today's call is being recorded. I'll now turn the call over to your host John Bluth. Sir, you may now begin.

Thanks, Jesse. Good morning, and welcome to BioCryst's second quarter 2021 corporate update and financial results conference call. Today's press release and accompanying slides are available on our website. Participating with me today are CEO, Jon Stonehouse; CFO, Anthony Doyle; Chief Commercial Officer, Charlie Gayer; Chief Medical Officer, Dr. Bill Sheridan; and Chief R&D Officer, Dr. Helen Thackray. Following our remarks we'll answer your questions. Before we begin, please note that 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. I'd now like to turn the call over to Jon Stonehouse.

Thanks, John. As you can see in the numbers we've reported today, we had $50 million in revenue, including $28.5 million of ORLADEYO net revenue in the second quarter. The ORLADEYO launch continues to go very well. We're now on the ninth month of the launch and have a consistent and growing body of evidence from the marketplace that most patients are benefiting and staying on the drug. They are switching from injectable therapies that control their disease because they're achieving the combination of disease control and reduced burden of therapy on ORLADEYO. The commercial team has done a fantastic job of executing, despite extremely challenging circumstances with COVID limiting our ability for face-to-face interactions with our customers in the first half of the year. As you'll hear in more detail from Charlie, our launch success is a direct result of having a drug that patients want, a great plan centered around patient switches, and execution of that plan by an extremely talented and experienced team. This strong start to the ORLADEYO launch in the U.S. and approvals and launches starting outside the U.S. to get ORLADEYO to patients around the world gives us confidence that we will achieve sales this year of no less than $100 million and puts us on an excellent trajectory to exceed $500 million in global peak sales. A growing revenue stream from ORLADEYO enables us to continue to invest in our pipeline, advancing other important oral medicines for patients suffering from rare diseases. The best example of this is the BCX9930 program. In the first half of the year, we moved directly from Phase 1 into pivotal trials in PNH, which will begin enrolling later this year. Like HAE, patients with PNH tell us they want an effective therapy with a low burden of treatment. They tell us that the treatment burden with current therapies can be hours in an infusion center. We believe 9930 has the potential to offer a significant benefit to these patients, and we are thrilled that we are entering pivotal trials in this disease. Bill will share an update on our Phase 3 with you shortly. Our goal is to continue growing ORLADEYO while in parallel pursuing approvals and launches of 9930 across PNH, renal complement diseases, and many other complement disorders. BioCryst has discovered and developed what is shaping up to be a very attractive pipeline of oral medicines for patients suffering from rare diseases, and we're now demonstrating our commercial rare disease capabilities as well. I'll turn the call over to Charlie to give you more details on ORLADEYO.

Thanks, Jon. Quite simply, the ORLADEYO launch is going great. With Q2 building on our fast start in Q1. Long term clinical data also confirm what we knew; ORLADEYO is a very effective drug. Data from our APeX-2 trial presented at EAACI in July showed that patients who started on ORLADEYO 150 mg had an 80% reduction in attacks compared to baseline after 96 weeks, with the median attack rate most months being zero. The potential of this outstanding level of attack control with just one pill a day is what motivates patients and prescribers. In fact, our prescriber base grew by 50% in Q2, and patient switches from injectable prophy agents and acute-only therapy continue to drive the launch. We expected prophy switches to be the largest source of business for ORLADEYO, and that is exactly what is happening. 60% of patients starting ORLADEYO in the second quarter came from other prophy therapies, with Takhzyro representing over 40% of the Q2 prophy switches followed in order by Haegarda, Cinryze, and androgens. The HAE treatment paradigm in the U.S. has moved beyond outdated classifications like mild, moderate, or severe disease. The goal of modern prophy therapy is to prevent as many attacks as possible and to reduce the impact of any breakthrough attacks. That's why 60% of HAE patients were already treated with prophy at the time of the ORLADEYO launch. What patients want now is to control their attacks with the lowest possible burden of treatment. ORLADEYO is also contributing to prophy market expansion, as use of acute treatment continues to decline. Of the 40% of patients in Q2 who did not come from other prophy therapies, most switched from acute-only. Some of the acute-only switchers were patients returning to prophy after having given up on injectable products in the past. ORLADEYO is attracting a small, but important population of patients new to HAE therapy. ORLADEYO is transforming the HAE treatment landscape across all segments, allowing patients to prevent attacks with the lowest possible burden of treatment. Once patients switch, ORLADEYO is meeting their expectations, with now eight months since launch. We see patient retention trending in line with the 75% one-year retention in our APeX-2 clinical trial. Importantly, we see no differences in retention related to prior treatments that patients used. Medication compliance rates are also very high, nearing what we saw in clinical trials because, very simply, patients are self-motivated to prevent attacks, and they find it easy to take a daily oral therapy. We also made significant progress with payers in Q2. Patients and physicians warned us that the hassle and uncertainty surrounding coverage for new HAE medications could limit willingness to switch. As of today, the payers for approximately 70% of the HAE market already have coverage policies for ORLADEYO. This base, plus additional policies we expect, will allow many existing patients to transition to covered product over the rest of the year. The reassurance of broad coverage, combined with a high level of service and support offered by our patient services program, will also give new patients and their prescribers even more confidence to start on ORLADEYO. This launch is still in its early stages, and we are bullish about the future. Intent to prescribe is high across our target base, including those HAE treaters who have not yet prescribed ORLADEYO. The gradual increase in face-to-face calls, promotional events, and medical congresses will all add momentum to the launch. For all these reasons, we are very confident that ORLADEYO will achieve no less than $100 million in sales this year. Launches are also underway in Japan and Germany, and our European team is preparing to launch in the U.K., France, and several other markets over the next 12 months. We recently announced our regulatory filing in Israel, and we are continuing to file around the world. As I've shared with you today, the trends are strong in the ORLADEYO launch. As we seek to transform HAE care in the United States, we believe ORLADEYO also has the potential to transform HAE treatment globally, with each new market contributing to what we expect to be $500 million plus in peak sales. I'll now turn the call over to Anthony for the financials.

