Q2 2022 BioCryst Pharmaceuticals Inc Earnings Call

Okay.

[music].

Welcome to the Biocryst second quarter 2022 earnings Conference call. My name is Vanessa and I will be your operator for today's call. At this time all participants are in a listen only mode. Later, we will conduct a question and answer session. During the question and answer session with your question.

Welcome to the BioCryst second quarter 2022 earnings conference call.

My name is Vanessa and I will be your operator for today's call.

At this time, all participants are in a listen-only mode.

Good morning.

Thank you.

Enter the queue by pressing zero than one I will now turn the call over to your host Mr. John Bluth at Biocryst.

Thanks for taking my question.

This concludes our question and answer session.

Thanks, very much Vanessa good morning, and welcome to Biocryst second quarter, 2022, corporate update and financial results Conference call.

Later, we will conduct a question and answer session.

So a couple more for you on 9930.

I will now turn the call over to Mr. Stonehouse for closing remarks.

When you talk about a reasonable time frame, and a relatively small number of patients needed to find a safe and effective dose, can you just elaborate on how you define two things?

Yeah, thank you.

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 <unk>.

First, is a reasonable time frame the three months you talked about in prepared remarks?

Something I've learned, and I think we've learned as a company over many years, of working on many, many projects, is the importance of objectivity and following the evidence and the data in our decision-making.

And is that three months from today?

You know, whether it's clinical data that we're looking at to advance a program or market data, do we have the right profile that'll be competitive in the marketplace?

During the question and answer session, with your question, you can enter the queue by pressing zero, then one.

Or is that once you get three months of follow-up on a small number of patients, and it could take a few months to spool up enrollment again?

If you go into it wanting to see a certain thing, you're not going to be objective, and you could make the wrong decision.

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 Companys future performance <unk> achievements. These statements are subject to known and unknown risks and uncertainties, which may cause our actual results performance or achievements to be materially.

I will now turn the call over to your host, Mr. Jon Bluth at BioCryst.

And then second, how do you define a small number of patients?

We don't do that at BioChrist.

Thanks very much, Vanessa.

Is that a dozen, a couple dozen?

We look at the evidence, and we make our decisions based on what we see, and I think as a result of that, we're starting to create greater value and have more success, and Orladeo is the case study for that.

I'm just trying to figure out one investment.

So if you're not familiar with our thinking, we encourage you to get to know us better, and we can share with you.

We'll have more clarity here.

Yeah.

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.

Good morning and welcome to BioCryst's second quarter 2022 corporate update and financial results conference call.

And listen, it's not the only part that's important in success.

Today's press release and accompanying slides are available on our website.

So I think it's important to look at what we saw in the study that caused us to stop. So it was about 15 patients, roughly, in enrollment in the REDEEM studies that we saw this effect.

Thanks, John the Orla Dale launch continues to be very strong revenues on track to exceed $250 million. This year, new patient starts remained consistently strong now for six quarters in a row.

And so we think a similar number is roughly what will give us confidence, that we're not seeing the effect or we are.

And the time frame for that, as Helen said, it could take some months to get the revised protocols.

Prescriber base is expanding and deepening the 96 week data we've begun promoting is resonating with our customers and the switch data shows Orla Dale is maintaining disease control of decreasing disease burden.

These are major amendments, and so you've got to go to the regulatory authorities.

While the vast majority of our revenue is still from the U S sales from Europe are starting to grow and all of this is good news for HIV patients.

This is even more exciting when you realize there is so much more opportunity ahead of us, which leaves us to refine our guidance for this year to between 255 and $265 million and continue to track towards $1 billion at peak.

Why is this important.

Having a meaningful product in the market growing quarter after quarter with very long IP creates an amazing base to build on.

Participating with me today are CEO Jon Stonehouse, CFO Anthony Doyle, Chief Commercial Officer Charlie Geyer,

In this challenging financial environment, having significant and steady revenue growth is rare and critically important to creating greater value.

Our plan is to repeat this orla Dale success with our pipeline molecules for other patients suffering from rare diseases.

Few companies can get one successful product to market, but if you're able to do it again and again you can compound value.

People, good science is also, but the decision-making on this stuff and the objectivity, is critical, and we think it affects value tremendously.

Key elements to getting there are having a strategy to bring therapies forward that patients truly want and being disciplined by following the data and insights gathered objectively to make informed business decisions about when to invest and where not to.

<unk> success is a great example of this wouldn't it have been nice back in the early days of the program of clinical trials and market research pointed to a clear and straight path to success, but that's not how it played out.

There were clear challenges and things that went differently than planned along the way.

And we were disciplined and objectively following the data studying the switch market carefully and quickly leverage those insights to make the investment decisions that ultimately are paying off today with our successful launch.

So thanks for your interest in our company, and have a great day.

We use this approach at all our capital allocation decisions, including our pipeline.

And thank you.

Ladies and gentlemen, this concludes our conference.

This disciplined approach is especially important in the current environment.

Thank you for participating.

We see the complement area and the ability to bring oral drugs to fill a large unmet needs for these rare disease patients.

As a massive opportunity that includes factor D and extends even more broadly to include other targets.

Our immediate decision is to allocate capital in the redeem and renew studies to see if we're able to achieve our goal of finding a safe and effective dose with <unk> 90 930.

If the data from the first small group of patients enrolled supports this goal we will continue to allocate capital to the 90 930 program if not we will stop its development, but still pursue factor D inhibitors as we've already invested in next generation backups and molecules that we hope will be improvements.

With the partial clinical hold now removed preparations to restart enrollment have begun.

And Helen will share more with you on what we know now and how we plan to proceed.

We have a successful rare disease launch with or the day of growing into a global blockbuster.

Chief Medical Officer Dr. Bill Sheridan, and Chief R&D Officer Dr. Helen Thackray.

Following our remarks, we will answer your questions.

We have an exciting pipeline of compounds. Some you know about and some you don't yet in.

Before we begin, please note that, today's conference call will contain forward-looking statements, including those 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.

And lastly, we have substantial capital to make thoughtful capital allocation decisions.

You should not place undue reliance on these forward-looking statements.

You may now disconnect.

This is a unique and very good spot to be in in the current environment and that brings me back to where I started.

And then it took about two months to see the effect in these patients. So once we got it up and running and we're enrolling patients, it'll be a couple of months before we feel like we're in the position where we know what we're seeing.

The tremendous market success of Orlando.

The steady and consistent revenue growth disciplined and objective decision, making on capital allocation and alternative financing sources like the additional debt from a theory, we recently drew down.

Are the things that give us confidence we can repeat the orla deyoe success with other molecules and create much greater value in the process.

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.

So I hope that gives you a little bit more frame.

Thank you.

Now I'll turn the call over to Charlie to share additional details on another strong quarter of growth for the day or Charlie.

I'd now like to turn the call over to Jon Stonehouse.

It's really hard to predict just because it takes time to get these things, approved and then start enrolling.

Thanks, John .

The consistent pattern of patient growth that we've seen since launch continued without interruption in the second quarter.

New patient prescriptions in Q2 were the best since the first quarter of the launch driven by continued broadening and deepening of the Orlando Prescriber base.

There is no sign this launch is slowing.

Our market research with HAE Treaters predicted this expansion and the 96 week data that we started promoting late last year is convincing physicians to prescribe when.

When they see the sustained median monthly attack rate of zero. They know that their patients can expect great efficacy.

When they see patients doing really well on Orlando in the real world in particular, those patients who switched after being controlled on injectable prophylaxis. They.

They were encouraged to increase prescribing.

Our prescriber data in Q2 reflect this pattern.

We added the most first time prescribers since the third quarter of last year and.

And we also had an identical number of repeat prescribers.

We saw an uptick in prescribing among the top 500 physicians that treat 50% of HAE patients.

60% of those tier one physicians have now prescribed orla Dale and they accounted for two thirds of new prescriptions in the quarter.

Our source of business is also very balanced with overall patient potential.

They are roughly 120 physicians in the top three dosshouse accounting for 30% of the HLA market opportunity.

And they prescribed 32% of the new early data prescriptions in Q2.

Roughly <unk> thousand 500 physicians represent the next 40% of the opportunity and that group accounted for 48% of prescriptions.

We also saw an improvement in patient retention.

Although it is too soon to call. This a trend we had the fewest number of discontinuation since Q3 of last year, even as the overall number of patients on Orlando has grown substantially.

Our metrics on access and reimbursement, which were already good also continued to improve.

The median time to shipment of reimbursed product for a new prescription is now under three weeks as our team helps patients move quickly through the prior authorization.

Health care providers worry about the burdens of the access process for HIV treatments. So the success of our patient service model adds to their confidence in prescribing Orla Dale.

We made more progress toward the globalization of oil a day Oh in Q2 with regulatory approvals in Canada, and Switzerland and final price agreements.

A final price agreements in Germany, France, as well as Switzerland.

We also entered a commercial distribution agreement with <unk> pharma for Latin America, and we expect to file for market authorization in multiple Latin American countries before the end of 2022.

While the ex U S contribution to 2022 sales will be small the progress we are seeing in Europe and other regions gives us confidence that ex U S sales for early Dale will reach at least $200 million at peak.

