BioCryst Pharmaceuticals Inc (BCRX) 2014 Q1 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the BioCryst First Quarter 2014 Conference Call. (Operator Instructions) As a reminder, this call is being recorded. I would now like to turn the call over to Rob Bennett. You may begin.

Yes, good morning, and welcome to BioCryst's first quarter 2014 corporate update and financial result conference call. Today's press release and accompanying slides for this call are available on our website, www.biocryst.com. At this time, all participants are in a listen-only mode. Later, we will open up the call for your questions and instructions for queuing up will be provided at that time.

Joining me on the call today are Jon Stonehouse, Chief Executive Officer of BioCryst; Tom Staab, Chief Financial Officer; and Dr. Bill Sheridan, our Chief Medical Officer.

Before we begin, I will read a formal statement as shown on slide 2 regarding risk factors associated with today's call. Today's conference call will contain forward-looking statements, including statements regarding future results, unaudited and forward-looking financial information, and Company performance or achievements. These statements are subject to known and unknown risks and uncertainties which may cause our 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 the forward-looking statements. For additional information, including important risk factors, please refer to BioCryst documents filed with the SEC, which can be found on our Company website. With that, I will turn the call over to Jon.

Thank you, Rob. Good morning, and thanks to everyone for joining us today. In the first quarter, we continue to build on the success we had last year and are laying a solid foundation to build BioCryst into the small molecule rare disease company. First and foremost, we are doing this by advancing our oral kallikrein inhibitors for the prevention HAE attacks. With three unique BioCryst-discovered molecules, we have the potential to bring normalcy to the lives of HAE patients and transform the HAE marketplace.

In addition, we are advancing two different antivirals -- one for flu and another for hemorrhagic fever viruses, both of which we believe will ultimately lead to stockpiling orders that provide nondilutive capital to the Company. This allows BioCryst to retain global rights to our rare disease assets and the associated value for our shareholders.

Finally, we plan to refill our clinical pipeline with novel BioCryst-discovered molecules focused on two validated rare disease targets. We are using the same technology platform, structure-based drug design that gave us the first potent and specific oral kallikrein inhibitors. Now I'll go a bit more into the detail of our most advanced programs, starting with BCX4161 and the OPuS-1 proof of concept trial in HAE patients.

We have closed enrollment in the trial and are on track to report top line results by the end of the second quarter. We are also completing our 13-week animal tox studies to support longer duration of patient dosing in our next trial.

We are continuing to advance our second generation kallikrein inhibitors through preclinical development, and Bill will share some new data that gives us even more confidence we have a good shot at achieving our targeted profile of one pill once a day, wipe out attacks, with at least one of our compounds.

Moving next to peramivir, we previously announced that our NDA was accepted and under review with the FDA with a PDUFA date of December 23. Our drug product contract manufacturer, or CMO, has recently informed us general reinspection by the FDA following the issuance of a warning letter. This reinspection led to the issuance of a Form 483, which contained a number of observations that are not directly related to peramivir but nevertheless must be addressed. At this time it is unclear if these findings impact our NDA or the supply of peramivir drug product. We will work with our CMO and the FDA to ensure that the manufacturer of peramivir drug product meets the requirements for approval.

Last but not least, we announced in early March the efficacy results of BCX4430 in animals infected by Marburg and Ebola virus published in the prestigious scientific journal Nature. The publication represents the first report of protection of nonhuman primates from filovirus disease by a small molecule drug and describes efficacy results generated from an ongoing collaboration between scientists at USAMRID and BioCryst. 4430 has shown unique, broad spectrum potential with meaningful activity against more than 20 RNA viruses in nine different families. This could make 4430 an attractive option for governments to stockpile, as it is one drug for multiple bugs.

We are advancing the preclinical development of 4430 under our contract with NIAID with a goal of starting a clinical trial in healthy volunteers during the first half of 2015. With that, I will turn it over to our CFO, Tom Staab, who will review our financials.

