BioCryst Pharmaceuticals Inc (BCRX) 2021 Q2 法說會逐字稿

Thank you all for standing by, and welcome to the BioCryst's Second Quarter 2021 Earnings Conference Call. (Operator Instructions) 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 will 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 reported today with $50 million of revenue, including $28.5 million of ORLADEYO net revenue in the second quarter. The ORLADEYO launch continues to go very well. We're now in 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 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 with the profile patients want, a great plan centered around patient switches and an execution of that plan by an extremely talented, 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 give us confidence we'll 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, where in the first half of the year we moved directly from Phase I 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 and our Phase III plans 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 the ORLADEYO launch.

Thanks, Jon. Quite simply, the ORLADEYO launch is going great, with Q2 building on our fast start in Q1. Long-term clinical data also confirmed 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 milligrams had an 80% reduction in attacks compared to baseline after 96 weeks, with a median attack rate in most months being 0. The potential to have this outstanding level of attack control with just 1 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 in 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 on ORLADEYO in the second quarter came from other prophy therapies. Takhzyro represented 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 giving up on injectable products in the past.

ORLADEYO is also 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 was meeting their expectations. With now 8 months since launch, we see patient retention trending in line with a 75% 1-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 as 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 all will 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 up $50 million. Of this, $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 noncash stock compensation for the quarter, were $72 million. And 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, no inventory or channel stocking. Strong new patient uptake and the success of our Quick Start patient assistance programs continues to be the main driver of our gross to 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, and 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. And 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 a guide.

Secondly, as Charlie said, we've made great strides in getting ORLADEYO on to policy thus far, but we still have work to do to complete this effort and transition new and existing patients to reimburse product.

Next, summer and the end-of-year holidays historically are slower periods for switches for HAE patients. More data in the next couple of months will help us ascertain if this impacts our trajectory.

And 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. And with that, I'll hand it over to Bill.

Thanks, Anthony. The successful launch of ORLADEYO is very exciting for the team at BioCryst to discover and develop this unique drug because we can see the profound impact that it is having on the lives of HAE patients.

Next in our development pipeline is BCX9930, our oral Factor D inhibitor for complement-mediated diseases. 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. And 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 intravenous C5 inhibitors because it can address both extravascular and intravascular hemolysis. These clinical advantages come on top of the expected dramatic reduction in burden of therapy.

Based on the results of our dose-finding proof-of-concept study, we met with regulators to reach agreement on study designs and have accelerated development of BCX9930 Phase I directly into pivotal trials.

Today, I'd like to share details about our pivotal trials in PNH to provide an update on our renal proven concept trial and discuss next steps in broadening our research and other indications.

Our 2 pivotal trials of BCX9930 are 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 the anemia with increased reticulocytes 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 response to C5 inhibitors. REDEEM-2 is a 12-week blinded randomized clinical trial of BCX9930 in approximately 57 patients with PNH not currently taking a compliment inhibitor. In both studies, after the controlled period, all patients received BCX9930 monotherapy to a formal week 52 safety evaluation and then roll over intralong-term extension. The primary endpoint in both trials has changed from baseline in hemoglobin with powering to detect a treatment effect of approximately 2 grams per deciliter. Given the much greater effect on hemoglobin that we have seen in our proven 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 and fatigue. And other endpoints include additional relevant clinical laboratory and health-related quality of life outcomes. Importantly, the blinding in REDEEM-2 allows us a 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 LDH agent 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 9 months, and the longest time on drug of 17 months. The 9 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, maintenance of improvement in biomarkers of hemolysis and PNH red blood for close size. All 9 of these patients have continued on therapy.

Turning now to the 6 C5 inhibitor inadequate response patients in our trial, 5 had high levels of C3 optimization on PNH red blood cells at baseline. Remember that's a marker setting up extravascular hemolysis, and all 5 continue to benefit from BCX9930. Recently, the investigators have decided to discontinue C5 inhibitor in 4 of these patients, including 1 patient who had required transfusions for hemolysis following COVID-19 vaccination, while being treated with both ravulizumab and BCX9930. These 4 patients are now continuing on BCX9930 monotherapy. 1 patient with an adequate response to C5 inhibitor who we discussed in March had a very large transfusion burden pretrial associated with pre-existing hypersplenism and other medical conditions complicating PNH. In this patient at baseline, the proportion of PNH red blood cells that were optimized by complement was only 0.8%, indicating the complement-mediated hemolysis is likely not a main factor in this individual's anemia. And 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 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 EFRA results from the proven concept trial provides us confidence that these trials can be recruited. Start-off 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 3 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 with pivotal studies for each of these indications.