The prescribing dynamics in the patient trends that we saw in Q2 confirmed to US that we are still in the early stages of the oral at Ao launch trajectory for <unk>.

Trends that we see tell us that oral data was on track not only for between 255 $265 million in sales in 2022, but also future market leadership and $1 billion in peak sales.

Thanks, Jon.

Unknown Speaker, Okay.

Unknown Speaker, But we're going to, you know, we're going to work as fast as we can, and, you know, we'll keep you updated along the way.

Now I'd like to turn the call over to Anthony.

Thanks, Charlie.

Unknown Speaker, Got it.

Or are there revenue performance for Q2 was really strong and takes our trailing 12 months revenue to just short of $200 million.

The Orladeo launch continues to be very strong. Revenues on track to exceed $250, million this year. New patient starts remain consistently strong, now for six quarters in a row. The prescriber base is expanding and deepening.

And I appreciate the kind of deliberate approach here, and I can understand how a small number, of patients can rule in a safety issue, but how do you get comfortable that a small number of patients can rule out a safety issue?

The 96-week data we've begun promoting is resonating with our customers. And the switch data shows Orladeo is maintaining disease control while decreasing disease burden.

Unknown Speaker, Yeah, maybe I'll start, and then you and Bill can jump in.

While the vast majority of our revenue is still from the U.S., sales from Europe are starting to grow.

And all of this is good news for HAE patients.

You know, the hypothesis is based on the data we've gathered to date, right, which, is a combination of the clinical data and what we saw at 400 and what we saw at 500, and then what we saw in ClinPharm and what we saw in laboratory tests and some recent animal studies.

With the consistency of new patient growth in the U S and continued expansion globally, we're really well positioned to achieve our updated revenue guidance of $255 million to $265 million for 2022.

This is even more exciting when you realize there's so much more opportunity ahead of us, which leads us to refine our guidance for this year to between $255 and $265 million and continue to track toward $1 billion at peak.

Why is this important?

And on from there to peak sales of the $1 billion.

Having a meaningful product in the market growing quarter after quarter with very long IP creates an amazing base to build on.

You can find our detailed second quarter financials in today's earnings press release, and I'd like to call your attention to a few items.

In this challenging financial environment, having significant and steady revenue growth is rare, and critically important to creating greater value.

Revenue for the quarter was $65 5 million of which $65 $2 million came from net sales of all the data we.

Our plan is to repeat this Orladeo success with our pipeline molecules for other patients, suffering from rare diseases.

We had around $2 2 million of non repeating reimbursement related accrual releases in the quarter and so early day on net revenue.

Related to Q2 was $63 million.

Having seen Q1 gross to net impacted by re authorizations co pay assistance resets and the government donut hole Q2 reimbursement rates and gross to net adjustments have normalized and should continue at current rates through year end.

Few companies can get one successful product to market, but if you're able to do it again and again, you can compound value.

Operating expenses, not including noncash stock compensation for the quarter was $90 million.

This was lower than we previously forecasted as the team worked hard to manage costs. During the 19 900 enrollment hold period with the with the program now moving forward, we've lowered our opex forecast for 2022 to $390 million to $400 million.

Cash at the end of the quarter was up $419 million, having achieved and maintained the required revenue thresholds to drove the additional $75 million debt tranches from our CRM pro forma cash is at approximately $492 million.

We have always been and will continue to be responsible and disciplined allocators of capital. This is especially true as we recommence enrollment of 930 program.

We have taken into consideration the delay to the program.

<unk> reduced probability of success and reduced our assumptions for peak penetration. Despite pass there's still significant value potential to support investment in the program. There are numerous markets that we can go into with 90 930, not just <unk>. These markets are big especially in renal indications.

This is a drug that patients want all of that results in a revenue potential for $99 30 vendors that is larger than that of <unk>.

Our intent is to progress as quickly as possible limit the additional investments and get to the point, where we have confidence that we have a safe and effective drug. If we can achieve this then we will continue to invest in moving the program forward. If we cannot then we will terminate the program and allocate capital elsewhere. This.

Key elements to getting there are having a strategy to bring therapies forward that, patients truly want and being disciplined by following the data and insights gathered objectively to make informed business decisions about when to invest and when not to.

This data driven objective unemotional approach has been a key factor in the successful launch of <unk> and will continue to guide us and all of the programs that we have going forward now I'll pass it over to Hilla.

Orladeo's success is a great example of this.

Thanks Anthony.

As we announced today the FDA has lifted their partial clinical hold on the VCX 90, 930 program and our pivotal trials in <unk> can resume enrollment along with our proof of concept trial in renal indications.

Wouldn't it have been nice back in the early, days of the program if clinical trials and market research pointed to a clear and straight path to success?

But that's not how it played out. There were clear challenges and things that went differently than planned along the way. And we were disciplined in objectively following the data, studying the switch market carefully, and quickly leveraged those insights to make the investment decisions that ultimately are paying off today with our successful launch.

This is an important step forward toward our goal of bringing a safe and effective factor D inhibitor to patients with <unk> and complement mediated renal diseases.

Thank you very much.

We use this approach in all our capital allocation decisions, including, our pipeline. This disciplined approach is especially important in the current environment.

We see the complement area and the ability to bring oral drugs to fill large unmet needs, for these rare disease patients as a massive opportunity that includes Factor D and extends even more broadly to include other targets.

Our immediate decision is to allocate capital in the redeem and renew studies to see if we're able to achieve our goal of finding a safe and effective dose with BCX9930.

We will reinitiate enrollment using a stepped up approach and a dose level of 400 milligrams twice daily together with encouraging hydration and more frequent safety testing for the first few months of each patient.

If the data from the first small group of patients enrolled supports this goal, we'll continue to allocate capital to the 9930 program.

And so we believe it's a threshold effect that causes the drug to go out of solution, and causes a clogging of these tubules, and so we think that if we don't see these elevations, we won't, you know, it's not something that'll linger on over time, right?

After review of the data and investigating the elevations in serum creatinine, we reported in April .

If not, we'll stop its development, but still pursue Factor D inhibitors as we've already invested in next generation backups and molecules that we hope will be improvements.

It's not, this drug doesn't accumulate, so it's not something that'll happen over time.

We've arrived at a hypothesis for the mechanism contributing to these observations and our proposal for how to address it.

It's not an exposure issue, it's a threshold issue, so that's why we think, you know, the, small number of patients in the early phase of the study will give us much more confidence.

Helen or Bill, anything else you want to say?

The hypothesis is the crystals are forming in the kidney when the concentration of the drug is highest in the urine.

And that this can be mitigated by lowering drug levels in the urine.

We will test this by lowering the dose from 500 milligrams twice daily to 400 milligrams twice daily and encouraging adequate fluid intake to achieve dilution of the drug as it is excreted in the kidney.

If we are correct and our hypothesis and these steps successfully address the problem.

This will mitigate the risk of elevated serum creatinine in patients receiving BCS 90 930.

The evidence in support of this hypothesis comes from clinical observations and laboratory studies as.

With the partial clinical hold now removed, preparations to restart enrollment have begun, and Helen will share more with you on what we know now and how we plan to proceed.

I would only add that the findings in that first group of patients that, you know, for, which we paused enrollment, those were pretty definitive.

As we shared in May the clinical evidence suggested that the serum creatinine elevations occurred only at the 500 milligram dose level and we're likely dose related in it.

They were pretty early, and I think if we don't see that in the first group that's about, the same size, as you said, it would give us increasing confidence.

This is going to be an incremental approach as well.

Additionally, our recent clinical pharmacology studies have shown that a large fraction of the administered dose VCX 90, 930 is excrete it by the kidney.

We need that first step.

We need to see that, and then we'll continue to follow them and add more patients.

Thank you.

Importantly, New laboratory studies have found VCX 90, 930 drug solubility is lowered over the typical ph range of human urine.

And recent non clinical studies have also demonstrated dose related crystal deposition in the renal tract and kidneys in animals.

Understanding that suggests mechanism contributing to the rise in serum creatinine.

It is likely to be a physical one where crystals form in the urine in the kidney when youre in concentration of the drives reaches a threshold level.

The crystals cause an inflammatory response with resulting damage to the kidney cells.

This would explain how kidney function is affected and why a rise in serum creatinine is observed with VCX 90, 930 at 500 milligrams.

It could further explain why it is happening only in some patients.

And at the 500 milligram dose level, when <unk> renal drug levels exceed a threshold for crystal formation.

This mechanism of injury is avoidable.

We believe that the keys to avoiding risks of adverse kidney effects are to reduce the load of drug excretion by lowering the dose.

And to maintain more daylight more dilute urine to further lower the concentration of excreta truck.

By encouraging adequate fluid intake, especially at the time of drug administration.

That dose reduction together with the dilution effect of hydration.

Is designed to maintain adequate levels of the drug circulating in the blood for efficacy.

While reducing the concentration on elimination in the kidney to avoid crystal formation.

Of course, we also need to maintain strong clinical efficacy.

As a reminder, the data from our phase one <unk> program support studying 500 400 milligrams twice daily.

When C. Five inhibitor naive patients were taking this dose 400 milligrams in the phase one program the hemoglobin rose from baseline by a robust amount I mean, four three grams per deciliter and no transfusions where required.