Thanks, Charlie. As you've just heard, the launch of ORLADEYO has been going very well, especially when we consider the impact that COVID continues to have on a global basis. ORLADEYO continues to create real value for patients, the company, and shareholders alike. And we are confident that we have built the foundation for a strong second half of the year. You can find our detailed financials in today's earnings press release, and I'd like to call your attention to a few items. Net revenue for the quarter was $50 million, of which $28.5 million came from net global sales of ORLADEYO and $15 million from our partner Torii following approval and completion of pricing negotiations in Japan. Our operating expenses, not including non-cash stock compensation for the quarter, were $72 million. We ended Q2 with $223 million in cash. This cash on hand, in addition to revenue generation and access to the additional $75 million available from Athyrium, continues to give us cash runway into 2023. Last quarter, we proactively addressed some questions that we had received, and I'd like to take the opportunity to do so again this quarter. As a reminder, we recognize revenue upon shipment from our specialty pharmacy to patients for use, not including inventory or channel stocking. Strong new patient uptake and the success of our quick start patient assistance programs continue to be the main driver of our gross net adjustment. As we said previously, this should normalize in the 15% to 20% range as we get towards peak sales. As Charlie described, we continue to be very encouraged by the results to date. We're very confident that net revenue for ORLADEYO for the year will be no less than $100 million, but there are both upside opportunities that could accelerate the launch trajectory and uncertainties that could slow us down. We need more time to see them develop and play out before providing more specific guidance. Some of these areas that we need to be cognizant of as we go into the second half of the year are: firstly, we're still early in the launch. As such, we need more time to let steady-state monthly prescriptions and customer retention develop further. We remain encouraged by what we're seeing so far, but it's still too early to accurately forecast our guidance. Secondly, as Charlie said, we've made great strides in getting ORLADEYO onto policies thus far, but we still have work to do to complete this effort and transition new and existing patients to reimbursed product. Next summer and the end-of-year holidays are historically slower periods for switches for HAE patients. More data in the next couple of months will help us ascertain if this impacts our trajectory. Lastly, there's a continuing impact due to COVID. With doctors and patient visits naturally declining due to the impact of the delta variant, we need more time to ascertain how this might impact the launch in the coming months. We'll be watching these opportunities and uncertainties to see how they influence our launch trajectory. But as I said, based on our performance in the first half of the year, we are very confident that net revenue for ORLADEYO will be no less than $100 million this year. One thing that is for sure is that ORLADEYO is a great product that is helping patients manage their HAE with both attack reduction and the freedom that a reduced burden of treatment brings. With the potential of this treatment combined with the opportunities for BCX9930 that Bill will discuss, I'm very excited to see the progress that we'll make in the second half of the year and beyond. With that, I'll hand it over to Bill.