Because BCX9930 inhibit Factor D, thus blocking the alternative pathway. 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 reentry submissions, approvals and launches throughout the world. This is an exciting time, and BCX9930 truly represents a pipeline in a molecule. We are 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.

Now I'd like to hand the call over to Jon 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 in PNH, with more indications to follow. And 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.

(Operator Instructions)

First question is from the line of Ken Cacciatore of Cowen & Company.

Congratulations, team, on the success of the rollout. It's just fantastic to see. And 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 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 through the balance of the year and all good reasons. I guess I was just wondering about this initial start and as we think about pacing of patients in terms of how they see the clinician through the balance of the year. So are there normally, on average, 2 patient visits or 1 patient visit? Just trying to understand your ability to capture how many kind of bites at 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.

Charlie, I'll take the last two. You can 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, we'll have some of our existing patients now with the new coverage policies rolling over to paid product in the second half of the year.

And then, Ken, with regard to the no less than $100 million and the pacing and clinic visits, I mean you're directionally right in terms of roughly 2 visits per year. But I think Charlie and Anthony did a really good job of telling you the things that could go very positively, that could increase beyond the $100 million and those things that would keep us closer to the $100 million, the uncertainties that like the summer months. We just -- this is the first July and August that we have of launching this drug. So we just want to see that play out before we give more finite guidance.

And then on Europe, as Charlie said in his prepared remarks, you should expect that the uptake is different than in the U.S., that the ramp is slower.

Germany, the launch is underway. They had some pretty heavy COVID restrictions that they just released, I think, in July, now with the Delta variant. I'm not sure that they're going to put those restrictions back to limit patients coming into the universities and clinics and the like.

So we just got to see how that plays out over time. I think those will be bigger contributors next year. And as Charlie said in his prepared remarks, we'll be seeing additional countries launching as we get pricing agreements.

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

Team, congrats on another great quarter. So you're seeing patients adopting and switching from both prophy and on-demand options to ORLADEYO. We're just curious how you're thinking about the on-demand versus prophy will shake out in the next few years. And can you comment on how the patient access through medical acception versus formulary has changed this quarter versus last quarter. And I have a quick follow-up.

Charlie, I'll take the first one, you take the second.

So Brian, with regard to prophy in on-demand market, it's shrinking every day. And it's not just us that are shrinking it. Takeda, CSL with their prophylactic therapy. So honestly, we said 80-20. Ultimately, when it settles out, it could be 90-10 just given how patients really -- I think they always wanted prophylactic therapy. They want to prevent attacks. And now that there's an oral option, we're just seeing a lot of enthusiasm.

Yes. And then Brian, on your question about the medical exemption trend, we had a lot of success in the first half that we've talked about before, getting patients covered via medical exemption. 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. And what it's going to mean is that for new patients coming on to product, they're going to start getting to pay product a lot faster, a lot sooner in the process. So we still pursue medical exemptions when needed, we still have successes there. But increasingly, coverage will be through formal coverage policies.

Okay. And related to 9930 in 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 endpoint in the REDEEM-1?

Sure. This is Bill here. The primary endpoint in both studies is the same. It's a 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 2 studies. And quite frankly, we're very confident of exceeding what we've put in for the power in terms of approximately 2 grams change in baseline hemoglobin based on the proof-of-concept results.

Remember, these studies also have to provide a safety data base. 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 an MDA. And you mind just repeating your second question?

Regarding LDE change, whether that was 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 analysis and LDH is really biomarkers, intravesical analysis. So we measure all the biomarkers, but it's not a key secondary endpoint in REDEEM-1.