Clinical observation was consistent with our PTA PK PD work showing that 400 milligrams twice daily provided plasma levels above the exposure needed to achieve near complete inhibition of the alternative pathway of complement.

Given that evidence we believe that 400 milligrams twice daily will achieve similar efficacy results to those we saw in phase one.

So what comes next.

I would only add that it gives you confidence to complete enrollment in the studies.

Yeah, that's right.

If we are correct and our hypothesis.

And as the steps we are taking are the right ones to resolve the elevation in serum creatinine, while maintaining strong clinical efficacy.

Thank you.

Our next question is from Maury Raycroft with Jefferies.

We will be able to confirm this in the clinic.

Our next steps are actually lower the dose for patients already on study while in parallel we reopened the studies to enrollment.

Hi.

Thanks for taking my question.

For Orladeo, can you elaborate more on what the ideal patient is to switch and the ideal, patient to benefit from Orladeo?

To do this we will proceed with regulatory submissions for the amended protocol from the redeemed clinical trials.

I guess are there some observations that you're seeing from the front line on that, that you can talk about?

Yeah.

We've included simple hydration instructions for all patients.

Hey, Maury.

And for new patients. We've included a revised regimen to get to the 400 milligram dose level with a short initial step up in dose.

We are also amending the renew trial with similar measures.

And initiating the status to reopen to enrollment at the 400 milligram dose in that trial.

Good question, and yes, we're starting to get an increasing amount of evidence about, the ideal patient, and it really is patients who were already well-controlled on another prophy drug.

If they had a very low attack rate coming in, most of those patients tend to stay at, the same low attack rate on Orladeo, and so I think as more and more physicians start seeing that and as more and more patients start experiencing that, that's where we're going to see the trend of switching, continuing, and maybe even increasing.

In terms of testing our hypothesis, we will assess patients in the first months of reopening enrollment in the redeem and renew trials.

And Charlie, when you say low attack rate coming in, you mean on their prophy therapy? Exactly, on their existing prophy therapy, and then they switch and keep the same low, attack rate on Orladeo.

And we will observe patient outcomes closely to determine if the data.

On safety at 400 milligrams supports continuing to invest through to completion of the pivotal studies.

Provided we can recruit patients in a timely manner and the initial data are supportive of safety and efficacy will proceed.

If the data are not supportive we will discontinue the 90 930 program and redirect our efforts and investments elsewhere in our pipeline.

So how are we notice.

As we resume enrollment at 400 milligrams, we will look for an absence of the early rise in serum creatinine and new patients enrolling in the study.

You will recall that over the first few months of enrollment and redeem one and redeemed two.

And in about one third of the first 15 patients we saw a rapid rise in serum creatinine at 500 milligrams.

As we enroll patients at 400 milligrams that will give us a good basis for comparison to inform our next steps.

Look at it like this.

It's about the same small number of patients are treated.

Without similar observations.

This will build confidence that the hypothesis is correct and the protocol adjustments are sufficient to address it.

By monitoring for serum creatinine at more frequent intervals in the first three months, we will gather the information we need to determine if our hypothesis is correct and if our revised amendment sufficiently resolve the problem.

On an individual patient.

More frequent monitoring will allow us to identify any changes in the near term and react swiftly if warranted.

Both for each individual safety on trial and for any appropriate decision on continuing the program.

It's clear to us that the need for better treatment options in these diseases is significant.

Our investigation, we have received unwavering encouragement from our investigators and patient organizations in both the hematology and nephrology communities to find a path forward for <unk> 90, 930, if there is one.

We are pleased that the FDA has removed the partial clinical hold following their review of our data our investigation findings and our proposed protocol adjustments.

Because of this high unmet need in <unk> and other complement mediated diseases and because we believe making a limited additional investment now to test. This hypothesis is warranted by the potential value of the program is successful we continue to pursue our goal of bringing safe and effective factor D inhibitor to the market for these patients.

We are working hard to achieve fiscal.

And we will make the decisions on where to invest in our pipeline based on sound evidence and where we can create the most value.

Got it.

Now I'll hand, the call back to John .

Thanks Helen.

And thanks for providing all of the detail on 9930 as well.

Let me conclude by summarizing where we are.

We have a successful rare disease launch with Orladeo growing into a global blockbuster.

The early data launched through six quarters continues to be strong with no signs of slowing down and we are on our way to global peak sales of $1 billion.

We have an exciting pipeline of compounds, some you know about and some you don't yet. And lastly, we have substantial capital to make thoughtful capital allocation decisions.

This is a unique and very good spot to be in in the current environment, and that brings, me back to where I started, the tremendous market success of Orladeo.

The steady and consistent revenue growth, discipline, and objective decision-making on capital allocation and alternative financing sources like the additional debt from Ethereum we recently drew down are the things that give us confidence we can repeat the Orladeo success with other molecules and create much greater value in the process.

We have a testable hypothesis with $99 30 that we believe we can answer in relatively short order.

And if 400 milligrams B I D is a safe and effective dose we have an asset potentially more valuable than orla Dale if not we move onto the rest of our pipeline to find the next door the days.

We have a very solid balance sheet and when the capital markets are challenging like they have been for a while now we can access other sources of capital.

Add this all up and you can see we are creating meaningful value now and we have the potential for much greater value in the future.

That concludes our remarks, and we'll now open up the call to your questions.

I'm just wondering for the actual molecule, do you have an understanding of why it's, crystallizing, and is that something that is relevant as to why the molecule is actually crystallizing?

Now I'll turn the call over to Charlie to share additional details on another strong, quarter of growth of Orladeo.

Thank you we will now begin our question and answer session. If you have a question. Please press zero then one on your Touchtone phone if you wish to be removed from the queue. Please prestero than two if youre using a speakerphone. Please pick up the handset first before pressing the numbers. So that is star then one to queue up.

Charlie?

So, Helen, you or Bill?

Yeah, I can take that.

With a question we have our first question from Stacy <unk> with Cowen <unk> Company.

Yeah.

Hi, all thanks, so much for taking our questions and congratulations on a rate.

Thanks, John. The consistent pattern of patient growth that we've seen since launch continued, without interruption in the second quarter. New patient prescriptions in Q2 were the best since the first quarter of the launch, driven by continued broadening and deepening of the Orladeo prescriber base.

Our Lady of quarter. So we have a few questions.

There is no sign this launch is slowing. Our market research, with HAE Treaters predicted this expansion, and the 96-week data that we started promoting late last year is convincing physicians to prescribe. When they see the sustained median monthly attack rate of zero, they know that their patients can expect great efficacy.

So, we have, since making these observations, as I said in the remarks, we've done further, work in the laboratory and we've been able to establish the solubility level, the pH range in the urine.

It's simple crystal formation as a result of the molecule's chemistry, so there's nothing, really special about it.

When they see patients doing really well on Orladeo in the real world, in particular those, patients who switched after being controlled on injectable prophylaxis, they were encouraged to increase prescribing. Our prescriber data in Q2 reflect this pattern.

But now that we know that, we know what to look for.

First on the 90 930 update can you speak about the patients that have stayed on the <unk> trials.

We added the most first-time prescribers since the third quarter of last year, and we also had an identical number of repeat prescribers.

Got it.

Are there any safety measures that are being monitored.

We saw an uptick in prescribing among the top 500 physicians that treat 50 percent of HAE patients. Sixty percent of those Tier 1 physicians have now prescribed Orladeo, and they accounted for two-thirds of new prescriptions in the quarter.

Okay.

Updates there sounds like they are on 500 milligrams and that will be adjusted to 400. So that's the first question those patients and then for the second.

Our source of business is also very balanced with overall patient potential.

Can you talk about kind of the FDA decision a little bit earlier than expected. So should we look into that as any read through.

It's clearly an overhang for the street, so any details would be appreciated there. Thank you.

So Helen do you want to take the first one I'll take the second one.

Although it is too soon to call this a trend, we had the fewest number of discontinuations, since Q3 of last year, even as the overall number of patients on Orladeo has grown substantially. Our metrics on access and reimbursement, which were already good, also continued to improve.

Thanks for taking my questions.

Sure. Thanks.

The median time to shipment of reimbursed product for a new prescription is now under, three weeks, as our team helps patients move quickly through the prior authorizations.

Thanks for the question so with regard to patients on their deemed trials, we have continued to monitor them.

Healthcare providers worry about the burdens of the access process for HAA treatments, so the success of our patient service model adds to their confidence in prescribing Orladeo.

Thank you.

We made more progress toward the globalization of Orladeo in Q2, with regulatory approvals, in Canada and Switzerland, and final price agreements in Germany, France, as well as, Switzerland. We also entered a commercial distribution agreement with Pint Pharma for Latin America, and we expect to file for market authorization in multiple Latin American countries before the end of 2022.

While the ex-U.S. contribution to 2022 sales will be small, the progress we are seeing, in Europe and other regions gives us confidence that ex-U.S. sales for Orladeo will reach at least $200 million at peak.

The prescribing dynamics and the patient trends that we saw in Q2 confirmed to us that we, are still in the early stages of the Orladeo launch trajectory.

The trends that we see tell us that Orladeo is on track not only for between $255 and, $265 million in sales in 2022, but also future market leadership and a billion dollars in peak sales.

Patients who remain on drug are doing so because per the partial clinical hold.

