BioCryst Pharmaceuticals Inc (BCRX) 2019 Q3 法說會逐字稿

Ladies and gentlemen, thank you for standing by and welcome to the BioCryst third quarter corporate update.

(Operator Instructions) Please be advised that today's conference is being recorded.

(Operator Instructions)

I would now like to hand the conference over to your speaker today, Mr. John Bluth at BioCryst.

Please go ahead, sir.

Thanks very much, Skyler.

Good morning, and welcome to our call.

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

Participating with me today are CEO, Jon Stonehouse; Chief Medical Officer, Dr. Bill Sheridan; CFO, Tom Staab; Chief Business Officer, Megan Sniecinski; and Charlie Gayer and Jinky Rosselli from our commercial leadership team.

Following our remarks, we'll answer your questions.

Before we begin, I want to direct your attention to Slide 2, which discusses our use of forward-looking statements and potential risk factors regarding an investment in BioCryst.

As detailed on the slide, today's conference call will contain forward-looking statements, including those statements regarding future results, unaudited and forward-looking financial information as well as the company's future performance and/or achievements.

These statements are subject to known and unknown risks and uncertainties, which may cause our actual results, performance or achievements to be materially different from any future results or performance expressed or implied in this presentation.

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

For additional information, including a detailed discussion of our risk factors, please refer to the company's documents filed with the Securities and Exchange Commission, which can be accessed on our website.

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

Thank you, John, and thank you all for joining us this morning.

We have important new information to share with you today: clinical results from the 48-week APeX-S and APeX-2 trials and extensive patient, physician and payer market research.

The new clinical results support the meaningful benefit patients are getting from 7353, and the market research supports a very strong willingness from patients to use it.

We remain on track to submit our NDA this quarter, our JNDA and MAA in the first quarter of 2020 and to launch next year in the United States.

I will also provide a financial update, and we will be happy to take any financial questions in Q&A.

You can find our third quarter financial details in today's earnings press release.

As I mentioned, we have a lot of new information to share with you today that's updated our view of the 7353 market opportunity.

Bill will review the clinical results in more detail, and the data are clear.

Over a full year of taking therapy, patients are doing very well on our one capsule once a day oral treatment and having very few breakthrough attacks.

We are also sharing with you today the comprehensive market research we conducted with the profile from the 24-week readout of ApeX-2.

Our team used industry standard data and methods and has quantified a larger HAE population in the U.S. than previously estimated.

We also conducted research to understand the current and future view of the treatment landscape.

Fundamental to any research is having a robust sample to ground our insights.

This can be challenging in rare diseases.

However, we were able to gather a very large sample of patients and physicians, which adds to our confidence in the market understanding.

Charlie will review the results in detail.

But in summary, while patients are satisfied with their current therapy, they want more.

No matter what their current therapy is, many are very willing to use 7353.

The physician data is very consistent with the patient data and supports their expectation to prescribe.

Lastly, the payer research supports a willingness of payers to reimburse.

All this together adds up to significant value from 7353.

With that intro, I'd like to turn the call over to Bill to go over the new clinical data.

Thanks very much, Jon.

We have gained important new insights into the safety and efficacy of 7353.

The analysis through 48 weeks of treatment describe a drug that continues to be safe and well tolerated in clinical trials, and delivers rapid and sustained prevention of HAE attacks over time with a low rate of discontinuations.

First, let me walk you through the key design elements of each trial and describe how patients progress to 48 weeks.

As noted on Slide 3, in the ApeX-2 trial, we randomized 121 patients with HAE to 1 or 2 doses of 7353 or placebo.

As we reported in May, all 108 patients who completed part 1 continued into part 2 of the trial.

Placebo patients were then randomized to 1 of the 2 7353 doses.

And patients who had received 110 milligrams or 150 milligrams in part 1 continued on the same dose in part 2. We are pleased to see that 30 or 40 or 75% of the patients randomized to 150 milligrams at the start of the study have completed 48 weeks of treatment.

The open-label APeX-S trial shown on Slide 4 enrolled 227 patients, 100 on the 110-milligram dose and 127 on the 150-milligram dose.

For this trial, HAE patients were eligible if their physician's assessment was that they could benefit from oral prophylactic treatment.

The NDA analysis, 23 subjects on the 150-milligram dose had not yet reached 48 weeks and 73 had completed 48 weeks of dosing.

The estimate for attention through 48 weeks at the 150-milligram dose is 73%.

Now let's turn to the efficacy results through 48 weeks.