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

Can you maybe provide a little more color on what kind of gross to net you're seeing at this point? I know you said the majority of patients in the second quarter were receiving reimbursed drug. But kind of 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 over from free product on to reimburse, and as Charlie said, as more new patients come directly on to -- or quicker on to reimbursed product, we've absolutely seen them get better quarter-over-quarter. We're not going to give specific details therein. But what we did say was we still feel really strongly about that idea that we're going to get 15% to 20% in line with other small molecules as we approach peak sales. And honestly, kind of really happy with the way things are playing out from a gross to net.

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

The majority paid, is that what you're asking?

Yes.

In Q1, Liisa, we were. The majority were on free product. In Q2, the majority were paid. So the pace -- the trend is that.

Got it. Okay. And then on -- 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 6 months since launch? What kind of compliance persistence are you seeing?

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

Yes. So Liisa, in APeX-2, we saw 75% 1-year patient retention. And what we're seeing so far, 8 months into the launch, is we're trending within that. So we're -- the patient retention is really good. And I think this is -- a big part of this is a reflection of this drug works really well. And the data we presented at EAACI with 80% reduction in attacks versus baseline shows that patients do really well on this drug.

And then as far as just compliance, I mentioned it's been very high, close to our clinical trials rate, which were in the 90% range.

It was high 90s.

It was high 90s in clinical trials. And I think that's just a reflection of patients know that when they take 1 pill a day, it's easy and it's going to help them prevent attack. So they're self motivated to do so.

Okay. Great. And then turning now to oral Factor D. Kind of really interested in this basket study that you're doing of kind of renal complement diseases. Can you talk about how you're thinking about that study? I'm assuming proteinuria is going to be the endpoint. When would you measure that? And like is that kind of important across all these diseases? And 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. That's a good approach.

Yes. Bill, maybe focus on the quality of selecting patients that really truly have the disease, what we're doing to make sure that we have that and the clarity around the endpoints.

Right. So we've -- I think in previous calls, I've mentioned that we've had fantastic discussions with external nephrology experts in a series of meetings to help us think about all of these questions. And what's really critical is making sure that we have patients who have active disease in the first place and not those without disease. So that's why there's -- as I mentioned on the call, we'll be doing kidney pathology. So there will be a baseline and a follow-up biopsy to assess that. That's very important. And we'll be doing very well standardized and comprehensive assessments of the kidney pathology and the role of the complement system in each of these diseases. That's number one.

In a proof-of-concept study like this, I don't like the idea of a single endpoint. I'd like to mention everything, right? So we're measuring everything. We're measuring a whole suite of biomarkers. You're absolutely correct that proteinuria is a very attractive endpoint and that -- and by the way, in the FDA's initiative with industry and academia around this whole topic of endpoints in kidney diseases, the combination of reduction in proteinuria and stabilization of the renal filtration rate is the direction that the field has headed quite independently of C3 or complement-mediated diseases. So that will be a discussion with regulators after we've got the proof-of-concept results in terms of choice of primary endpoint for a phase -- for a pivotal study. And each disease is separate, but I think that the existing evidence out there on the effect of complement inhibitors, for example, C3 glomerulopathy makes it pretty clear that you can see benefits pretty quickly in people with active disease.

Yes. And Liisa, the other thing I'd point out is we've gone from a study where we were Phase I looking at PNH patients to -- in the second half of the year, we're going to be in pivotal studies in PNH patients and then 3 more indications in renal disease. So 4 indications, we're going to be pursuing by the end of the year, which is very, very exciting for us.

Next question is from the line of Jessica Fye of JPMorgan.

Congrats on the quarter. 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. ex Canada 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. When -- the best way to think about the $28.5 million 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. So sorry, for Q2 and then for this year, the majority of the revenue is going to come from the U.S.

In terms of the gross to net in the second half of the year, I'd say the trend will continue, right? So as we continue to get more and more patients on, and as Charlie said, we continue to get more payer coverage, I would expect that the gross to nets themselves will tighten. Now as we move off medical exception and on to reimbursed via coverage, there will be some adjustment, but it will be overweighted by new patients coming on and then the transition of existing patients on to that reimbursed product. So my expectation is that's really 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 drug? Does this happen early on? Or is it more kind of steady over time?