We're continuing to drive benefits they continue on drug there.

Their results have supported that.

And we are reducing the dose in all patients.

And then on the FDA question, we said the end of the third quarter, because we didn't know how many rounds, we'd go back and forth with the FDA and when we've said in the complete response to their whole day reviewed it and we got off clinical hold so we got off faster than we originally planned.

Alright, Thats very helpful. Thank you.

Thank you we have our next question from John <unk> with JMP Securities.

Now I'd like to turn the call over to Anthony.

As a reminder, if you have a question, please enter the queue by pressing zero, then one.

Thanks, Charlie.

We have our next question from Gina Wang at Barclays.

Orladeo revenue performance for Q2 was really strong and takes our trailing 12-month revenue, to just short of $200 million. With the consistency of new patient growth in the U.S. and continued expansion globally, we're really well positioned to achieve our updated revenue guidance of $255 to $265 million for 2022, and on from there to peak sales of a billion dollars.

Hey, good morning, Thanks for all the color on the dialogue or the update I just wanted to ask previously you discussed two different patterns of the creatinine elevations some patient pulling it early and then some developing over time.

You can find our detailed second quarter financials in today's earnings press release, and I'd, like to call your attention to a few items. Revenue for the quarter was $65.5 million, of which $65.2 million came from net sales, of Orladeo.

We had around $2.2 million of non-repeating reimbursement-related accrual releases in, the quarter, and so Orladeo net revenue specifically related to Q2 was $63 million.

Having seen Q1 gross to net impacted by reauthorizations, copay assistance, resets, and the government, donut hole, Q2 reimbursement rates and gross to net adjustments have normalized and should continue at current rates through year-end.

Thank you very much for taking my questions.

Operating expenses, not including non-cash stock compensation for the quarter, were $90.4, million.

$75 million debt tranches from Ethereum, pro forma cash is at approximately $492 million.

We have always been and will continue to be responsible and disciplined allocators of, capital.

These mitigation steps on the.

The louder, but wondering if you could talk about the potential of this.

Cropping up over time for patients as they stay on.

930 long term.

So let me start and then you had bill can jump in so I think the important thing is a small number of patients like we saw in the early start to the enrollment of the redeemed study is going to give us a sense of the first pattern, which was that acute rise in those same patients we're going to continue to track over time, and we will get a sense of what happens.

I have a few regarding the Olidayu, and so I hope I did not miss it.

This is especially true as we recommence enrollment in the 19-30 program. We have taken into consideration the delay to the program, applied a reduced probability of success, and reduced our assumptions for peak penetration.

Just wondering, have you mentioned the patient retention rate?

Despite that, there's still significant value potential to support investment in the program.

Would they still maintain at a 70%?

There are numerous markets that we can go into with 99-30, not just P&H.

And regarding the new patient, percentage of patient that switch from other prophy, what was the number there?

Would that still like 50%?

These markets are big, especially in renal indications.

And this is a drug that patients want.

All of that results in a revenue potential for 99-30 that is larger than that of Orladeo.

Over time with the same small group of patients. So I think we get the benefit from both patterns with this early group of patients.

Our intent is to progress as quickly as possible, limit the additional investment, and get to the point where we have confidence that we have a safe and effective drug.

If we can achieve this, then we will continue to invest in moving the program forward.

And I can answer on the.

Another point on the early ryzen. This slow trend. We think this is a threshold effect, we think it's a threshold that the drug concentration in the year and that could explain both the early rise findings and the slow later findings, we expect to be able to answer each of those questions and the first small group of patients who were enrolled.

And then quickly on the pricing, I know you finalized in Germany, France, and Switzerland.

That's helpful. And then maybe a couple of follow ups, how long you've discussed a few different procedural steps to get new patients and wondering.

What are the comparison, you know, the price compared to the U.S. price?

And I'm sorry, one last question.

When do you think you could start dosing new patients and redeem and renew and then also just thinking about this early evaluation what is the bar that's acceptable to you have to see a complete absence of serum creatinine or is there any discussion with FDA about what.

What can you see thats tolerable and what is intolerable here.

So maybe in the second one the stopping rule in the first one is pretty straightforward.

Yes, so we have some work to do initially with just to get the protocols up and running.

If we cannot, then we will terminate the program and allocate capital elsewhere.

Regarding Factor D, how much initial capital allocation will you put for that program?

This data-driven, objective, unemotional approach has been a key factor in the successful launch of, Orladeo and will continue to guide us in all of the programs that we have going forward.

Now I'll pass it over to Helen.

Yeah, go ahead.

We have to submit to countries and sites that will take a few months and then we will be enrolling from there we expect that side.

Thanks, Anthony.

Great.

Hi, Gina.

As we announced today, the FDA has lifted their partial clinical hold on the BCX 99-30 program, and our pivotal trials in P&H can resume enrollment, along with our proof-of-concept trial in renal indications. This is an important step forward toward our goal of bringing a safe and effective, factor D inhibitor to patients with P&H and complement-mediated renal diseases. We will reinitiate enrollment using a step-up approach and a dose level of 400 milligrams, twice daily, together with encouraging hydration and more frequent safety testing for the first few months in each patient.

So retention, it's too soon to call it a trend, but it appears to be getting better. It's been a real focus of the team, particularly in improving retention early in therapy so, that patients don't give up too early. The overall retention rate since launch, I think I've said before, was in the mid-60% retention since launch.

So on patient retention, what I did note is that we had a decrease in discontinuations, in Q2.

It's similar to that, but what's really important now is we see some signs that this is improving.

Within the first few months of experience with the first patients will have the opportunity to see data. So this is an incremental approach first is get to the.

Our readiness for startup then get to enrollment and get the data.

And in terms of what we're looking for then we think that this is a threshold effect as I said the goal is to avoid that and so what we're looking for is to patients to be dosed at the 400 milligram dose level and for us to be seeing in those new patients that were not observing these findings it if.

After review of the data and investigating the elevations in serum creatinine we reported in April, we have arrived at a hypothesis for the mechanism contributing to these observations and our proposal for how to address it. The hypothesis is that crystals are forming in the kidney when the concentration of the, drug is highest in the urine, and that this can be mitigated by lowering drug levels in the urine. We will test this by lowering the dose from 500 milligrams twice daily to 400 milligrams twice, daily and encouraging adequate fluid intake to achieve dilution of the drug as it is excreted in the kidney.

If we are correct in our hypothesis and these steps successfully address the problem, this will mitigate the risk of elevated serum creatinine in patients receiving BCX9930. The evidence in support of this hypothesis comes from clinical observations and laboratory studies. As we shared in May, the clinical evidence suggested that the serum creatinine elevations, occurred only at the 500 milligram dose level and were likely dose-related. In addition, our recent clinical pharmacology studies have shown that a large fraction of the administered dose of BCX9930 is excreted by the kidney.

Importantly, new laboratory studies have found BCX9930 drug solubility is lowered over the, typical pH range of human urine, and recent non-clinical studies have also demonstrated dose-related crystal deposition in the renal tract and kidneys in animals. Understanding that suggests a mechanism contributing to the rise in serum creatinine. It is likely to be a physical one where crystals form in the urine in the kidney when urine, concentration of the drug reaches a threshold level.

If we have serum credit in major increases in serum Creatinine, then we don't have a drug that's safe and effective right. So it's pretty straightforward and on the first point, we're going to go as fast as we can right.

It's hard to predict how quickly that will happen, but we're going to go as fast as we can.

I'll jump back in the queue. Thanks for taking the questions.

Yes.

We have our next question from Chris Raymond with Piper Sandler.

Yes. Thanks, two questions I guess first on 90 930.

The crystals cause an inflammatory response with resulting damage to the kidney cells. This would explain how kidney function is affected and why a rise in serum creatinine, is observed with BCX9930 at 500 milligrams.

Maybe could you provide a little bit more color on that.

Sort of hydration protocol, I guess youre describing.

It could further explain why it is happening only in some patients and at the 500 milligram, dose level when intrarenal drug levels exceed a threshold for crystal formation.

Just trying to understand what specifically youre.

You submitted to FDA in terms of.

What patients need to do is it.

This mechanism of injury is avoidable. We believe that the keys to avoiding risk of adverse kidney effects are to reduce the, load of drug excretion by lowering the dose and to maintain more dilute urine to further lower the concentration of excreted drug by encouraging adequate fluid intake, especially at the time of drug administration. That dose reduction, together with the dilution effect of hydration, is designed to maintain, adequate levels of the drug circulating in the blood for efficacy while reducing the concentration on elimination in the kidney to avoid crystal formation.

Is it more of the hydration.

Or does the lower dose I guess.

You're hypothesizing.

Alleviate this issue in.

And maybe just give us a sense of how this sort of translates into the real world.

If in fact, you keep going with US with this hydration protocol and it's approved and then there's this requirement for patients.

To hydrate.

And then the second question on Orlando.

We've done some some kols checks.

I'm kind of curious what you guys are seeing in the larger market.

The feedback we've gotten is that overall profi share is relatively growing steadily but share of new patients is really where the.

The bolus of uses like 80% or more of new patient. So we started from one of our Kols. So I guess I'm just kind of curious what are you seeing in the broader market.