Thank you, Jon, and good morning, everyone. Today I'd like to summarize the key elements of our first quarter 2014 financial results, and to reiterate our 2014 financial guidance. As mentioned in previous quarters, we continue to abide by a single financial principle of focusing our cash resources on advancing our core programs to value-creating milestones and eliminating noncritical spending. The first quarter of 2014 is yet another example of the benefit of this simple but dedicated focus.

I am pleased to report the following -- (1) Our first quarter operating cash utilization of $5 million reflected a 44% decrease from the first quarter of 2013; and (2) consistent $1.6 million level of general and administrative expenses reflected an appropriate run rate in which dedicated a significant majority of our financial resources to research and development.

On slide 6, you see revenue for the first quarter of 2014 was $3.5 million, and is in line with the $3.6 million recorded in the first quarter of 2013.

In the first quarter of 2014, total revenue included $1.8 million of royalties from Shionogi and Green Cross associated with sales of peramivir; $1.3 million of collaborative revenue associated with reimbursement of BCX4430 and peramivir expenses; and the remainder represented by collaborative revenue amortization from corporate partnerships.

At a summary level, royalty and collaborative revenue were essentially the same in 2014 and 2013. However, in 2014, NIAID-based collaborative revenue associated with the development of 4430 replaced a decreased level of collaborative revenue under the BARDA/peramivir contract.

First quarter 2014 R&D expense was $9.2 million, up 27% from $7.2 million in the first quarter of 2013. This increase was associated with greater development activity within our HAE portfolio including our second generation compounds, as well as costs for our broad spectrum antiviral, BCX4430. The overall increase was partially offset by lower development expenses associated with the conclusion of peramivir clinical development and the termination of our BCX5191 development program.

As you evaluate our 2014 R&D expense, 62% of these costs were dedicated to our portfolio of HAE product candidates. This concentration is consistent with our 2014 guidance given in February, whereby, we forecast higher R&D expenses due to increased clinical activity for BCX4161, and more substantial preclinical development on our two second generation molecules.

Moving below the operating line, we incurred $1.2 million of noncash interest expense in the first quarter of 2014 and 2013. We also recorded a mark-to-market hedge loss of $1.5 million in the first quarter of 2014 as compared to a gain of $2 million in 2013. Both interest expense and the hedge mark-to-market adjustments relate to our nonrecourse notes and related hedge acting in conjunction with the RAPIACTA royalty monetization.

Our net loss per share was $0.17 in the first quarter of 2014 compared to a $0.09 loss per share incurred in the first quarter of 2013. The higher net loss resulted from increased R&D expenses and, to a lesser extent, the loss on our foreign currency hedge associated with the yen-US dollar exchange rates.

Moving on to slide 7, I'd like to discuss our cash balance and cash usage. We ended the quarter with cash and investments of $34.2 million. Based upon current plans and expectations, we expect our existing cash to provide us liquidity into the first quarter of 2015. As mentioned earlier, our operating cash usage for the first quarter of 2014 was $5 million and decreased significantly from the $8.9 million utilized in the first quarter of 2013. As a reminder, operating cash use excludes any impact of our royalty monetization, hedge collateral, posted or returned, and any other nonroutine cash flows.

In regards to financial guidance, our operating outlook for 2014 remains unchanged. As such, we continue to forecast operating cash usage to be in the $35 million to $43 million range, and operating expenses to be in the $48 million to $59 million range. Importantly, as we mentioned in February, we have specifically excluded equity-based compensation expense from our operating expense guidance. Thus, any equity-based compensation expense incurred should be added to our operating expense guidance to arrive at total operating expenses for 2014. In the first quarter of 2014, our total equity-based compensation expense was $1.6 million. Now I'd like to turn the call over to Bill for an update regarding our second-generation kallikrein inhibitors. Bill?

Thank you, Tom. As Jon mentioned, we are pursuing a second-generation kallikrein inhibitor program with a goal of once daily oral prophylaxis for HAE. I am pleased to report that both of the second-generation plasma kallikrein inhibitors that we have advanced into full preclinical development are progressing as planned through the nonclinical studies required to file INDs. We have recently completed additional dosing and PK studies from the most advanced of the two compounds and the results are shown on slide 8.