Yes. Just the -- what we said is we're trending toward that 75% for 1 year. So typically, patients make that decision in the first few months. That's what we saw in clinical trials and 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, right? So as Charlie said, it was an 80% reduction from baseline over 96 weeks which is incredibly effective. And so patients need to give time to get to that point.

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

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 therapies 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.

And then we also -- we 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, is this a bolus or just a point in time? It just very -- if we leave you with anything, it's a very consistent growth. Very consistent.

Got it. Okay. And then for Charlie, you mentioned that 70% of HAE patients now are on a reimbursement policy. Can you maybe talk about how that policy compares to coverage of other products? And when do you expect the remaining 30% piece?

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

Okay. And let me squeeze in one last one for Anthony. I know there's not -- you're not providing OpEx guidance, but can you give us some maybe directional color for the second half after both R&D and SG&A saw some ramp-up in the second quarter. So how should we think about the second half for those line items?

So I think, Anthony, just focus on kind of where are we making the investments.

Yes. So Serge, 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 those.

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. And so if I look at where we are at the moment, can you take that as a run rate and then expect additional investments? Yes, I mean, we -- there's value to be unlocked and created in those areas, and we will continue to invest as long as it makes sense to create that value.

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

Congratulations from me as well on a really spectacular quarter. I just wanted to get a little bit of color. So 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. But I wanted to just maybe get a little bit of color on a couple of those caveats, namely summer vacation schedules and COVID. So as we kind of enter the middle of August, I'm just wondering how those 2 factors are trending so far this quarter relative to how you exited 2Q. And then I have a couple of follow-ups.

So good question, Tazeen. And as Jon said, this is our first summer. And yes, people are going on vacation, doctors and patients, and so that's something we're watching. But demand has been consistent and strong thus far.

As far as COVID, we were able to -- we launched in COVID, we've been prepared for this, we've done well throughout COVID. The team -- our sales team was able to make more in-person calls in Q2, and that makes a difference, but they're prepared for anything that comes. So we're watching it. But with the Delta variant is something that could affect things in the rest of the year just in terms of slowing in-person medical meetings, et cetera. But we're very confident in our $100 million -- no less than $100 million for the year.

Yes. And I would just add to that, Tazeen. If the lockdown -- if there's less face-to-face stuff, right, like medical meetings, we're hoping that the college meeting -- yes, the college meeting in the fall, in November, is face-to-face. And we've heard that attendance will be fantastic. But if that doesn't happen and it's virtual again, that's a missed opportunity. Getting patients together, getting physicians together face-to-face is an opportunity. If COVID prevents that from happening, that will be a missed opportunity. But we're very, very confident that no less than $100 million for the year.

Okay. 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 the kind of how COVID is -- it was the prevalence of COVID and what are the local policies affect our ability to do face-to-face, but we're not seeing any trends in terms of patient uptake that we could read directed to that.

Texas is a great example. The state doesn't require mask, but the city of Austin requires mask, right? So there's just high, high variability even within a state.

Okay. And then last question for me is maybe on the PNH market. So there was a recent approval from the TELUS an RP3 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 would 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 3 or 4 day...

Twice a week, 20 milliliters per injection.

Yes. So from a burden of therapy, Tazeen -- and if we've learned anything in HAE, it's about controlled disease and it's about reduced burden of therapy. And 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.

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

Congrats on the progress. A couple on ORLADEYO. You mentioned that there's 50% new prescribers. Can you tell us how many prescribers you have now and how your targeting approach has been going? And if you have any color on kind of the average number of patients per prescriber that are on ORLADEYO.

Good questions, Jon. So what I've said before is our number 1 tier of targets is about 500 doctors that treat about 50% of existing HAE patients. And we've made great progress, great penetration into that group. But still the majority of them have not prescribed. But the intent to prescribe is really high amongst them. So we have a lot of opportunity there that we're very bullish about. And then we've made a lot of progress into the next tier of our prescriber list.

What I'll say about the kind of the number of patients per doctor, we've had prescribers who have prescribed for multiple patients with ORLADEYO. And that's the goal, we want to go broad across the prescriber base and then deep within the prescribers.

But the average doctors 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, right, that -- doctors who maybe put 1 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. And 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?