The attack rates for the ApeX-2 completers populations are displayed on Slide 5. Patients treated with 150 milligrams had a baseline attack rate of 2.9 per month, which declined immediately to 1.4 in month 1 and to 1.0 by month 12.

Clearly, patients are continuing to respond to 7353 through the entire 12 months.

In addition, placebo patients who were randomized to 7353 after 24 weeks showed a strong treatment effect with attack rates dropping to approximately 0.5 per month at month 12 for the 150-milligram dose.

These crossover results in part 2 strongly support the primary analysis results from part 1. Overall, these 48-week ApeX-2 efficacy results show us that patients' attack rates were reduced to 1 attack per month or less from a baseline of approximately 3 per month with sustained efficacy through the entire 12 months.

This is an outstanding clinical outcome for a once-daily oral medicine.

Patients are experiencing significant benefits from our drug.

The APeX-S trial tells the same story.

In a completers analysis for the 150-milligram patients shown on Slide 6, the pattern of mean attack rates in APeX-S is strikingly similar to APeX-2.

When we showed our results to leading HAE experts, they also asked about median attack rates, and these are shown on Slide 7 for both studies.

In 6 of the 12 months in APeX-S, more than half of the patients had 0 attacks, including in month 12.

To provide a full picture of safety, all data from both studies was included in an integrated safety analysis summarized on Slide 8. In total, 342 HAE patients received daily oral dosing with 7353, representing 232 patient years of exposure and up to 77 weeks of follow-up.

There were no new safety findings.

BCX7353 was safe and generally well tolerated.

Drug-related serious adverse events were uncommon and occurred in 3 patients or 0.9% and resolved after stopping or interrupting 7353 with no sequelae.

We were interested in the pattern of gastrointestinal adverse events, and these are also tabulated on the same slide.

The overall rate of GI AEs was fairly similar for 7353 and placebo patients.

Nausea was more common with placebo, and diarrhea and abdominal pain were more common with 7353.

The incidence of other types of GI events was fairly similar.

Generally, these events were mild and brief, did not need medication and led to discontinuation of 7353 in only 3% of patients.

Most GI events occurred early in treatment with rapid decline in incidents after the first month.

In previous trials, we noted transient with the enzyme elevations without sequelae in several HAE patients, all of whom had prior treatment with androgens, which are well known to affect the liver.

So we analyzed that in detail in APeX-S.

As noted on Slide 4, 2/3 of the 227 subjects in this trial had passed prophylactic treatment with androgens, and current androgen patients could remain on the androgen treatment up to 7 days before starting our drug.

The analysis is shown on Slide 9. And overall, 15 subjects or 6.7% had a lab result of ALT greater than 3x the upper limit of normal.

These labs were not associated with symptoms and resolved whether or not 7353 dosing was stopped, interrupted or continued.

The interesting finding is that there is a very clear-cut association of high ALT with recent androgen use.

All but 2 subjects with increased ALT had stopped androgen 7 to 9 days prior to study.

Summing across both those groups, ALT levels more than 3x the upper limit of normal was seen in 14 of 49 patients who had discontinued androgens within 1 month prior to study entry compared to only 1 of 104 patients who discontinued androgens more than 1 month prior to study entry and 0 of 74 patients who had never used androgens.

Even though the findings were limited to temporary and asymptomatic elevations in lab test results, in order for patients to have the best experience studying our drug, we will advise a 1-month washout period for current androgen patients before beginning 7353.

This advice will be more relevant outside the United States as androgen treatment in the U.S. is much less common than in other countries.

Indeed, in the rigorous U.S. market research that Charlie will describe, only 3 of 100 patients were currently taking androgens.

So with this compelling body of evidence, we have the profile of a safe and generally well-tolerated drug that is demonstrating a significant benefit for patients.

As I noted earlier, we crossed our NDA threshold of at least 100 patients on 150 milligrams daily through 48 weeks.

We're now in the final stages of compiling the NDA and on track to submit it to the FDA this quarter.

With these results in hand and an NDA on the way, we are moving very close to delivering a major advance in HAE therapy for patients, and that is very exciting.

Now I'd like to turn the call over to Charlie to share our new market research evidence with you.

Thanks, Bill.

We have completed a significant amount of in-depth quantitative and qualitative market research to understand the opportunity for BCX7353 since receiving the APeX-2 24-week results in May.

The message is resoundingly clear.

HAE patients want to use 7353, physicians will prescribe it, and payers are willing to reimburse.