In this display, the y-axis represents the ratio of the plasma drug concentration to the 50% inhibitory concentration of the drug in the contact activation assay for kallikrein activity that we have described on prior calls, and the y-axis is time relative to dosing of drug.

The chart on the left of the slide gives results the last of six daily oral doses in rats receiving 10 milligram per kilogram per day. Day 6 widely represents steady state PK. And throughout the 24-hour period, drug concentration exceeds four times the EC50 generally by a large margin.

The chart on the right of the slide shows the same type of information, the single oral doses in nonhuman primates at 10, 30 or 100 milligrams per kilogram. The exposure was generally dose-proportional and exceeded the target of four times the EC50 by a large margin at all doses. These experiments confirmed the earlier observations of maintenance at adequate drug levels through 24 hours after dosing, and provide further support for testing a therapeutic once daily dosing schedule in the clinical for prophylaxis of HAE attacks.

Thanks, Bill. So, the summary of this call is we continue to make steady progress in advancing our programs. Results from the OPuS-1 trial later this quarter represents our next important milestone. As we have said throughout the course of the year, the main objective of this study is to get a sense of 4161 exposure in HAE patients and associated clinical benefit. The greater the benefit, the more interesting 4161 is for the HAE market. When you look at our entire kallikrein inhibitor program, 4161 and the two second-gen compounds, we are confident in our ability to bring forward a treatment for HAE patients that has the potential to really change their lives. So, this concludes our prepared remarks. We will now open it up for your questions.

(Operator Instructions) Our first question comes from Charles Duncan of Piper Jaffray. Your line is open.

Hi, guys. It's Roy in for Charles. Thanks for taking the question. Looking at the data Bill was just talking about, the second-gen data, how predictive do you think that is for the future human studies, and how does it compare to the prior data from 4161?

I think it is very important data. We know a lot from the work of academic groups about the role of kallikrein, the central role of kallikrein in the pathophysiology of hereditary angioedema. For example, there was a recent paper from Dr. Chicardi's group in Milan that expanded our knowledge about kallikrein inhibitory activity in the blood being low in people with hereditary angioedema. So, I think that there is no doubt that. So, getting adequate coverage of the enzyme is what the PK is all about for the second generation compounds. And at 24 hours, we have so much drug present even after a single dose in the monkeys and at steady state in the rats that we are more than 10 times the 50% inhibitory concentration of the drug. And that's an interesting benchmark. Because if you look at the normal range of C1 inhibitor, for example, and map that to the degree of kallikrein inhibition, you get an assay the low limit of the normal range in normal people who never get an attack of angioedema is about 9 times the 50% inhibitory concentration, a C1 inhibitor in that assay. So, getting into that range of multiples of EC-50 I think is, on the basis of all the science, is quite predictive of the opportunity to have a once-a-day pill.

And what we need to see are two things. We need to see safety and put the drug in the clinic, and then we need to see [symbol of] PK curves in people with the similar ratios at 24 hours. And these are very high bioavailability drugs, and both in the rat and the monkey they are behaving very well. So, I think on that grounds we are optimistic that we will see good PK in people.

Okay. And if you do see this long tale in humans, let's say, is there any reason we shouldn't think of maybe three-time, two-time-a-week dosing?

I think that more frequently you give a drug the less the fluctuation from Cmax to trough level is, so the easiest thing to remember, by the way, for most people in taking a vitamin tablet or whatever it is they are taking, is take it once a day. So, I think that on the grounds of good PK and medical practice, and on the grounds of remembering to take your pill, a once-a-day tablet is actually preferable to a twice-a-week tablet.

Okey-dokey. And then moving on to peramivir. Do you guys have any -- you said you were going to work with the CMO, but do you have any direct involvement with the manufacturing? Any ideas about maybe timeline to resolution? And do you have any recourse if the program is delayed?

So, we are working directly with the manufacturer. We are in contact with the FDA as well, and between the three of us we're trying to figure out how we get through these issues and make sure that we can manufacture peramivir in a way that it gets approved and then makes it commercially available. It's too early for us to -- you know, this is pretty recent stuff, and so it's too early for us to really give you any sense of timing yet. But as we get more updates we'll keep you informed.