Thanks, Anthony. The successful launch of ORLADEYO is very exciting for the team at BioCryst who discovered and developed this unique drug, because we can see the profound impact that it is having on the lives of HAE patients. Next up in our development pipeline is BCX9930, our oral Factor D inhibitor for complement-mediated diseases. But at our March R&D Day, we heard from a leading expert physician and a patient advocate who is living with PNH about the unmet needs of correcting anemia, relieving fatigue, and reducing red blood cell transfusions. We also heard about their enthusiasm for our oral Factor D inhibitor. BCX9930 has a great opportunity to substantially improve PNH disease control compared to the currently available intravenously infused C5 inhibitors because it can address both extravascular and intravascular hemolysis. These clinical advantages come on top of the expected dramatic reduction in treatment burden. Based on the results of our dose-finding proof-of-concept study, we met with regulators, reached agreement on study designs, and have accelerated the development of BCX9930 from Phase 1 directly into pivotal trials. Today, I'd like to share details about our pivotal trials in PNH, provide an update on our renal proof-of-concept trial, and discuss next steps in broadening our research into other indications. Our two pivotal trials of BCX9930 oral monotherapy in patients with PNH, REDEEM-1 and REDEEM-2, have been designed as rigorous randomized controlled trials with the goal of supporting broad labels around the world. Details of these studies can be found in the slide set on our website. For both trials, patients must be anemic and show a bone marrow response to anemia with increased reticulocyte count. The dose of BCX9930 in both trials is 500 milligrams BID. REDEEM-1 is a 24-week open-label randomized clinical trial of BCX9930 in approximately 81 PNH patients with inadequate responses to C5 inhibitors. REDEEM-2 is a 12-week blinded randomized clinical trial of BCX9930 in approximately 57 PNH patients not currently taking a complement inhibitor. In both studies, after the controlled period, all patients received BCX9930 monotherapy through a formal week 52 safety evaluation and then roll over into a long-term extension. The primary endpoint in both trials is change from baseline in hemoglobin, powered to detect a treatment effect of approximately two grams per deciliter. Given the much greater effect on hemoglobin that we have seen in our proof-of-concept study, we're very confident of hitting the primary endpoint in both trials. The key secondary endpoints in both trials include assessment of transfusions, fatigue, and other endpoints include additional relevant clinical laboratory and health-related quality of life outcomes. Importantly, the blinding in REDEEM-2 allows us the unique opportunity to rigorously understand the impact of BCX9930 on fatigue scores and other health-related quality of life outcomes. Finally, patients in REDEEM-2 must have a high level of urgency in screening, and percentage change from baseline in LDH is an additional key secondary endpoint only in that trial. Turning to our ongoing rollover study for the dose-ranging trial, patients have continued to take BCX9930 BID, with average dosing duration now exceeding nine months and the longest time on drug of 17 months. The nine patients who are naive to C5 inhibitors have all continued to benefit from BCX9930 monotherapy with maintenance of hemoglobin responses, no red blood cell transfusions, and maintenance of improvement in biomarkers of hemolysis and PNH red blood cell clone size. All nine patients have continued on therapy. Turning now to the six C5 inhibitor inadequate response patients in our trial, five had high levels of C3 oxidation on PNH red blood cells at baseline. Remember, that's a marker setting up extravascular hemolysis. And all five continue to benefit from BCX9930. Recently, the investigators have decided to discontinue C5 inhibitor in four of these patients, including one patient who had required transfusions for hemolysis following COVID-19 vaccination while being treated with both ravulizumab and BCX9930. These four patients are now continuing on BCX9930 monotherapy. Another patient with inadequate response to C5 inhibitor who we discussed in March had a very large transfusion burden pre-trial associated with pre-existing hyposplenism and other medical conditions complicating PNH. In this patient at baseline, the proportion of PNH red blood cells that were oxidized by complement was only 0.8, indicating that complement-mediated hemolysis was likely not a main factor in this individual's anemia. Although the rate of red cell transfusions was reduced with BCX9930 compared to pre-study, this patient has decided to withdraw from the trial. BCX9930 has continued to be safe and well tolerated with increased duration of dosing. We've seen no safety signals with up to 17 months of exposure. Overall, the continued benefits and safety profile for our proof-of-concept trial patients are very encouraging and form the basis for our confidence in moving to pivotal trials in PNH. Although PNH is a competitive space for clinical trials, the enthusiasm for our pivotal program from top investigators and PNH patient advocates based on our excellent results from the proof-of-concept trial provides us confidence that these trials can be recruited. Startup activities are now underway around the world, and we expect to begin enrolling patients later this year. We are also on track to begin our proof-of-concept trial in renal complement-mediated diseases by the end of the year. This will be a basket study including three cohorts of patients with C3 glomerulopathy, IgA nephropathy, or primary membranous nephropathy. Each cohort will enroll up to approximately 14 patients. The trial will collect comprehensive clinical activity, pathology, and biomarker outcomes to estimate treatment effect size and facilitate endpoint selection for pivotal studies for each of these indications. Because BCX9930 inhibits Factor D, thus blocking the alternative pathway, and because this pathway is involved in many diseases, and because our clinical evidence confirming this mechanism of action is compelling, we plan to drive development across multiple additional indications leading to regulatory submissions, approvals, and launches around the world. This is an exciting time, and BCX9930 truly represents a pipeline in a molecule. We're moving this program forward with all due speed, investing fully to complete development of this unique medicine as fast as possible and bring it to patients who need it. And now, I'd like to hand the call over to John to wrap up.