So Bill, you might want to clarify that dosing first because we did have 500 in that study.

Yes. So we had several cohorts of different dose levels in the proof of concept and we had individual intrapatient versus escalation 2 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 and we know that in the HAE programs that we did. So how do we cope with uncertainty about that? What we do is select terrific sites all around the world and cast a broad net, and that's the way we approach it.

So as I mentioned in my remarks, we've had fantastic interactions with leading hematologists and the 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. And the fact that it's an oral medicine is a big deal.

So it's really hard to predict. And so we look forward to having the study start up and seeing that the enrollment goes and then we'll be in a better position.

Yes, Jon, I'd add, too, that with the appellate drug on the market in the U.S. and other competing studies going on, and it's 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, which is their teams work to be sponsor of choice. So the relationships that they build with the 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.

Next question is from the line of Maury Raycroft of Jefferies.

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 III studies? And 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?

Do you want to take that?

Yes. So Maury, as I mentioned on the call, the 80% reduction in the tax over 96 weeks shows that this drug really works over the long term. And so 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 -- we're going 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.

And then as far as -- I think you're asking...

Script renewal.

The script renewal, yes, so compliance rate. What we saw in our clinical trials was really high compliance, high 90%. And we're seeing very close to that in the real world. And that's a reflection of this drug works. Patients know what it does. And it's really easy to take, 1 pill a day, and they're being very compliant.

Got it. That's helpful. And then for the PNH study, just wondering if you can provide any more specifics into when the 4 patients on 9930 discontinued C5 and any more perspective into the 1 patient that remains on C5 combo?

Bill, do you want to take that?

Sure. I think that as we've mentioned in previous calls, the decision to move -- to discontinue the C5 inhibitor in each individual patient is made by the site investigator. And if you look at the existing evidence from the Factor D inhibitor program from another sponsor, it took many, many months. And they reported data after a year and still 3 of the 10 patients haven't been switched to monotherapy by that time.

So we're not in any hurry here. We don't need the data for any particular reason right now. We're moving ahead with our pivotal studies. And it was, as I mentioned in my remarks, these -- the discontinuation of the C5 inhibitor in the 4 patients, where the investigators have made that decision already was recent. So in PNH, you'd like to see the data mature over time. So it was very recent.

The other part of your question was about the individual who hasn't switched yet. Just like in the other study, it's just a matter of time for the investigator to make the decision, I think.

Next question is from the line of Brian Abrahams of RBC Capital Markets.

This is Steve on for Brian. Congrats again on the quarter. So looking through this week's FDA adverse event report, it looks like there are a few GI events for ORLADEYO that were reported. And can you comment on any feedback you've received from physicians on any reports of dose reduction due to GI issues?

Yes. I'll take that one, Steve. And 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. And we've had 75% retention, I think in the clinical study. I'm not even sure if we had a drop out, maybe 1, due to GI adverse events.

So anyway, we're 9 months into the launch, and it's absolutely meeting our expectations in terms of what we're seeing. And then I think the other thing that's really important is our salespeople making sure that they're setting expectations with the physician to counsel the patient properly and then our patient services group also working very carefully.

Because really, when you think about it, if you have the opportunity to not really 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? And so that's the key to this. And so far, so good.

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

Yes. I would just add that what we're seeing in the FDA (inaudible) database, for example, is totally consistent with our labeled adverse event description. We have a site at effective drug.

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

This is Nicole Gabreski on for Chris. Congrats on the quarter. So I guess just 2 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, I guess, what's been the most common driver of discontinuations 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 in switching? Just wondering if you have any feedback there.

Yes. Charlie, do you want to take the 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 and 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. And so as Jon was talking about earlier, some of that -- 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 and more patients have a good experience with ORLADEYO.

Yes. And on the discontinuations, let me just stress first that, as Charlie has said at least 3 times today, we're within the range of what we saw in the clinical trial. So 75% or greater are staying on our drug. So the discontinuation rate is pretty low. And the mix is all over the board, right? It can be adverse events. No drug works on everybody, so it could be 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, huge thank you to all of our employees. I mean the commitment that 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. And 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, for those of you in particular that have stuck with us. Just -- 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.