And is there any recourse potentially if there is a delay?

I don't want to even think about that right now. My preference is to solve it, and so that is what we're really focused on.

Okay, thank you.

Our next question comes from Brian Abrahams of Wells Fargo Securities. Your line is open.

Just wondering if you could talk about maybe on completed enrollment, how many patients you ended up with in the study, and I guess how satisfied you are with the types of patients that are in the study in terms of the population, the number of attacks, frequency of attacks that you were initially targeting?

Thanks for the question. We are very pleased that we have completed enrollment. This is an orphan disease. The population is not big, and we were targeting a fraction of that, a group of patients who have the most severe -- well, the most frequent attacks, I should say. I think we can look at everybody with this disease as having a severe illness, because of the life-threatening nature of the disease. So, we are looking at a small population of a small population. So, being able to complete enrollment in a pretty quick time frame, I think we're very pleased with.

We've got a total of 24 patients who were randomized and received at least one dose of study drug and who will therefore contribute to the analyses of efficacy and safety. And we are working to finish the study, clean the data, do the analyses, and we're on track to be able to report the results before the end of the second quarter.

We're not going to give any more specificity around exactly when the last patient was enrolled. I think you a pretty good sense from what I've said that you can be confident that we will be reporting the data.

Yes, and I think your other question, Brian, was around, are we getting the kinds of patients that we wanted to get, and I think our view is that, yes. Germany was the right place to go. The fact that they have diaries on a high attack rate, I think we feel pretty good about the quality of the type of patient we got into the study.

Are there any differences, I guess, in the German versus UK sites in terms of how they collect data on frequency and severity of attacks?

I think that -- I'm not expecting site effects -- s-i-t-e, not s-i-d-e. I'm not expecting effects by site. I mean, that's always an analysis you do in clinical trials. You look to see whether the patients on one side are behaving differently and we are not expecting that.

And we only have one UK site.

Got it, okay. And then just on peramivir, I guess would you -- first of all, would you be able to get approval on, you know, given the conditions as the manufacturer right now, could you still, I guess, get approved or other things need to be resolved? I'm wondering, is this a gaining factor for regulatory approval or is it a rate-limiting step for your ability to have supply for potential stockpiling sales?

We are still working through the details, Brian. I think the goal is that we still are able to get approval and we have a quality manufactured product that we can use to supply for this upcoming flu season. So, as I said before, this is pretty new information to us and we are still sorting through it. We are in conversations with the CMO, we're in conversations with FDA, and we are working really hard to meet the PDUFA date and have drug available for the upcoming season. And if we find out that that changes, we'll let people know.

Got it. Thanks for taking my questions.

Our next question comes from Liisa Bayko of JMP. Your line is open.

Can you remind us of, really what your level of detection is? I know you've got patients with high frequency of attack at one per week with 25 patients in the study. What is your level of detection there?

Sure. I think the benchmark to look at is the [Lev] study on Cinryze published in the New England Journal of Medicine, which, just for those who are unfamiliar with that, it was a 12-week randomized crossover design and the placebo period in that study had an observed attack rate of 1.06 per week. So, our eligibility criterion with regard to attack rate for the patients in OPuS-1 was a minimum of one per week. So, we will see when we unblind the data what is the observed attack rate. And so long as it is compatible with our eligibility criterion and the standard deviation is not out of line with previous experience, then that would suggest that we have plenty of opportunity to see an effect. In other words, there is enough of an attack rate you can see a difference when you have a drug on the active drug period. So, I think with 24 patients on study, that's an adequate sample size given the type of patients we intended to enroll, and we'll see the outcome once we unblind it.

And you'll be looking, you'll be analyzing the data within each patient as they are control, correct?

Correct. And we'll also, obviously, look at the appropriate descriptive statistics across the whole group of patients. So, it's a very thorough statistical analysis plan. The primary endpoint is attack frequency. We will also be looking at the quality of life associated with whatever treatment benefit we see, and also attack severity. But the main mission here is the attack frequency.