I will review the key findings of the market research, but I'll start by describing on Slide 12 an HAE prevalence study that we recently completed.

Confirming the size of the addressable HAE population in the United States was a critical first step in our market assessment.

Historical prevalence estimates relied on epidemiological studies conducted outside the U.S. Our comprehensive study used U.S. administrative claims data from Symphony Health Solutions and applied a proprietary methodology to identify unique HAE patients with recurring medical claims for specific diagnosis codes, laboratory tests and HAE specific medications.

We then extrapolated from the database population to the total U.S. population, normalizing for demographic factors.

The study informs a U.S. prevalence of approximately 10,000 HAE patients with 7,500 being diagnosed and treated with HAE-specific medications.

Slide 13 describes the quantitative market studies that we conducted to evaluate current market dynamics as well as patient and physician reactions to the 24-week data from APeX-2.

These studies provided us with primary evidence from a very large base of 100 HAE patients and 175 physicians who treat HAE.

The 175 physicians treating -- reported treating an average of 7.6 HAE patients per year, which means we have perspectives from doctors who manage over 1,300 HAE patients or more than 10% of all HAE patients in the U.S.

Slide 14 shows the blinded profile of 7353 that was shared with HAE patients and treating physicians in the study.

We asked those 100 patients about their willingness to use 7353 on an 11-point Likert scale.

Slide 15 shows that 59% of patients are very willing to use 7353 as measured by top 3 box scores, which is a strong predictor of future behavior.

Furthermore, 71% are very willing to use the product if their physician recommends it.

Slide 16 shows that 79 of the 100 patients in our survey reported using injectable or infused HAE prophylaxis therapies, 63% of CINRYZE, 60% of HAEGARDA and 47% of TAKHZYRO patients reported they are very willing to use BCX7353.

We analyzed responses even further by looking at those patients who reported being very satisfied with their current injectable or infused therapy, again, measured as top 3 box scores on an 11-point scale.

You can see in the light green columns that half of the patients who reported being very satisfied with their current injectable therapies are also very willing to use 7353.

Turning to Slide 17.

You can see that no drug is perfect, and patients continued to have breakthrough attacks on injectable and infused prophylaxis therapies.

The mean number of attacks reported over the past 3 months among CINRYZE patients was 1.6 attacks; HAEGARDA, 0.9 attacks; and TAKHZYRO, 1.8 attacks.

During our qualitative research, we heard repeatedly that patients are grateful for the advances in injectable and infused therapies over the past decade.

But as our quantitative data and qualitative insights highlight, patients also are tired of coping with the burdens these therapies add to their lives, such as storing and transporting products that require refrigeration, planning and preparing injections and the discomfort of repeated needle sticks.

The ease of an effective oral prophylaxis therapy will help make HAE a smaller part of their lives.

And as the data show, patients are very eager to use 7353.

This strong demand correlates directly with the outstanding clinical experience that HAE patients are having in APeX-2 and APeX-S that Bill shared with you earlier.

The data on Slide 19 show that HAE-treating physicians are aligned with patients.

Each of the 175 physicians in our study reported the distribution of treatments used within their current patient base.

Today, they report using indicated prophylaxis therapies on 58% of their patients.

After showing them the blinded product profile, we asked the physicians to reallocate treatments for their current patients in a future state where 7353 is available.

The data show physicians expect to treat over 40% of their patients with 7353.

They anticipate switching current prophylaxis patients to 7353 as well as increasing their overall use of prophylactic therapy to 80% of their patients.

Payer reactions to a blinded profile of BCX7353 also aligned with our data on patient demand and physician-prescribing intent.

We conducted interviews with pharmacy and medical directors from U.S. payers and PBMs that cover over 100 million lives.

They understood the value of an oral prophylactic therapy for HAE and expressed a broad willingness to pay for 7353 if it is priced in line with the market basket of current injectable and infused prophylactic treatment options.

Looking ahead, we are using our detailed understanding of the U.S. HAE market to build out the critical marketing, sales and marketing -- market access initiatives that will lead to a successful launch.

We recently deployed a competitively sized MSL team that is now meeting with the top-tier of HAE treaters.

Over the past months, we hired the General Manager of our U.S. commercial team as well as a head of U.S. sales, both of whom have outstanding records of success in several ultra-rare diseases, including HAE.

We also have made substantial progress in developing a patient services and hub strategy for BCX7353 that we believe will be best-in-class.