Thanks, Bill. The launch of ORLADEYO is off to a fantastic start with even more success to come. We're launching our pivotal program with 9930 and PNH with more indications to follow. Our R&D team continues to advance additional molecules towards the clinic. It is an exciting time at BioCryst and an exciting time to be a BioCryst shareholder. We look forward to keeping you updated on our progress as we continue to build our company. That's it for the prepared remarks. Operator, we're now going to open it up for questions.

Thank you, speakers. Speakers, first question from the line of Ken Cacciatore of Cowen & Company. Your line is now open.

Congratulations team on the success of the rollout. It's just fantastic to see. Just wondering if you could give us some commentary around the pacing of patient starts through the quarter, so we can try to get an understanding of where we were exiting. And just to confirm, I believe you said roughly 70% of patients were on paid drug at this point. I just want to make sure we can confirm that. And understandably good nuance about no less than $100 million to the balance of the year and all good reasons. Just wondering about this initial start. And as we think about the pacing of patients in terms of how they see the clinician through the balance of the year. So, they're normally on average two patient visits or one patient visit. Just trying to understand your ability to capture how many kind of bites of the apple you get to convert patients. So just kind of any nuance on how these patients typically present themselves to the clinicians? And then, also maybe just early commentary about Europe. I know it's early in Germany. But any nuance around what we're seeing there so far? Thanks so much.

Charlie, I'll take the last two. You could take the first two. Thanks, Ken. So, on the pacing of new patient starts since launch, it's been really strong and consistent right from the beginning, month over month, and so I think that's part of a reflection of the 50% increase in prescribers that we've seen. So, very strong. You were asking about the coverage. What we said today is that 70% of payers now have coverage policies established. In Q2, the majority of our patients were already receiving reimbursed product. But as both Anthony and I said, some of our existing patients now with the new coverage policies will roll over to paid product in the second half of the year.

Ken, regarding the pacing and clinic visits, you're generally correct about the estimate of around two visits per year. Charlie and Anthony explained well the factors that could significantly increase our revenues beyond $100 million, as well as the uncertainties that might keep us close to that figure, particularly in relation to the summer months. This is our first July and August since launching the drug, so we want to observe how that unfolds before providing more specific guidance. As for Europe, as Charlie mentioned, the uptake there will differ from the U.S. and is expected to be slower. The launch in Germany is in progress, and they recently lifted some strict COVID restrictions which could affect patient access to universities and clinics. We need to see how these developments unfold. Over time, I anticipate these factors will contribute more significantly next year, and as Charlie noted, we will see additional countries launching as pricing agreements are reached.

Thanks so much.

Next question is from the line of Brian Cheng of Cantor Fitzgerald. Your line is now open.

Good morning, team. Congrats on another quick quarter. And thanks for taking my question. So you're seeing patients adopting and switching from both prophy and on-demand options to try ORLADEYO. We're just curious how you're thinking about the on-demand versus prophy shakeout in the next few years? And can you comment on how the patient access through medical exceptions versus formal reach has changed this quarter versus last quarter? And I have a quick follow-up. Thanks.

Charlie, I'll take the first question and you can address the second. Brian, concerning the prophylactic and on-demand market, it's declining consistently. It's not just us experiencing this shrinkage; Takeda and CSL are seeing a similar trend with their prophylactic therapies. Honestly, we mentioned a possible 80/20 split, but as things settle, it could lean more towards 90/10, especially considering that patients have always preferred prophylactic therapy. They want to prevent attacks, and the introduction of an oral option has generated significant enthusiasm.

Yes. And then Brian on your question about the medical exception trend. We had a lot of success in the first half that we've talked about before getting patients covered via medical exception. What's great now with 70% of the market having access to ORLADEYO coverage is that, as I said in my remarks, that gives patients and prescribers a lot of confidence coming in. What it's going to mean is that for new patients coming onto the product, they're going to start getting to paid product a lot faster, a lot sooner in the process. So, we still pursue medical exceptions when needed. We still have successes there, but increasingly coverage will be through formal coverage policies.

Okay. And related to 9930 and PNH, just curious if you can tell us the rationale behind the difference in the primary endpoint for REDEEM-1 versus REDEEM-2. And then will there be a change in LDH included as a part of the secondary endpoints in REDEEM-1? Thank you for taking my question.