Can you maybe walk through the key factors that would drive differences in exposure for this particular drug?

So, in contrast to the second generation compounds, which have very good bioavailability, 4161 has low RO bioavailability, and that tends to go along with more variability in exposure. So, you may recall that the coefficient of variation on our PK parameters in the Phase 1 study in healthy individuals was about 50% or 70%, and that's on our poster that we had at AAAAI for each of the PK parameters. That is more than you would get with a perfectly bioavailabile oral drug, so you might get, say, 20% or 30% CV, so there is going to be more variability here. And what we don't know at the moment -- and we'll get some insight from OPuS-1 -- is the greater variability going to be similar in patients with hereditary angioedema to normal people? The small bowel does get affected by attacks of angioedema. I don't have a particular reason to think that in between attacks the absorption of drugs would be abnormal. That research hasn't been done by anybody, so there are no reports in the literature of the bioavailability of oral drugs in people who have HAE.

You would certainly imagine that if you had a facial attack and you couldn't swallow, or you had an abnormal attack and you had cramping abdominal pain and diarrhea, under those circumstances a normal drug is not going to get absorbed. But I think in between attacks, the baseline assumption is the absorption will be similar, but we'll find out soon.

Okay, fair enough. That's it for me. Thank you very much.

Our next question comes from Mario Corso of Mizuho. Your line is open.

Yes, just a couple of things. I am wondering kind of what progress you have made on the animal toxicology for 4161 since the last conference call. Any specifics you can give there and kind of timing and on trackness. And then, in terms of the PK of the next generation -- and, again, I'm not sure if this piece was asked or answered, but when you think about the comparability between the animal and the human PK with 4161, is it very comparable, so we could then extrapolate the animal data with next generation? And then, finally, on peramivir, so obviously commercial drug versus targeting BARDA and federal government procurement is different, so I'm just wondering if in that setting you think there is much more flexibility in terms of how you could resolve this manufacturing issue, whether it's with the current CMO or another one? Thank you.

Sure. Thanks for the question. I'll take the first couple and Jon will take the last one. With regard to the progress on the second generation compounds, everything is on track. The major tasks in developing a drug in the nonclinical phase and filing an IND are scaling up the chemical synthesis process, manufacturing high quality drug substance, formulating the drug product according to GMP manufacturing large scale to prepare for the clinic. And at the same time supplying the drug for the animal studies that are needed for the IND, and stepping through all of the safety pharmacology and toxicology studies. So, our previous guidance that we would be in the clinic in the first half of next year and moving forward into Phase 1 is still on track. So, there is nothing for either compound at the moment that says that is at any risk whatsoever.

With regard to how to think about the PK of second-gen compounds in relation to 4161, as we go from rats to monkeys to people with 4161, which the structure of that drug has nothing to do, by the way, with the structure of the second-gen compounds. The bioavailability, if anything, goes down. So, the exposures you get in rats can be much higher than the exposures in monkeys, which in turn are much higher than the exposures in people. So, it doesn't really scale very well. That is more of a risk in drugs with low bioavailability to start with.

So, in contrast, what we already know about the second generation compounds is that as we go from rats to monkeys, it is scaling very well and we are getting very good exposure in the monkeys. We got very good exposure in the rats, the high bioavailability compounds. And on the basis of the data we currently have, we would predict that they will be high bioavailability compounds in people and we will get good exposure in people. So, using 4161 is not the right comparator of those for that particular question.

And then on the parameter question, let me first say that this is a large, sterile product, fill and finish contract manufacturer, and it's in their best interest. You know, we are one of many, many, many products that they make at this facility. It is in their best interest to get this stuff resolved. It's not just a peramivir issue. Specifically around commercial supply versus procurement, Mario, the only thing I can say is the experience we had back in 2009, and the way that process worked when we got a procurement order was that we got an RFP to get into contract negotiations. We negotiated a contract fairly quickly, and then we manufactured new supplies, because they have specific labeling, they have a configuration they want, at least they did back then, of how they wanted it packaged. And so you are correct that it's likely that we would make special manufactured product for the government following a procurement order.