And now, I'd like to turn the call back over to Jon.

Thank you, Charlie.

With the additional clinical data Bill presented, an evidence-based understanding of the size of the U.S. HAE population and robust market research to understand the current and future treatment preferences from patients and physicians, we see once-a-day oral 7353 generating at least $500 million in peak global sales.

We are fully investing in the launch of 7353 to make it accessible to patients soon after approval.

To ensure we have the resources for a successful launch, I've mentioned previously our goal to add approximately an additional $100 million to the balance sheet by year-end.

We are evaluating and pursuing a number of different sources for this capital.

We have the option to access an additional $30 million from the current debt agreement with Midcap.

We are also exploring royalty financing opportunities, and we expect equity will play a role.

Yesterday, we announced a Japanese licensing deal with Torii with a $22 million upfront payment, which is a component of the $100 million we plan to add this year.

Now I'd like to turn the call over to Megan to say a few words about why we're so excited about Torii as a partner and the opportunity in Japan.

Thanks, Jon.

Our partnership with Torii represents a tremendous step forward for HAE patients in Japan given the high unmet need and lack of prophy treatments approved in the market today.

After running a competitive process, we selected Torii for several reasons.

First, BCX7353 fits with their growth strategy to in-license products that complement their existing franchises.

They have a proven track record of successfully launching HIV products in license from an established U.S. biotech.

They grew that business in Japan by investing in KOL engagement, increasing disease awareness and patient education and successfully partnering with patient groups.

This experience, combined with their broad reach of their 300 medical representatives, positions Torii well to bring the first oral once-daily prophy treatment to HAE patients in Japan.

As Jon mentioned, there's a $22 million upfront payment.

And in addition, there's a future approval milestone of up to $20 million, depending on timing of the PMDA approval and outcome of our pricing negotiation.

We will also receive tiered royalty payments ranging from the mid-teens to potentially 40% depending on the level of net sales and our Sakigaki status.

We remain on track to submit our Japanese NDA next quarter with the potential for PMDA approval in the second half of next year.

With an experienced, highly motivated partner and lack of treatment options today in Japan, we see our partnership with Torii as an exciting combination to support a successful launch of 7353 and to accelerate HAE's patient access to this important treatment in Japan.

With that, let me now turn it back to Jon.

Thanks, Megan.

Let me wrap up with this.

We have powerful and consistent long-term clinical data from both APeX-2 and APeX-S.

Patients on 7353 are having significant and sustained reductions in their HAE attacks.

They see this effect quickly and is sustained through 48 weeks.

Patients who start on therapy stay on therapy as evidenced by the 75% of patients completing 48 weeks of treatment despite the availability of other options.

We've also done a tremendous amount of work and gathered important data to more accurately understand the market and the value of 7353.

We have utilized a robust methodology to size the U.S. HAE patient population.

We have also gathered critical insights into current and future treatment choices through our comprehensive market research.

Both patient and physician data tell us the same thing.

Patients are very willing to use, and physicians are expecting to prescribe 7353 regardless of current treatments even when they're very satisfied with injectable therapy.

Why?

Because we have a one capsule once-a-day oral therapy, and patients want more than their current injectables.

They want a life where they're not reminded of their disease every time they stick themselves with a needle or look in their refrigerator and see their medicine.

They want more.

And we believe, for many, 7353 is what they've been waiting for.

With this information in hand, we see significant value with 7353.

We see potential peak global sales exceeding $500 million.

So now, it's all about executing our plan: regulatory submissions by year-end, and in the first quarter of next year, continuing the preparation for a successful launch, starting in the U.S. next year and accessing capital through the different options we now have available to properly resource this plan.

These are very exciting times for us at BioCryst, and we look forward to sharing more of our progress with you as we continue to execute our plan.

With that, operator, we'll open it up for questions.

(Operator Instructions) Our first question comes from Jessica Fye with JPMorgan.

A couple about the data updates this morning.

First, can you elaborate?

On the patients who discontinued these studies, I think, like, Slide 4, who didn't discontinue for adverse events, what were they discontinuing for?

Jessica.

Bill.

Thanks for the question.

There are a whole variety of reasons for discontinuation.

And including other intercurrent illnesses, for example, people choosing to have some other type of treatment.

So the overall discontinuation rate due to adverse events, as I mentioned on the call, was very large.

Okay.

And on the discontinuations that were for adverse events, I think there are a few that are kind of captured under a bucket of Other.

Can you talk about what some of the other reasons were?