This is Bill. Yes. The primary endpoint in both studies is the same. It's change from baseline in hemoglobin. The powering ability of what you can detect is a little bit different because of the difference in sample size between the two studies. Quite frankly, we're very confident of exceeding what we've put in for the power in terms of approximately two grams of change in baseline hemoglobin based on the proof-of-concept results. Remember, these studies also have to provide a safety database, so we could have had a smaller sample size in REDEEM-1 perfectly easily with a slightly different hemoglobin target for powering purposes. But we need the additional subjects for safety for NADA. And would you mind repeating your second question?

Regarding LDH change, whether that would be included as a part of the REDEEM-1 study?

No, it won't. So I think that the issue for most patients who have an inadequate response to C5 inhibitors is extravascular hemolysis, and LDH is really a biomarker of intravascular hemolysis. So, we measure all the biomarkers, but it's not a key secondary endpoint in REDEEM-1.

Got it. Thank you.

Next question is from the line of Liisa Bayko of Evercore ISI. Your line is now open.

Hi, guys. Great quarter and thanks for taking the question. Can you maybe provide a little more color on what kind of gross to nets you're seeing at this point? I know you said the majority of patients in the second quarter were receiving reimbursed drug. But what does that mean as we think about gross to net adjustments?

Yes. Thanks, Liisa. So, they continue to improve quarter-on-quarter. So, as more patients move over from free product onto reimbursed, and as Charlie said, as more new patients come directly onto the reimbursed product, we've absolutely seen them get better quarter-over-quarter. We're not going to give specific details there, but what we did say was we still feel really strongly about that idea that we're going to get to 15% or 20% in line with other small molecules as we approach T-cells. Honestly, I'm really happy with the way things are playing out from gross to net.

Okay. And I guess, were you at the majority last quarter? Just kind of thinking about how things have evolved?

In Q1, the majority were on free product, and in Q2, the majority were on paid. So the trend is this.

Got it. Okay. Thank you. And then, in terms of compliance persistence, I realize that's kind of an unknown factor for the future. But can you maybe tell us what you're seeing so far in these first sort of six months since launch? What kind of compliance persistence are you seeing?

So, you might want to reference what we saw in the clinical trial and then how it relates to that.

Yes. So, Liisa, in APeX-2 we saw 75% one-year patient retention. What we're seeing so far, eight months into the launch, is we're trending within that. So, the patient retention is really good. A big part of this is a reflection of this drug working really well. The data we presented at EAACI with an 80% reduction in attacks versus baseline shows that patients do really well on this drug. As far as compliance goes, I mentioned it's been very high, close to our clinical trials rate, which were in the 90% range.

It was high 90s.

Okay, great. And then turning on now to oral factor D, I'm kind of really interested in this basket study that you're doing of renal complement diseases. Can you talk about how you were thinking about that study? I'm assuming proteinuria is going to be the endpoint. When would you measure that? And is that important across all these diseases? What sort of levels do you think you need to reduce to be competitive? Maybe just give us a little more color on how you're thinking about that approach? Thanks.

Yes. Hey, Bill. Maybe focus on the quality of selecting patients that truly have the disease. What we're doing to make sure that we have that, and then clarity around the endpoints.

We've had excellent discussions with external nephrology experts in a series of meetings to help us address these questions. It's crucial to ensure that we have patients with active disease rather than those with burned-out disease. Therefore, we will be conducting kidney pathology assessments, including a baseline and follow-up biopsy to evaluate this. It's essential that we have well-standardized and comprehensive assessments of kidney pathology and the role of the complement system in each of these diseases. In a proof-of-concept study, I prefer not to focus on a single endpoint but rather to measure a wide range of biomarkers. While proteinuria is indeed an appealing endpoint, the FDA's initiative with industry and academia regarding endpoints in kidney diseases indicates that the combination of reduced proteinuria and stable neural filtration rate is the direction the field is moving, regardless of C3 glomerulopathy or complement-mediated diseases. We will discuss the primary endpoint choice for a pivotal study with regulators once we have the proof-of-concept results. Each disease is distinct, but existing evidence on the impact of complement inhibitors in C3 glomerulopathy suggests that benefits can be observed relatively quickly in patients with active disease.

And Liisa, I want to highlight that we have transitioned from a Phase 1 study involving PNH patients to pivotal studies in PNH patients and three additional indications in renal disease during the second half of the year. So by the end of the year, we will be pursuing four indications, which is very exciting for us.

Okay, great. Thank you.

Thank you.

Next question is from the line of Jessica Fye of JPMorgan. Your line is now open.