And if youre seeing a similar sort of proportion there what kind of lag do you anticipate before this really starts to accelerate total share. Thanks.

Of course, we also need to maintain strong clinical efficacy.

As a reminder, the data from our Phase 1 PNH program supports studying 400 milligrams, twice daily. When C5 inhibitor-naive patients were taking this dose, 400 milligrams in the Phase 1 program, the hemoglobin rose from baseline by a robust amount, a mean of 4.3 grams per deciliter, and no transfusions were required. This clinical observation was consistent with our PKPD work, showing that 400 milligrams, twice daily provided plasma levels above the exposure needed to achieve near-complete inhibition of the alternative pathway of complement.

So what comes next?

Given that evidence, we believe that 400 milligrams twice daily will achieve similar efficacy, results to those we saw in Phase 1.

If we are correct in our hypothesis, and if the steps we are taking are the right ones, to resolve the elevation in serum creatinine while maintaining strong clinical efficacy, we will be able to confirm this in the clinic.

So you want to take the first one on hydration, yes.

Our next steps are to lower the dose for patients already on study, while in parallel, we reopen, the studies to enrollment.

To do this, we will proceed with regulatory submissions for the amended protocols in the, redeemed clinical trials. We've included simple hydration instructions for all patients. And for new patients, we've included a revised regimen to get to the 400 milligram dose level, with a short initial step-up in dose.

So it's 99 three the titration protocol is actually really simple.

We are also amending the renewed trial with similar measures, and Initiating the Steps to Reopen to Enrollment at the 400mg Dose in that Trial.

In terms of testing our hypothesis, we will assess patients in the first months of reopening enrollment in the Redeem and Renew Trials, and we will observe patient outcomes closely to determine if the data on safety at 400mg supports continuing to invest through to completion of the pivotal studies.

Provided we can recruit patients in a timely manner and the initial data are supportive of safety and efficacy, we will proceed.

If the data are not supportive, we will discontinue the 9930 program and redirect our efforts and investment elsewhere in our pipeline.

It's simply too.

Encourage hydration, while on the drugs that could be as simple as taking the drug with a glass of water, we have not prescribed specifically what it should be.

But it is encouraging hydration.

So how will we know this?

Reasoning behind that is that we're taking a two pronged approach to be able to get the year end concentration below the thresholds for formation of any crystals and that's both with the dose reduced within the effective dosing range and the addition of hydration in order to get to that sustained level below that threshold.

As we resume enrollment at 400mg, we will look for an absence of the early rise in serum creatinine in new patients enrolling in the study. You will recall that over the first few months of enrollment in Redeem I and Redeem II, and in about one-third of the first 15 patients, we saw a rapid rise in serum creatinine at 500mg.

Hold for Crystal formation in terms of where this would go in the store.

Next is used in the real world, It's really quite simple because this is as simple as take your medicine with a glass of water and.

And so we think that this is very achievable.

Great Charlie you want to take that Dave.

This.

Thanks for the question.

And as far as the overall switch rate, I think I just mentioned a minute ago, but about 50% of the patients have switched from other prophy, and then the other 50% is mostly switching from acute only, and then some patients who are naive to therapy starting Orladeo as their first drug.

So first of all overall, 50% about 50% of the patients that are on early day of today have switched from another prophylaxis product and Thats really in proportion to what we think is the market market share. So about half of those switchers proceeds switches are coming from Tech zero, then haegarda and <unk>.

And so on.

Sure.

<unk> talked about the prescriber base, we've got a really big prescriber base and so I think we're still early in this process of getting all the different kols to to fully understand this and I think in the future. They will switch more patients but across the overall market theres been a lot of switching and as more and more doctors get familiar with our data.

And see the real world efficacy that those those proceeds switches are having I expect that the trend will continue.

Thank you.

We have our next question from Jessica Fye with J P. Morgan.

Yeah, Charlie, I think part of her question was retention, and those folks, it's actually, better in the- Yeah, oh, sorry.

Hey, guys. Good morning, Thanks for taking my questions. So a couple more for you on 90 930.

Yeah, right.

That was the other part.

You talk about a reasonable timeframe at a relatively small number of patients needed to find a safe and effective dose can you just elaborate on how you define two things.

First is a reasonable timeframe. The three months you talked about in prepared remarks and is that three months from today or is that once you get three months of follow up on a small number of patients and it could take a few months to spool up enrollment again.

And then second.

How do you define a small number of patients is that a dozen a couple dozen.

Just trying to figure out when investors will have more clarity here.

Yeah.

I think it's important to look at what we saw in the study that caused us to stop right. So it was about 15 patients roughly in enrollment in the redeemed studies that we saw this effect and so we think it's a similar number is roughly what will give us confidence that we're not seeing the effect of where we are.

And the timeframe for that as Helen said, it could take some months to get the.

Our revised protocols. These are major amendments and so you've got to go to the regulatory authorities and then.

It took about two months to see the effect in these patients. So once we got it up and running and we're enrolling patients it'll be a couple of months before we see we feel like we're in the position where we know what we're seeing so.

I hope that gives you a little bit more frame. It so it's really hard to predict just because it.

It takes time to get these things approved it and then start enrollment.

As we enroll patients at 400mg, this will give us a good basis for comparison to inform our next step.

We look at it like this.

We're going to work as fast as we can.

We will keep you updated along the way.

Got it and I appreciate the kind of deliberate approach here.

If about the same small number of patients are treated without similar observations, this will build confidence that the hypothesis is correct and the protocol adjustments are sufficient to address it.

And I can understand how a small number of patients can rule in a safety issue, but how do you get comfortable that a small number of patients can rule out a safety issue.

Yes, maybe I'll start and then you and bill can jump in the hypothesis is based on the data we've gathered to date right, which is a combination of the clinical data and what we saw at 400 and what we saw at 500 and then what we saw in Clinton farm and what we saw in laboratory tests and some recent.

By monitoring for serum creatinine at more frequent intervals in the first three months, we will gather the information we need to determine if our hypothesis is correct and if our revised amendments sufficiently resolve the problem. On an individual patient level, more frequent monitoring will allow us to identify any changes in the near term and react swiftly, if warranted, both for each individual's safety on trial and for any appropriate decision on continuing the program.

It's clear to us that the need for better treatment options in these diseases is significant.

Throughout our investigation, we have received unwavering encouragement from our investigators and patient organizations in both the hematology and nephrology communities to find a path forward for BCX9930 if there is one.

We are pleased that the FDA has removed the partial clinical hold following their review of our data, our investigation findings, and our proposed protocol adjustments.

Because of this high unmet need in PNH and other complement-mediated diseases, and because we believe making a limited additional investment now to test this hypothesis is warranted by the potential value if the program is successful, we continue to pursue our goal of bringing a safe and effective factor D inhibitor to the market for these patients.

We are working hard to achieve this goal, and we will make the decisions on where to invest in our pipeline based on sound evidence and where we can create the most value.

Animal studies and so we believe it's a threshold effect that causes to the drug to go out a solution and causes a clogging of these tubules and so.

Now, I'll hand the call back to John.

Thanks, Helen.

Let me conclude by summarizing where we are. The Orladeo launch through six quarters continues to be strong with no signs of slowing down, and we are on our way to global peak sales of $1 billion, access other sources of capital. Add this all up, and you can see we are creating meaningful value now, and we have the potential, for much greater value in the future.

We think that if we don't see these elevations we won't.

That concludes our remarks, and we'll now open up the call to your questions.

And that will linger on over time right. It's not this drug doesn't accumulate so it's not something that will happen over time, it's not an exposure issue. It's a threshold issue. So.

That's what that's why we think the small number of patients in the early phase of the study will give us much more confidence Helen or bill.

Anything else you want to say I would only add that the findings in that first group of patients.

For which we paused enrollment those are pretty definitive they were pretty early and I think if we don't see that in the first group is about the same size as you said.

It would give us increasing confidence this is going to be an incremental approach as well we need that first step we need to see that and then we'll continue to follow them and add more patients.

Thank you.

We add that gives you confidence to complete enrollment in the studies.

Yes.

All right.

Thank you. Our next question is from Maury Raycroft with Jefferies.

Thank you.

We will now begin our question and answer session.

Hi, Thanks for taking my question.

If you have a question, please press zero, then one on your touchtone phone.

Yeah, so, and I've mentioned this in previous calls, that the retention of people switching, from injectable prophy at six months for Taxiro, Higarda, Synrise is in the high 70%, and that's based on the fact that they were well-controlled before, and most of those patients stay well-controlled on Orladeo.

For Orlando.

Can you elaborate more on <unk>.

What the ideal patient as you switch and the ideal patient to benefit from all the data I guess theres some observations that youre seeing from that from the frontline on that that you can talk about.

And then you had a question about EU pricing.

Yeah, Hey, Maury.

So our German list price is about 156,000 euros.

The Swiss price is a little bit higher than that, so you get a sense for how that compares, to the U.S., where our WAC pricing is $499,000.

Good question and yes, we are starting to get an increasing amount of evidence about the ideal patient and it really is patients who were already well controlled on another profi drug.

And then, Anthony, you want to take the capital allocation question?

Yeah, sure.

Obviously, they had a very low attack rate coming in.

Most of those patients tend to stay at the same low attack rate on Orlando.