Depression, for example, in one case.

None of the discontinuations formed a pattern of adverse events that rose to having more than one instance.

So [there wasn't] a pattern there.

Okay.

And then with respect to the 4-week washout for androgens, the deal looks pretty clear.

But what's the basis for picking 4 weeks versus some other timeframe?

And do you see any possibility that the FDA would want you to study something like that prospectively?

The answer to the last question is no.

I think that the data is crystal clear.

Four weeks seems like a reasonable length of time based on the information because we had all but 1 patient out of the 15 in that timeframe stop the androgens.

And I think that it's a very interesting finding when people stop androgens.

Typically, nobody's going to measure it with a function test.

So this is the first time it's been detected actually.

And when you look in other product labels, in the randomized placebo-controlled trial environment, the rate of ALT above 3x the upper limit of normal is about 5% or so.

In our randomized placebo-controlled trial, it was 1 out of 81.

And of course, in that study, all the patients coming in had a washout that was quite a bit longer than 28 days actually.

And Bill, when you're referring to other drugs, you mean other drugs in HAE.

Correct.

Yes.

So that's part of the landscape of treatment of HAE to have been on androgens in the past.

And some of the patients coming into our studies were still taking them and decided to stop.

So I think we've now identified how to manage it basically, and it's quite easy.

You just take the androgens and wait a little bit and then start our drug.

Okay.

Got it.

And I have a couple on the financial side maybe for Jon.

You mentioned the potential royalty monetization as a means to bring in cash.

Any chance you could sort of outline in broad strokes what something like that would look like or what your priorities would be on the terms of a transaction like that?

And kind of related to that, I think you extended the deadline on the additional tranche from Midcap to I think it's the end of this month.

Should we think about the plans to bring more cash into the company is materializing within that timeframe?

Yes.

So I'm not going to go into the details of any potential financing until we get it done.

So sorry, I can't give you any more detail on the royalty.

I think the Midcap option was an important one for us to have as a part of that renegotiation with Midcap.

And we have -- I think the main point is we have flexibility, and we have different options to choose from to get to the $100 million.

Our next question comes from Liisa Bayko with JMP Securities.

I was curious, the data is really interesting and a lot to nibble on and dig into.

But just comes to mind the question that did you see any differences in response rates with people who are on androgens previously versus P1 inhibitors?

Liisa, we analyzed patient baseline demographic and disease factors as covariance in the APeX-2 randomized controlled trial analysis that we reported in May, and none of those things were really significant in the final model.

So androgens is one of the things we looked at.

Our next question comes from Maury Raycroft with Jefferies.

Congrats on the updated data and the progress.

I was wondering for the 30 -- 150 mg patients that had the 2.9 attacks per month at baseline and then decreased to 1 attack per month at month 12, are the residual attacks these patients having less severe?

And do you have a sense that these patients would stay on therapy for the longer term?

So -- yes, I think that's a great question.

From the data, all we can analyze is which box did they check on their daily report form if they have an attack.

So that doesn't really tell the full story.

I mean when we talk with the physician investigators at the sites who still have patients on study, uniformly, they're telling us that the patients have said things like this drug has changed my life, transformed my life and I can manage my attack that the -- the breakthrough attacks that do occur, I can manage more easily.

I think that, that story, like with other drugs, will be interesting to follow over time because the longer people stay on their prophylactic treatment, the less fear there is and less stress.

And all of that helps manage the disease.

Yes.

I was -- Maury, I was with one of our big KOLs last week and they were talking about a couple of patients that they have on study.

And they said they have the occasional breakthrough attack, but the severity, in some cases, they're not even treating some of these attacks.

So -- and that's where Bill got the quote of "These are life-changing." So we don't have the hard data from our study because there's only certain things that the patients check.

But from the feedback we're getting, it's real manageable.

Got it.

That's helpful.

And then for discontinuations, just wondering if you're seeing discontinuations align with your responder analysis?

And can you use some of the info and data from that to feed into your switching strategy for 7353?

That's an interesting question.

I think the main thing that I'm getting out of all of this data is that people are benefiting.

And because they're benefiting, they're staying on the drug.

The feedback that we've had from our medical advisory boards that we've done across the United States in the last few months after we got the 24-week data is that, here, you've got an oral drug.

Side effects don't appear to be an issue, the efficacy looks good.

It's oral and why not use it.

And we know how to put people on drugs, and the physicians tell us that they know how to put people on new drugs.

They know how to manage switching people from one drug to another.