Good morning. Congrats on the quarter. I guess, first, I'm not sure if I missed this, but the $28.5 million of ORLADEYO sales, can you just break out what if any contribution came from Europe or basically anything ex-U.S. or extra pan in that number? And then, is there any way we should think about how much of a tailwind you might see in the back half from gross to net due to improving coverage and less free drug?

Yes. Thanks, Jess. The best way to think about the 28.5 is the vast majority, almost all of it came from the U.S. Jon said, Europe had just kicked off, Germany kicked off in June, Japan in Q2. So I think they'll be more valuable in terms of revenue generation in 2022. The majority of the revenue is going to come from the U.S. In terms of the growth to nets in the second half of the year, I'd say the trend will continue. As we continue to get more patients on, and as Charlie said, we continue to get more payer coverage, I would expect that the gross to net will tighten. Now as we move off medical exception and on to reimbursed via coverage, there will be some adjustment, but it'll be overweighted by new patients coming on and the transition of existing patients onto that reimbursed product. So my expectation is that the rest of the year the gross to net will continue to lower.

Okay, great. And I think you mentioned that patient retention is 75%, like similar to the trial. Can you help us better understand the time course over which patients figure out if they're going to stay on drugs? Does this happen early on? Or is it more steady over time?

Yes. Jess, what we said is we're trending toward that 75% for one year. Typically, patients make that decision in the first few months. That's what we saw in clinical trials, and then that's what we're seeing in the real world.

And the other thing I'd say, Jess, is this EAACI data that we have where you see patients doing better over time. One of the things that we're really encouraging is that patients really give it a fair shot to get the full benefit. As Charlie said, it was an 80% reduction from baseline over 96 weeks, which is incredibly effective, and patients need to give time to get to that point.

Next question is from the line of Serge Belanger of Needham & Company. Your line is now open.

Hi, good morning and thanks for taking my questions. Congrats on the progress. First question on ORLADEYO. I know you haven't disclosed the number of patients on drug, but can you give us an idea of how many new patients started ORLADEYO therapy in the second quarter?

So, you're right, Serge. We haven't commented on the specific number. What I can say is, again, the demand has been strong and consistent, and new patients are now the great majority of our patient base since launch. We also continue to expand our prescriber base. So we had 50% more prescribers in Q2 than we did in Q1, and that trend continues. So we have a lot of growth in front of us.

Yes. And Serge, if this question is around whether this is a bolus or just a point in time. If we leave you with anything, it's a very consistent growth, very consistent.

Next question is from the line of Charlie Gayer of Cantor Fitzgerald. Your line is now open.

Thanks. Good question, Serge. So, all of the policies established thus far are at parity with other prophy products. That's our strategy. We want to make sure that patients and their prescribers can make the treatment choice. I think it's a reflection of how well payers are receiving ORLADEYO. We're not going to stop at 70% and we're actually having really good continuing discussions with additional payers. We expect that number to go up and coverage will be even stronger by the end of the year.

Next question is from the line of Anthony Doyle of RBC Capital Markets. Your line is now open.

It's a good question. We continue to invest in the rollout of ORLADEYO on a global basis. We've talked about the launch going well in the U.S. We've talked about expansion into Europe and then markets beyond that. So, we'll continue to invest in the commercial side of the house. And then, Bill talked about BCX9930, which is a really big deal for us in terms of both the pivotals and then the proof-of-concepts that we have. So we will continue to invest in those areas. If I look at where we are at the moment, can you take that as a run rate and then expect additional investment? Yes. There's value to be unlocked and created in those areas, and we will continue to invest as long as it makes sense for it to create that value.

Next question is from the line of Tazeen Ahmad of Bank of America. Your line is now open.

Hi, guys. Good morning. Thanks for taking my question and congratulations from me as well on a really spectacular quarter. I just wanted to get a little bit of color. You've been really thoughtful about providing your sense about how the rest of the year could look with at least $100 million in sales projected and some caveats to that. I wanted to just maybe get a little bit of color on a couple of those caveats, mainly summer vacation schedules and COVID. As we enter the middle of August, I'm just wondering how those two factors are trending so far this quarter relative to how you exited Q2? And then, I have a couple of follow-ups.

Good questions, Tazeen. As Jon mentioned, this is our first summer. People are taking vacations, including doctors and patients, which we're monitoring. However, demand has remained consistent and strong so far. With regard to COVID, we launched during the pandemic and have been prepared for it. Our sales team managed to increase in-person calls in Q2, which has made a difference. They are ready for any challenges ahead. We are keeping an eye on the situation, particularly with the delta variant that could impact in-person medical meetings and other activities for the remainder of the year. Nonetheless, we are confident in achieving at least $100 million in sales for the year.