And so I think as more and more physicians start seeing that and as more and more patients started experiencing that.

That's where we're going to see the trend of switching continuing and maybe even increasing and Charlie when you say low attack rate coming in you mean on their appropriate they're exactly ordinary existing proceeds therapy and then they switch and keep the same low attack rate on road out.

Got it and.

Any and thanks for providing all of the detail.

940 as well.

I'm just wondering for the actual molecule do you have an understanding of why it's crystallizing and is that something that is relevant.

The molecule was actually crystallizing.

And your Bill, Yes, I can take that so.

We have since making these observations as I said in the remarks suites.

Further working on laboratory and we've been able to establish the viability level.

Each range and the year end.

It's simple crystal formulation formation.

As a result of that.

Molecules chemistry, so theres nothing really special about it.

But now that we know that we know what to look for.

Got it okay. Thanks for taking my question.

Thank you as a reminder, if you have a question. Please enter the queue by pressing zero that one we have our next question from Gena Wang of Barclays.

If you wish to be removed from the queue, please press zero, then two.

Thank you very much for taking my questions I have a few regarding the.

All of that and so I hope I did not Mitchell just wondering have you mentioned the patient retention rate would this to maintain at 70% and regarding the new patients percentage of patients to switch from other profi.

Was the number there was that to like 50%.

And then quickly on the pricing I know, you've finalized in Germany, France and Switzerland.

What about the comparison.

The price compared to the U S price.

And then sorry, one last question regarding factor D. How much initial capital allocation.

Good.

For the program.

Go ahead, Sir Great Hey, Jamie so on patient retention.

I'd note is that we had.

The decrease.

In discontinuation in Q2, so retention.

Too soon to call it a trend, but it appears to be getting better it's been a real focus of the team, particularly in improving retention early in therapy. So that patients don't give up too early the overall retention rates since launch.

Said before was in the <unk>.

Mid 60%.

Retention since launch it's similar to that.

But what's really important now as we see some signs that this is this is improving.

And as far as the overall switch right.

I think I, just mentioned a minute ago, but about 50% of the patients have switched from other protein and then the other 50% is mostly switching from acute only and then some patients who are naive to therapy, starting <unk> as their first drug yes, Charlie I think part of your question was retention in those folks, it's actually better than those sorry, yet right.

The other part.

I've mentioned this in previous calls that the retention of people switching from injectable profi.

At six months for tax Iroh Haegarda Cinryze is in the high 70%.

And Thats based on the fact that they were well controlled before and they stayed most of those patients stay well controlled on Orlando.

And then you had a question about EU pricing sorry.

So our German list price is about 156000 euros.

The Swiss prices, a little bit higher than that so you get a sense for how that compares to.

The U S, where our WAC pricing is $499000.

And then Anthony you want to take the capital allocation question.

So, from a capital allocation perspective, it's, you know, it'll depend, on how quickly we can move through the trials.

From a capital allocation perspective.

Our intent is to move as quickly as possible.

Depends on how quickly we can move through the trials. Our intent is to move as quickly as possible Helen talked about it being incremental in terms of how we move forward with the program.

Helen talked about it being incremental in terms of how we move forward with the program.

One thing I will say is we've talked about it being a small number of patients that we, need at the start.

One thing I will say is we've talked about have been a small number of patients that we need at the start.

We've also said in the guidance that we've reduced our opex guidance down to $390 to $400 million for the year.

We've also said in the guidance that we've reduced our opex guidance down to $390 million to $400 million for the year. So.

So, that in combination with the revenue increase in the guidance means from a net cash burn perspective, you know, we're definitely in a better spot now than we were previously.

That in combination with the revenue increase in the guidance means from a net cash burn perspective.

We're definitely in a better spot now than we were previously so.

So, listen, we'll be absolutely responsible and smart in terms of how we invest that capital. It is the right investment in capital at this point in time given the potential returns.

We will be absolutely responsible.

And smart in terms of how we invest on capital. It is the right investment and capital at this point in time, given the potential returns.

Thank you very much.

Thank you very much.

If you're using a speakerphone, please pick up the handset first before pressing the numbers.

We have our next question from Brian Abrams with RBC Capital Markets.

We have our next question from Brian Abrahams with RBC capital markets.

So that is star, then one to queue up with a question.

Good morning.

Good morning, Thanks for taking my questions and congratulations on the continued strong or the day of launch.

We have our first question from Stacy Ku with Cowen & Company.

Thanks for taking my questions and congratulations on the continued strong, early data launch.

For me I guess, a 99% to 30.

Are there.

<unk> different considerations with regard to this crystal formation for <unk> patients versus those with underlying kidney disease.

Hi, all.

A few for me, I guess on 9930, are there mechanistically different considerations with regards to this crystal formation for P and H patients versus those with underlying kidney disease?

Secondly, on the interim assessment that youre going to be doing well efficacy be part of that and will the FDA have any requirements that they'll need to sign off on before that.

Secondly, on the interim assessment that you're going to be doing, will efficacy be a part of that and will the FDA have any requirements that they'll need to sign off on before the trial is expanded out?

And then lastly, on Orladeo, it sounds like you're reiterating your billion-dollar peak sales estimate.

The trial is it expanded out and then lastly on <unk>.

Thanks so much for taking our questions, and congratulations on a great Orladeo quarter.

Sounds like Youre reiterating your billion dollar peak sales estimate I'm, just wondering if theres any.

So, we have a few questions.

I'm just wondering if there's any evolution in the parameters that form your confidence around that.

Evolution and the parameters that that form your confidence around that it sounds like the U S. Ex U S breakdown is.

It sounds like the U.S.-ex-U.S. breakdown is similar to what you had expected before, but just wondering if the improving retention, new patient starts, degree of overall market growth, how those factors are evolving to continue to shape that goal.

Thanks.

Similar to what you had expected before but just wondering if the improving retention.

Patient starts degree of overall market growth how those factors are evolving just continue to shape that goal. Thanks.

So how do you want to take the 90 930, and then Charlie can take the deal yes.

Do you want to take the 9930 and then Charlotte can take the Orladeo?

Yeah.

So the first question was.

Is there any mechanistic difference in this.

Patients with different diseases.

So the first question was, is there any mechanistic difference in this in the, patients with different diseases?

We don't think so no hypothesis is crystals, forming when theres a high concentration of to drive.

And we don't think so. The hypothesis is crystals forming when there's a high concentration of the drug excreted in the urine.

Excrete it in the year and that is a dredge.

Dredge that's independent of disease. So once we have solved this force dose that is safe and effective in one disease, we would expect that to be relevant in all diseases.

That is a drug that's independent of disease.

So once we have solved this for a dose that is safe and effective in one disease, we would expect that to be relevant in all diseases.

The second question was in terms of what we are assessing on an interim basis and the study is a simple safety assessment is simple observation. If we see continued episodes of horizon creatinine and patients being dosed at 400 milligrams. Then we will know that we're seeing it if we're not we won't be.

The second question was in terms of what we are assessing on an interim basis in the study.

This is a simple safety assessment.

It's simple observation.

If we see continued episodes of a rise in creatinine in patients being dosed at 400 milligrams, then we'll know that we're seeing it.

If we're not, then we won't be.

And that's the extent of the interim view.

And that's the extent of the interim view as.

Yeah.

Question two is around the FDA and efficacy there were no requirements by the FDA. There are always looking at a benefit risk and clearly they see some benefit in keeping the patients on the study and us continuing to study, but from an efficacy perspective, if we have breakthrough hemolysis, we'll see that in and we're evaluating whether the.

And his question too was around the FDA and efficacy.

DMC can look at the blinded data are unblinded data as well from an efficacy perspective so.

There were no requirements, by the FDA. They're always looking at a benefit risk and clearly they see some benefit in keeping the patients on the study and us continuing the study.

But from an efficacy perspective, if we have breakthrough homolysis, we'll see that.

We're concerned about both Brian and those we said before the goal is a safe and effective drug.

And we're evaluating whether the DMC can look at the blinded data or unblinded data as well from an efficacy perspective.

Yeah.

Brian .

As far as the $1 billion.

Nothing significant has changed so we do have as you know we do a lot of market research a lot of a lot of planning and as we see the real world evidence real world results matching up what we expected.

We gain even more confidence and reiterate so.

So we're concerned about both, Brian, and we said before the goal is a safe and effective, drug.

Brian, as far as the billion dollars, nothing significant has changed.

What we're seeing in Europe set early uptake.

The the pricing that we've been able to achieve is in line with our expectations and so that gives us great confidence in getting to at least $200 million in the rest of the world and then the real world evidence that I've talked about coming out of patients who are switching to oral at al.

We do, as you know, we do a lot of market research, a lot of planning, and as we see, the real-world evidence, the real-world results matching up what we expected, we gain even more confidence and reiterate.

So what we're seeing in Europe, the early uptake, the pricing that we've been able to, achieve is in line with our expectations, and so that gives us great confidence in getting to at least $200 million in the rest of the world.

And then the real-world evidence that I've talked about coming out of patients who are, switching to Orladeo in the U.S. and the fact that most of those patients are staying on drug and having a great experience gives us that much more confidence.

In the U S and the fact that most of those patients are staying on drug and having a great experience gives us that much more confidence and then what I said about our prescriber base expanding all of this just gives us more confidence in where this drug is headed in beauty.