Make sure you get the hub right and cover the insurance.

Yes.

That's the feedback.

Yes.

And with regard to the switching strategy, and Jinky and Charlie, you guys can jump in, but I'll take a first shot at it.

What the data tell us in a really large sample size, right, Charlie?

I don't know if you caught it, but he said, these 175 physicians cover 1,300 HAE patients in the U.S. That's over 10% of the HAE patient population.

What the data are telling us is that patients are very willing to use our drug, right?

And it doesn't matter where they come from.

If they're on injectable therapy and you saw the different breakdown of the different drugs and patients being very satisfied, and they're still very willing to try our drug.

So the data says patients are very willing to use our therapy.

So the other piece of information we're sharing with you today is when patients go on therapy, they stay on therapy, right?

And that's evidenced by the 75% of patients staying on therapy for 48 weeks.

And you can see from the attack rate reductions that they're doing really well, and that's why they're staying on therapy.

So the combination of the 2, I believe, is very strong for getting people on and keeping people on.

And that's our switching strategy.

I don't know if you guys have anything to add.

They're shaking their head no.

Okay.

And last question is just if you guys can outline a few different pricing scenarios or strategies that could play out.

And based on your payer data, where were the payers focused on for strengths and weakness points?

Yes.

I'll start, and then Charlie can jump in.

So for competitive reasons, obviously, we're not going to get into the detail of pricing.

I think some new information that we got through this data, both the market research with payers and the market research with physicians and patients, is this idea of a steep discount isn't necessary with the fantastic profile that we have with this oral once-a-day therapy.

And Charlie, I don't know if you want to add any more color to the payer research.

Yes.

I think, Maury, the other thing that I would add around the payer research is the first thing we did with the payers is show them the blinded profile of 7353 and before even getting into pricing scenarios.

We just asked them what they found to be acceptable, and they said the price range that they find to be acceptable is the range of prices of current injectable and infused prophylaxis therapies.

So they understand the value of an oral prophylactic therapy.

They think that this is going to be a very useful product for patients, and they would be willing to reimburse for it.

And kind of where we cross the tipping point, and tell me, Charlie, if I got this right, is if we had charged a premium...

That's right.

They're not going to pay extra for the convenience, but they understand why it's important for patients.

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

A couple of questions for me.

First, can you remind us if you'll be seeking FDA approval of both of the 7353 doses in the upcoming NDA filing?

And then how do you expect the association of androgen discontinuation and elevations in ALT to be reflected in the label?

You think it could be a black box warning or just kind of a dosing recommendation?

Serge, thanks for your question.

So on the last question, absolutely not.

We don't expect that at all.

We will propose to advise what I said on the call, which is cease androgen use at least 28 days prior to starting our drug.

Let me add one more point to that, Bill.

I think the other piece is we don't think this is a phenomenon distinct to our drug, right?

We think it's androgens.

And you can see from the elevations in liver enzyme rates that other drugs in the space have similar percentages.

So this is not -- we don't believe this is unique to 7353.

We think it's androgens.

Right.

It's a phenomenon of HAE patients and their exposure to androgens.

Like I mentioned earlier, in another randomized controlled trial with another prophylactic drug in this space, it was 3 out of 84.

And in our randomized controlled trial, it was 1 out of 81.

And we've now had the opportunity to identify that it's all about how recently you've taken the androgens.

And if you look at -- if you bothered to do the statistics on the contingency table from that slide, you will find that the chance that this is a random effect is less than 1 in 10,000.

So it's a very compelling evidence.

With regard to the doses, the better efficacy at the 150-milligram dose and the lack of any evidence whatsoever of dose relationship with any of the adverse effects tells us that we should market the 150-milligram dose, and that's what we're proposing to do.

So that's what we'll be submitting.

We submit all of the data, of course, but the proposed label is 150 milligrams once a day.

Okay.

And then for the acute HAE program, you mentioned in one of the upcoming key milestones to [comment] the ZENITH-2 trial.

Can you just tell us what additional work needs to be done on this acute oral formulation before you undertake that Phase III program?

So one of the really interesting findings from the market research is just how we really understand the current and future breakdown of acute and prophylaxis.

A lot of numbers have been thrown around, people saying things are going to move to acute.

That's not what our data tell.

And we had -- like I said, we have a very robust sample size.

You heard Charlie say that physicians see the future, 80% prophylaxis.

So it's a tiny segment.