Yes, I would just add to that, Tazeen. If there are fewer face-to-face interactions, such as medical meetings, we are optimistic that the College Meeting in November will be held in person, and we've heard that attendance will be great. However, if it ends up being virtual again, that would be a missed opportunity. Bringing patients and physicians together in person is valuable. If COVID hinders that, it would be unfortunate. Nonetheless, we remain very confident in achieving at least $100 million for the year.

Thanks for that, Jon. And maybe another question on COVID. Is there any impact that you're seeing geography-wise on uptake? So, I guess we are to believe the reports that we see that cases are surging in highly populated states like Texas, Florida, California. Are you seeing any kind of correlation between the higher rates of delta in those states and your ability to get traction there?

What we've seen throughout the year is how COVID is affecting prevalence in local policies affecting our ability to do face-to-face. But we're not seeing any trends in terms of patient uptake that we could directly attribute to that. Texas is a great example. The state doesn't require masks, but the City of Austin requires masks. There's just high variability even within a state.

Okay, thanks. And then the last question for me is maybe on the PNH market. There was a recent approval from the TELUS for their C3 inhibitor. As you think about how this market is evolving, does that change the way you think about the market in any way and how your drug could be positioned there?

Yes. I think the really simple answer is we've got a twice-a-day oral drug and that is, Charlie remind me every three or four days.

Twice a week 20 milliliters per injection.

Yes. So from a burden of therapy, Tazeen, if we've learned anything in HAE, it's about controlled disease and it's about reduced burden of therapy. That combo gives patients a real opportunity to have a treatment regime that they've been dreaming about, right? So, I think we could be very competitive with all injectables.

Okay, thanks, Jon.

You're welcome.

Next question is from the line of Jon Wolleben of JPM Securities. Your line is now open.

Hey, good morning. Thanks for taking the questions. Congrats on the progress. A couple on ORLADEYO. You mentioned that there's a 50% new prescribers. Can you tell us how many prescribers you have now and how your targeting approach has been going? If you have any color on the average number of patients per prescriber that are on ORLADEYO?

Good questions, Jon. Our number one tier of targets is about 500 doctors that treat about 50% of existing HAE patients. We've made great progress, great penetration into that group, but still the majority of them have not prescribed. The intent to prescribe is really high amongst them. We have a lot of opportunity that we're very bullish about. We've made a lot of progress into the next tier of our prescriber list. What I'll say about the kind of number of patients per doctor is we've had prescribers who have prescribed for multiple patients with ORLADEYO. That's the goal. We want to go broad across the prescriber base and then deep within the prescribers. The average doctor is still getting started with ORLADEYO at this point, so we expect a lot more of those multiple prescribers in the future.

Yes. And all of that leads to upside, Jon, at the end of the day that doctors who maybe put one patient on have a good experience and start to put more on over the course of the rest of the year.

That's helpful. And maybe one or two on 9930. Can you comment on how you're thinking about enrollment timing for both REDEEM-1 and REDEEM-2? Given that we're starting at a higher dose versus what you did in the proof-of-concept, do you expect any difference in outcomes or responses without the titration that you did earlier? Thanks.

So, we had several cohorts of different dose levels in the proof-of-concept, and we had individual intra-patient escalation too that we've had plenty of experience in the range of 500 milligrams twice a day and also at 400 milligrams twice a day. We chose to go with the higher dose. There were no safety differences. We haven't had any safety signals. So 500 milligrams twice a day very comfortable, and we expect to see very good responses at that dose. With regard to the enrollment. Until we've really started enrolling, it's sort of hard to predict in rare diseases how you're going to go. We learned that in the HAE programs that we did. How do we cope with uncertainty about that? We select terrific sites all around the world and cast a broad net, and that's the way we approach it. We've had fantastic interactions with leading hematologists and with patient advocates about the data that we shared in March. They're very enthusiastic about testing this drug for all of the reasons that I mentioned, to improve patient care. The fact that it's an oral medicine is a big deal, so it's really hard to predict. We look forward to having the studies start up and seeing how the enrollment goes.

Yes, Jon, I'd add too that with the appellate drug on the market in the U.S. and other competing studies going on in a rare disease, it's challenging. But one thing that I'll say, and Bill and Helen won't brag about this, but they should, is their teams work to be sponsor of choice. The relationships they build with study coordinators, with the site staff, with the site PI is the best honestly. And so, that makes a difference in terms of enthusiasm for working with us.

Got it. Thanks and congrats again on the great quarter.

Thanks, Jon.

Next question is from the line of Maury Raycroft of Jefferies. Your line's now open.