And then what I said about our prescriber base expanding, all of this just gives us, more confidence in where this drug is headed.

Yeah, and quarter after quarter, it keeps getting better, right?

Quarter after quarter it keeps getting better we're growing sales, we're expanding prescribing, we're getting more into the funnel in terms of new patients.

We're growing sales, we're expanding prescribing, we're getting more into the funnel in terms, of new patients.

You know, our confidence goes up every single quarter.

Our confidence goes up every single quarter, there is no sign of slowing down.

There is no sign of slowing down.

That's really helpful.

That's really helpful. Thank you guys.

Thank you, guys.

We have our next question. Our next question comes from Sarah <unk> with Needham <unk> Company.

We have our next question.

Our next question comes from Serge Bellagio with Needham & Company.

Hi.

Good morning.

Hi, good morning.

First, on the 9930 update, can you speak about the patients that have stayed on the RE-M trials?

I guess one on 9930 to start off, did I hear correctly that you are evaluating some of, the backup molecules to 9930?

I guess, one on 90 930, you can start off.

Did I hear correctly that you are evaluating some of the backup molecules.

<unk> 930.

And if I did hear correctly, how close are they to being ready for clinical evaluation?

If I did hear directly.

So are there too.

Being ready for clinical evaluation.

And then on Orladeo, a couple for Charlie, can you talk about where you are with market, share now and in terms of new patient ad cadence, how it progressed in the second quarter and maybe whether you expect summer seasonality impacts on that cadence?

And then on the oral a deal a couple for Charlie can you talk about where you are.

With market share now.

And.

In terms of new patient add cadence.

Progress in the second quarter.

And whether you expect.

Summer seasonality impacts on that cadence. Thank you.

Thank you.

Are there any safety measures that are being monitored?

So I'll take the backup one, Charlie, and then you take the Orladeo new patient.

So I will pick that back up with each other and then you take the or the day of.

New patients.

Any updates there?

Yeah, we're always working on backups, and we didn't slow down.

Yes, we're always working on on backups, and we didn't slow down.

We've always put, you know, full court advance on them.

We've always put full.

Advance.

I said in the remarks that we're investing fully in those, and so I can't tell you yet, you know, when it's ready to share more broadly, but, you know, there are multiple backups, and as we have more data, we'll share that with you.

Said in the remarks that we're investing fully.

In those and so can't tell you yet.

Ready to share more broadly but.

There are multiple backups and as we have more data we'll share that with you and then I think the other pieces. We worked have improved molecules as well and you saw that with that move from oral stat.

And I think the other piece is, you know, we work to have improved molecules as well, and you saw that with the move from Mavoralstat to Orladeo.

Deyo and so in this program, we're trying to do the same.

And so, you know, in this program, we're trying to do the same, you know, whether or not we'll, be successful is to be determined, but full speed ahead on the backups.

And that will be successful is to be determined but full speed ahead on the backups.

And then as far as market share.

And then, Serge, as far as market share, we've shared some of our market research in the, past.

We've shared some of our market research in the past I think most recently some data from earlier this year.

I think most recently, some data from earlier this year, the survey showed Orladeo share, of about 12 percent. That was probably a little ahead of where we actually were in the market at the time, but then we've grown since then.

The survey showed Orlando share of about 12%.

That was probably a little ahead of where.

Where we actually were in the market at the time, but then we've grown since then so it's and physicians see market research see this becoming their most prescribed drug in the future and as we've said before all we need is 25% to 30% market share in the U S to get to about 700 5800.

So it's, and physicians see, in our market research, see this becoming their most prescribed, drug in the future, and as we've said before, you know, all we need is 25 to 30 percent market share in the U.S. to get to about $750, $800 million towards that billion dollars of peak sales.

Towards that $1 billion of peak sales. So it's growing all the time, we're doing well.

So it's growing all the time.

We're doing well.

And then, as far as the new patient cadence, I mentioned in the remarks that we had the, most new patient prescriptions in Q2 since the very first quarter of the launch, and that's, you know, really significant now, six quarters in, no signs of slowing down.

And then as far as the new patient cadence.

I mentioned in the remarks that we had the most new patient prescriptions in Q2 since the very first quarter of the launch and Thats.

Really significant now six quarters in no signs of slowing down and as far as the summer slowdown.

And as far as the summer slowdown, any differences there?

Any differences there.

Yeah, we'll see.

We'll see we'll talk about that after after Q3, but we ended Q2 in June really strongly so I feel good about where we are.

We'll talk about that after Q3, but we ended Q2 in June really strongly, so I feel good, about where we are.

And thank you.

Thank you.

Youre welcome. Thank you.

And thank you we have our final question from lease tobacco with Evercore ISI.

We have our final question from Liisa Bayko with Evercore ISI.

Hi, Thanks for taking my question.

I understand what you're saying about the threshold effects for $99 30.

You did have some patients that.

Had these elevations and some that didnt any ability to decipher what that is and what's your threshold.

I know you saw it in 15 patients like if you see one case is that enough.

To stop.

What's your threshold for like seeing cases.

As you.

Go into this next phase now.

So I will take the questions. So on the threshold, yes, we have seen this in some patients not all we do think this is a threshold effect.

What that means is that in some patients under some circumstances crystals could be forming and we're pretty close to the edge of that threshold with the 500 milligram dose.

Sure.

And that means that with the two pronged approach and Thats part of why we're taking that two pronged approach of reducing the dose and hydration, we could see that we get below the threshold for all patients at all all the time and Thats. The goal is to avoid this.

So this is this is hypothesis we are still working on this we need to serve in the clinical setting if we've addressed this with 400.

But that's why we think it's happening it's sporadically occurring because we're close to the thresholds some at the time, but not all the time.

And then the stopping rule and I think that's important for people to now yeah. So so and the question is one case enough. So what we think is that.

There are multiple things that can also occur in patients with these diseases that can cost rise in serum creatinine.

We like we want to make sure that we are assessing any rise in serum creatinine in the context of what's happening with the patient.

And if it is likely to be related to the drought or something else. So we're assessing these will review them together with our D&C, we have a stopping rule in the studies that is if we see three.

Events that are that are serious events and that are considered to be related to the drug that's the point at which we would stop the study.

Okay.

30 cases.

Okay.

Then.

This notion of inferring so like what makes you believe that 400 is sort of below that threshold.

So it's a hypothesis and it's based on what we see at this point in the data we have not observed at 400 milligrams and we do have.

Every patient in the phase one went through the 400 milligram stage of dosing.

It's a drug concentration thing if you have less drug and you'll have more hydration less chance of having it go out a solution right. So.

As logic there too.

Okay.

Okay and then.

Sorry, I may have missed it but did you break down sales like U S. Japan rest of world or could you do that.

Okay.

We have not broken that out yet Lisa.

And the reason we haven't is that the majority of it is U S. So the other stuff isn't significant enough to report out but it is growing I mean, what I said that in the remarks that it's nice to see you or you are growing and that's not surprising because now we've got pricing now we've got promotion now patients are getting on therapy. So over time, we will.

Break it out but at this point.

Vast vast majority of the U S.

Okay, and then one quick question I've been getting questions.

From clients lately about the types of patients is down a little for longer than six months.

And is there any relationship between sort of severity of disease. In response. So if you could just kind of talk about the kind of patients who tend to be more sticky.

Dan.

Ah.

Related question on severity in response to the dam.

Yes.

Yes.

Type of patient that tends to be the most sticky are again those are those patients who were well controlled on another drug and then switched over to Orlando and remain well controlled and so.

That they were on prophylaxis prior suggested they needed their attacks controlled.

And and then they've maintained that same rate on all of that yes. This idea of.

Attack severity or frequency of attack people control their disease now so that's like that's an old way of looking at it now the way you should look at it is where are we getting the business. We're getting it from people that are controlled on their injectable therapy, but don't want the burden of therapy. The injectable therapy. Those are the people, we're getting and that will continue.

To grow and we will get more and more share of that.

Alright. Thanks.

Youre welcome.

Thank you.

This concludes our question and answer session I will now turn the call over to Mr. Stonehouse for closing remarks.

It sounds like they are on 500 milligrams, and that will be adjusted to 400.

Hi, thanks for taking the question.

So, that's the first question, those patients.

I understand what you're saying about the threshold effect, for 9930, yet you did have some patients that, you know, had these elevations and some that didn't.

And then for the second, can you talk about kind of that FDA decision a little bit earlier, than expected?

Any ability to decipher what that is?

So, should we look into that as any read-through?

It's clearly an overhang for the street, so any details would be appreciated there.

Thank you.

And what's your threshold?

Thank you.

So, Helen, you want to take the first one, and I'll take the second one?

You know, I know you saw it in 15 patients.

Like, if you see one case, is that enough to stop?

Something I've learned and I think we've learned as a company over many years of working on many many projects.

You know, what's your threshold for, like, seeing cases as you, you know, go into this next phase now?

So I can take the questions.

So on the threshold, yes, we have seen this in some patients, not all.

Sure.

So it's three cases.

We do think this is a threshold effect. What that means is that in some patients under some circumstances, crystals could be forming.

Thanks for the question.

Okay.