And then when you look at the current therapies that patients are on when we ask patients, there was a very small percentage of people currently on managing their disease through acute treatment.

So we think this is a great data set, robust data set that supports that.

Everything's going to prophylaxis and probably faster than everybody thinks.

So with regard to the acute program, it's obviously secondary to getting our prophylaxis program across the finish line.

We're still working through things we need to work out with regard to the formulation, and we're still in the process of talking with the regulators on the path forward for the Phase III.

As soon as we get through that and work through that, we'll let you know.

Our next question comes from Brian Abrahams with RBC Capital Markets.

Thanks for all the helpful detail for both the clinical and market research data sides.

A couple of questions on efficacy and then one on safety.

Just first on efficacy, it looks like the attack rate per month declines a lot more substantially in the patients going from placebo to 150 mgs for the second 6 months of APeX-2 versus in those first 6 months in the placebo-controlled portion.

So I'm wondering if you have any potential explanations for this.

Is this just potentially a product of selecting for the completers?

Is it just the lack of a placebo arm?

Are these patients any different?

Are there any differences that would potentially make these patients more responsive?

And then I have a couple of follow-ups.

Okay.

Brian, yes, good question.

I think that what I see here is consistency with what we reported in May.

So in May, we reported that the 150-milligram dose was better than the 110-milligram dose.

Both had statistically significant improvements compared to placebo.

Now we're switching the placebo to 110 milligrams or 150 milligrams, and we're seeing that 150 milligrams is better than 110 milligrams.

So it's consistent.

I think that this is exactly what we expected to see based on the randomized control trial 24-week analysis.

And in our view, this is further evidence supporting selection of the 150-milligram dose per market.

Yes.

Brian, I think the data is really striking.

And what's important is you see there's a big placebo effect, number one.

And so these patients aren't starting out at 3 attacks per month at month 6 on placebo.

They're more at -- if you eyeball it, it's around 2, and they go down to a half an attack.

So it may be from where they're starting.

But it's very striking, the benefit that we see here.

Got it.

That makes sense.

So it could be just a product of starting at a different point.

And then I guess on the -- also on APeX-2, can you guys talk about the attack rate reduction data through 48 weeks for patients who are on 48 weeks of 150 milligrams and also for those rolling over from placebo to 150 on an intent-to-treat basis versus a completers analysis?

Of course, we have those analysis.

I think the intent-to-treat analysis show a more dramatic decline over time.

And with longer studies, you have to be careful about interpreting how the dropouts affect the month by month by month data.

That's why we've shown the completers analysis because we've got a bunch of people, and we've got data for every person for every month.

But the ITT analysis show a decline over time and attack rate.

Got it.

That's very helpful.

And then maybe one last question on the safety side.

For patients who were on androgens recently, when in the course of 7353 dosing did the ALT spike tend to occur?

Was that early on?

Or was it -- did it tend to be later?

And then I realize that based on your market research, the rates of patients who are actually -- would be coming in on androgens are pretty low.

But for those who are, how would you plan to bridge those patients through the 28-day washout period?

Would you recommend some sort of alternative prophylaxis or just on-demand treatment?

Sure.

So really, really interesting questions.

So in 2 of the 15 who had ALT more than 3x the upper limit of normal, actually, it was more than 3x the upper limit of normal at baseline before our drug was even started.

And in almost every case, the abnormality was detected at the very first study visit at week 2 or at the next one at week 4. So it's temporally associated extremely strongly with recent discontinuation of androgens.

And when we set up APeX-S in the United States in -- earlier this year and started opening sites, our initial protocol there had prospectively looking at people stopping androgens and waiting a month before starting 7353.

We haven't presented that data today because that part of the study is not mature.

But in the first few subjects who we've enrolled, we've had at least a couple who we have seen prospectively elevation in androgens within a week or 2 of, I beg your pardon, elevation in ALT within a week or 2 of stopping androgens in the absence of any other drug getting started.

It's a very clear story.

And you can ask, well, what's going on here?

Androgens are anabolic steroids.

They grow things, right?

So things like liver cells are going to get [topped].

And in simple language, you're going to get hypertrophy.

And when you stop anabolic steroids, what happens?

You get catabolism.

So none of this should be a surprise in reality.

It's just that people have never looked at it before because why would you?

Our next question comes from Gena Wang with Barclays.

The first question, just wondering if you can remind us, the 150 milligram, how many pills are these?

How many capsules?

One capsule once a day.

Okay, good.