Hi. Good morning, everyone. I'll add my congrats on the quarter. For ORLADEYO, what is the latest update on real-world efficacy you're seeing compared to the Phase 3 studies? Do you have a way to collect some of the real-world data to potentially publish it at some point for reference? I guess what's your plans there? And I know you're not providing a lot of specifics. But can you provide any more perspective into script renewal that you're seeing at this point?

As I mentioned on the call, the 80% reduction in attacks over 96 weeks shows this drug really works over the long term. In the real world, that's what we're hearing. Patients are doing really well on this drug regardless of whether they're coming from other prophy products, which is 60% of our patients, or switching from acute-only, which is most of the other 40%. Yes, we do plan to keep looking not only at our long-term clinical data but also additional real-world data from the U.S. and around the world, and you can expect us to look to publish things in the future. As far as script renewal, what we saw in our clinical trials was really high compliance, and we're seeing very close to that in the real world. That's a reflection of this drug works. Patients know what it does, and it's really easy to take one pill a day, and they're being very compliant.

You're welcome.

Yes. Overall, continued benefits and safety profile of our proof-of-concept trial patients are very encouraging and form the basis for our confidence in moving to pivotal trials in PNH. Although PNH is a competitive space for clinical trials, the enthusiasm for our pivotal program from top investigators and PNH patient advocates based on our excellent results from the proof-of-concept trial provides us confidence that these trials can be recruited.

Next question is from the line of Brian Abrams of RBC Capital Markets. Your line is now open.

Hi. This is Steve on for Brian. Thanks for taking our question, and congrats again on the quarter. Looking at this week's FDA Adverse Event Report, it looks like there are a few GI events for ORLADEYO that were reported. Can you comment on any feedback you've received from physicians on reports of dose reduction due to GI issues?

Yes. I'll take that one, Steve. Maybe Bill if you need to add any color to it. I mean, that's a known adverse event that's in our package circular and we've seen it in the clinical trials. It's mild. It typically goes away fairly quickly. We've had 75% retention. I'm not even sure if we had a dropout due to GI adverse events. We're nine months into the launch, and it's absolutely meeting our expectations in terms of what we're seeing. Our salespeople are making sure that they're setting expectations with the physician to counsel the patient properly, and our patient services group is also working very carefully. If you have the opportunity to not have any tolerability issues and be well-controlled on the drug—if you give it enough time and it's a once-a-day oral, why wouldn't you try, right? That's the key to this. And so far, so good.

Jon, we're hearing that patients are really happy on this drug.

Yes, I would just add that what we're seeing in the FDA sales database, for example, is totally consistent with our labeled adverse event descriptions. We have a safe and effective drug.

Last question is from the line of Chris Raymond of Piper Sandler. Your line is now open.

Good morning. This is Nicole Gabreski for Chris. Congrats on the quarter, and thanks for squeezing us in. I guess just two quick ones on ORLADEYO. Kind of just going back to patient retention, I know you just commented on the AEs. But I guess just with more time on the market, what's been the most common driver of discontinuation so far? Has it been response or tolerability related issues or access or potentially something else? And then just the second one, can you just remind us how active the HAE patient community is? Just trying to gauge how much word of mouth, as initial patients have had success on ORLADEYO, will lead to future patient growth and switching.

Yes, Charlie, do you want to take that second one first?

Sure. As far as the active HAE community, in the U.S., this is a really active community, very well organized, a lot of communication between patients. We see that as a big opportunity. What patients have not been able to do thus far just because of COVID is have in-person meetings, so as Jon was talking about earlier, some of that becomes a missed opportunity. But we expect word of mouth is really going to start to become very strong as patients talk to each other and as more patients have a good experience with ORLADEYO.

Yes. And on the discontinuations, let me just stress first that as Charlie has said these three times today. We're within the range of what we saw in the clinical trial. So 75% or greater stay on our drug. The discontinuation rate is pretty low, and the mix is all over the board. It can be adverse events. No drug works in everybody. It could be a lack of efficacy in some, but it's a mix. It's a really broad mix.

Thank you, participants. I'll now turn the call over to Jon Stonehouse for final remarks.

Great. Let me wrap up the call with a huge thank you to all of our employees. The commitment they've shown to be able to discover, develop, and now bring to market innovative drugs for patients suffering from rare diseases is absolutely amazing to me. They do it with a sense of urgency. They know that patients are waiting. So, thank you so much to all the employees of BioCryst. And thanks to our shareholders, especially those of you in particular that have stuck with us. We're really excited about the future of the company. I hope you are too, and we look forward to keeping you updated as the rest of the year unfolds. Thanks, and have a great day.

And that concludes today's conference. Thank you all for joining. You may now disconnect.