And we're pretty close to the edge of that threshold with the 500 milligram dose.

So, with regard to patients on the RE-M trials, we have continued to monitor them. Patients who remain on drug are doing so because, per the partial clinical hold, they were continuing, to derive benefits. They continue on drug.

And then just this notion of inferring.

That's what we infer. And that means that with the two-pronged approach, and that's part of why we're taking that two-pronged approach of reducing the dose and hydration, we could see that we get below the threshold for all patients all the time.

Their results have supported that, and we're reducing the dose in all patients.

So, like, what makes you believe that 400 is sort of below that threshold?

And that's the goal, is to avoid this.

Is the importance of objectivity and following the evidence in the data in our decision making.

And then on the FDA question, we said the end of third quarter because we didn't know, how many rounds we'd go back and forth with the FDA.

So it's a hypothesis, and it's based on what we see at this point.

So this is, you know, this is hypothesis.

And when we sent in the complete response to their hold, they reviewed it, and we got, off clinical hold. So, we got off faster than we originally planned.

In the data, we have not observed this at 400 milligrams, and we do have – every patient in the Phase I went through the 400 milligram stage of dosing.

We're still working on this.

All right, that's very helpful.

It's a drug concentration thing.

We need to observe in the clinical setting if we've addressed this with 400.

We have a question from John Wallen with JMP Securities.

Thank you.

If you have less drug and you have more hydration, less chance of having it go out of solution, right?

But that's why we think it's happening.

Hey, good morning, and thanks for all the color on the 9930 update.

So there's logic there, too.

It's sporadically occurring because we're close to the threshold some of the time, but not all the time.

Just wanted to ask, previously you discussed two different patterns of the creatinine elevations, some patients seeing it early and then some developing over time.

Okay.

And then the stopping rule, and, you know, what's the – I think that's important for people to know.

These mitigation steps seem to affect the latter, but wondering if you could talk about, you know, the potential of this cropping up over time in some patients as they stay on, 9930 long-term.

Okay.

Yeah, so – and the question is, is one case enough?

Whether it's clinical data that we're looking at to advance a program or market data do we have the right profile that will be competitive in the marketplace. If you go into it wanting to see a certain thing youre not going to be objective and you could make the wrong decision. We don't do that at Biocryst, we look at the evidence and we make.

And then, sorry, I may have missed it, but did you break down sales like U.S., Japan, rest of world, or could you do that?

So what we think is that there are multiple things that can also occur in patients with these diseases that can cause rise in serum creatinine.

We have not broken that out yet, Liisa.

Let me start, and then you and Bill can jump in.

We want to make sure that we are assessing any rise in serum creatinine in the context of what's happening with the patient, and if it is likely to be related to the drug or something else.

Yeah, and the reason we haven't is, you know, the majority of it is U.S., so the other stuff, isn't significant enough to report on. But it is growing.

So, I think the important thing is a small number of patients, like we saw in the early, start of the enrollment of the REDEEM study, is going to give us a sense of the first pattern, which was that acute rise.

So we're assessing these.

I mean, I said that in the remarks that it's nice to see you're growing, and that's not surprising because now we've got pricing, now we've got promotion, now, you know, patients are getting on therapy.

And those same patients we're going to continue to track over time, and we'll get a sense, of what happens over time with that same small group of patients.

We will review them together with our DMC.

So over time, you know, we will break it out, but at this point, it's vast, vast majority is U.S.

We have a stopping rule in the studies that is if we see three events that are serious events, and that are considered to be related to the drug, that's the point at which we would stop the study.

Okay, and then one quick question.

Okay.

So, I think we get the benefit from both patterns with this early group of patients. And I can answer another point on the early rise and the slow trend.

We think this is a threshold effect. We think it's a threshold of the drug concentration in the urine. That could explain both the early rise findings and the slow later findings.

We expect to be able to answer each of those questions in the first small group of patients, who were enrolled.

That's helpful.

Our decisions based on what we see and I think as a result of that we're starting to create greater value and have more success in <unk> as the case study for that so.

And then maybe a couple follow-ups.

I've been getting questions from clients, you know, lately about the types of patients who stay on Orladeo for longer than six months, and is there any relationship between sort of severity of disease and response?

Helen, you discussed a few different procedural steps to get new patients in.

So if you could just kind of talk about the kind of patients who tend to be more sticky, and then, you know, a related question on severity and response to Orladeo.

Wondering when do you think you could start dosing new patients in Redeem and Renew?

Thanks.

And then also when you're thinking about this early evaluation, what is the bar that's acceptable?

Do you have to see complete absence of serum creatinine or is there any discussion with, FDA about what can you see that's tolerable and what isn't tolerable here?

And so maybe on that second one, the stopping rule and on the first one's pretty straightforward.

Okay.

Yeah, the type of patient that tends to be the most sticky are, again, those patients who, were well-controlled on another drug and then switched over to Orladeo and remain well-controlled.

And so, you know, the fact that they were on prophylaxis prior suggested they, you know, they needed their attacks controlled, and then they maintained that same rate on Orladeo.

If youre not familiar with our thinking.

Yeah, this idea of, you know, attack severity or frequency of attack, you know, people control, their disease now, so that's like a, that's an old way of looking at it.

Now, the way you should look at it is, where are we getting the business?

Courage, you to get to know, it's better and we can share with you.

We're getting it from people that are controlled on their injectable therapy but don't want the burden of therapy, the injectable therapy.

Those are the people we're getting, and that'll continue to grow, and we'll get more and more share of that.

And listen it's not the only part that's important to success people. Good science is also but the decision making on this stuff and the objective is critical.

And we think it affects value tremendously. So thanks for your interest in our company and have a great day.

Yeah.

All right.

So we have some work to do initially, which is to get the protocols up and running.

Thanks.

We have to submit to countries and sites.

That will take a few months.

Thank you ladies and gentlemen, this concludes our conference. Thank you for participating you may now disconnect.

And then we will be enrolling from there.

We expect that within the first few months of experience with the first patients, we'll, have the opportunity to see data. So this is an incremental approach.

So it's get to the readiness for startup, then get to enrollment, then get to the data.

And in terms of what we're looking for then, we think that this is a threshold effect, as I said.

The goal is to avoid that.

And so what we're looking for is for patients to be dosed at the 400 milligram dose level, and for us to be seeing in those new patients that we're not observing these findings.

Yeah.

If we have serum creatinine, major increases in serum creatinine, then we don't have a, drug that's safe and effective, right?

So it's pretty straightforward.

And on the first point, we're going to go as fast as we can, right?

It's hard to predict how quickly that will happen, but we're going to go as fast as we, can.

I'll jump back in the queue.

Thanks for taking the questions.

Yeah.

Yep.

We have our next question from Chris Raymond with Piper Sandler.

Yeah, thanks.

Two questions.

I guess first on 9930, maybe could you provide a little bit more color on the sort of hydration, protocol, I guess you're describing.

I'm just trying to understand, you know, what specifically you submitted to FDA in terms, of, you know, what patients need to do.

Is it more of the hydration or the lower dose, I guess, that you're hypothesizing can alleviate, this issue?

And maybe just give us a sense of, you know, how this sort of translates into the real, world.

Yes.

You know, if in fact you keep going with this, with this hydration protocol and it's approved, and, you know, then there's this requirement for patients to hydrate.

And then the second question on Orladeo, you know, we've done some KOL checks.

I'm kind of curious what you guys are seeing in the larger market.

The feedback we've gotten is that overall prophy share is relatively growing steadily, but share of new patients is really where the, you know, the bolus of use is, like 80% or more of new patients, at least from one of our KOLs.

So I guess I'm just kind of curious, what are you seeing in the broader market?

And if you're seeing a similar sort of proportion there, what kind of lag do you anticipate, you know, before this really starts to accelerate total share?

Thanks.

So you want to take the first one on hydration?

Yep.

So with 9930, the hydration protocol is actually really simple. It's simply to encourage hydration while on the drugs. That could be as simple as taking the drug with a glass of water.

We've not prescribed specifically what it should be, but it's encouraging hydration.

The reasoning behind that is that we're taking a two-pronged approach, to be able to get the urine concentration below the threshold for formation of any crystals. And that's both with the dose reduced within the effective dosing range, and the addition of hydration in order to get to that sustained level below the threshold for crystal formation.

In terms of where this would go in the sort of next, if you use this in the real world, it's really quite simple.

This is as simple as take your medicine with a glass of water.

And so we think that this is very achievable.

Great.

Charlie, you want to take the Orladeo?

Hey, Chris.

Thanks for the question.

So first of all, overall, 50%, about 50% of the patients that are on Orladeo today, have switched from another prophylaxis product.

And that's really in proportion to what we think is the market share.

So about half of those switchers, prophy switchers, are coming from Taxiro, then Haygarda, and so on.

As, you know, I talked about the prescriber base.

We've got a really big prescriber base.

And so I think we're still early in this process of getting all the different KOLs to fully understand this.

And I think in the future they will switch more patients.

But across the overall market, there's been a lot of switching.

And as more and more doctors get familiar with our data, and see the real-world efficacy that those prophy switchers are having, I expect that the trend will continue.

Thank you.

You're welcome.

We have our next question from Jessica Fye with JPMorgan.

Hey, guys.