And then for the androgen users, I think, that you also just mentioned, wondering the underlying mechanisms, how much we know that causing why our treatment will use -- the use of androgen will lead to the liver enzyme elevation?

Sure.

And I didn't quite finish answering the other question, but I'll try to do them both.

So the first thing to point out, for those of you who are not familiar with the whole story about anabolic steroids and androgens, androgens are extremely well-known liver toxins.

And over the course of use, even at therapeutic doses let alone the doses abused in body building or what have you, they're liver toxins and you can get chronic hepatitis type features, you can get hepatocellular adenomas, hepatocellular carcinomas have been reported.

And they've also been reported in people with HAE taking androgens.

And there are a whole bunch of other side effects, of course, associated with masculinizing hormones.

So people want to get off them, but liver effects with androgens are extremely well known.

The new observation here is that there's an androgen withdrawal, acute androgen withdrawal effect.

And so that's really great.

I think the most important takeaway message is if you stop androgens more than a month out of the whole data and then wait a month, the likelihood that you will get high ALT is extremely small.

The negative predictive value is actually more than 99%.

So that's the way to solve the problem.

I see.

Okay, great.

And then last question, just regarding the price and based on your comments, should we expect largely in line price versus HAEGARDA or TAKHZYRO?

Yes.

Again, Gena, I'm not going to get into the specific prices.

What we've said in the past that remains true is we have a lot of pricing flexibility.

What's changed is that with this profile, we don't need to do a steep discount in pricing based on the attractive profile.

That's what payers tell us.

Your final question comes from Tyler Van Buren with Piper Jaffray.

Great to see the additional data out to 48 weeks, the durability of response.

And not surprised to see the patients respond nicely after taking placebo.

But I guess my question is kind of related to the line of thinking that Brian had, which is, it's natural that completers would -- you'd see some enrichment for responders.

But as it relates to, I guess, 70% and 90% responders in the survey, you clearly mentioned about half of them have the 70% and about 1/4 have about a 90% response at 24 weeks.

For those who are completing at 48 weeks, can you update the proportion of patients with a 70% or a 90% reduction in HAE attacks?

We certainly could.

I don't have that analysis, but we certainly could do it.

I think that the consistency in attack rate between both studies over time and the consistency in the response to study drug after placebo randomization compared -- after 24 weeks of placebo compared to right at the start, I think, is -- they were the main things we were looking for here.

So we're very happy with the 50% of patients getting more than 70% response from baseline in APeX-2.

And we're very happy with 75% of patients coming into the study completing 48 weeks.

But it's a good idea to look at the responders in both the completers and the ITT population over 48 weeks.

Yes.

And I think the other thing to just draw your eye to are the mean attack rates, right, for 48 weeks for both studies and then the median attack rates for both studies.

You can get it -- I guess, what I'm trying to tell you is you can get a sense that people are doing really well.

Really well.

Yes.

Do you have any idea what proportion of patients had 0 attacks in that second period or...

Well, the analysis that we've done, we've shown on Slide 7. And so that just looks at by month what's the median attack rate.

And you can see that it's pretty similar across the 2 studies.

And in APeX-S, in individual months, we've got 6 of the 12 months, where half of the 73 subjects or more had 0 attacks in that month.

So the notion of attack free is sort of fake.

If you look at the data that Charlie showed and all of the approved prophylactic therapies in every single one of them, there are breakthrough attacks.

So it's just -- if you look for a long enough time, you're going to get breakthrough attacks but that's the nature of the disease.

And at this time, I'd like to turn the call back over to Mr. Stonehouse for any closing remarks.

Well, so thank you again for your interest in joining us today.

As I said in the prepared remarks, these are really exciting times for us at BioCryst.

We see significant value with our once-a-day oral drug with 7353 for preventing attacks in HAE.

The data presented today, the drug works.

There's just no doubt the drug works.

Patients who go on therapy stay on therapy, so our ability to keep patients is going to be high.

And the market research says people want more, right?

They're -- while they're satisfied with what they're seeing with their injectable therapy, the idea of a once-a-day oral drug to prevent their attacks, manage their disease is extremely high.

And so we think that all of that adds up to significant value and peak global sales north of $500 million per year.

So it's all about execution now.

It's about getting the filings in, getting ready for launch.

And you can count on us that we're working very hard to put ourselves in a position where we maximize the value of this fantastic asset.

So thanks again for your interest, and have a great day.

Ladies and gentlemen, this concludes today's conference call.

Thank you for participating.

You may now disconnect.