Our next question comes from Serge Belanger of Needham & Company. Your line is open.

Good morning. A question on peramivir. Given the speed at which the FDA works and they had time to schedule a reinspection and issue additional 483s, I am assuming this is not a new warning letter sending for the last couple of months? So, do you know if there have been any prior impacts at this facility on FDA approval? Is there a manufacture of other products?

I am not aware of the impact to other products. But just to be clear, they were under a warning letter. They had a reinspection that I think they thought would then ultimately remove the warning letter and, in fact, they got a 483 with additional observations. So, that's how things transpired.

Okay. Are they US-based?

They are US-based, yes.

And then one question on the new small molecule discovery programs you initiated last June, the first quarter. I guess, just how much can you tell us about them and when could we expect some initial news?

I think on discovery programs the platform technology at BioCryst you need to remember is structure-based drug design. So, we go through (inaudible) and then crystallography steps, medicinal chemistry steps. There are obviously going to be [isolated] enzymes, potency assays, off-target assays, similar assays of activity, and then working you way up into animals as you iterate different designs. So, I think that the discovery process leading up to selection of an optimized lead can take a variable length of time. Two to three years is not an unreasonable estimate. If a project goes fantastically well, maybe it could be quicker than that, but I think you should have in your mind that it will be a couple of years before we go further than we have.

Yes, and we've said this before, the kind of two buckets, just to give you a little bit more clarity around validated target, right? One bucket is, there is a biologic already on the market and an oral would be a massive improvement. And then the second bucket is, again, a validated target but there is nothing, and so we are willing to take more of the clinical and regulatory risk because it's a really horrible disease and people die from it.

All right, thanks, and congrats on the progress.

Our next question comes from Ed Arce of Roth Capital. Your line is open.

Thanks. Most of my questions have already been asked and answered, but I just wanted to get a sense for, as you progress through this year and in through next year towards filing the IND, what are some of the key steps along the way for these next-gen products? And are there any steps that could perhaps accelerate the process at all? Thanks.

Thanks for the question, Ed. Interesting question. I think the tradition of the Company is to, once we decide to move a drug through the IND process is to do it in a very focused way. And clearly the opportunity for these compounds is so good that we're putting whatever resources necessary to make the drugs and test the drugs and compile the IND in a timely fashion. So, we have asked ourselves the same question you asked, and there is nothing more that we can do right now to accelerate the timeline. You have to go through the different steps of making a drug and doing the experiments, but it is a great opportunity and we are not wasting any time.

And I would say one big difference from the 4161 program is leading up until the Phase 1 data, we were doing everything in series and waiting for information and then making more drug and doing the next stage of tox. With the second gen, we're doing it all at risk, so that when we get -- when we are done with Phase 1 we can immediately move into Phase 2. We have the tox program done, we have the drug supply, so just because our confidence is really high in this program and we want to move it as quickly as possible.

Okay, great. Thanks, guys. That's all I had.

Our next question comes from Rahul Jasuja of Noble Capital Markets. Your line is open.

Hi, guys. A couple of questions. I think the first couple are up for Bill, and I think I had one for Jon. So, Bill, we talked about the second generation compound and there is different chemical class from 4161. Just wondering if the two second generation compounds are similar to each other in chemical class?

Yes, Rahul, thanks for the question. So, there are similarities, but they are unique molecules. It is not like one just has one more hydroxyl group or something. They are substantially different. They do have some commonalities and in both cases, as you said, they have nothing to do with the structure of 4161.

Okay. And then my next question for you, Bill, is -- well, maybe it's a devil's advocate question, but it's really sort of enhance my biology of the drug development process here with HAE. Part of what the serum protease is like by kallikrein is to regulate blood pressure and so on. So, are we with the very positive, consistent exposure and inhibition you're getting, is there an issue where you will monitor blood pressure in these patients? What's the thinking there?

Thanks for the question. It's an insightful question. So, bradykinin is involved in the regulation of blood pressure, and the kallikrein and kininogen system that makes the bradykinin involved in the regulation of blood pressure is predominantly tissue kallikrein and low molecular weight kininogen, respectively. So, this is -- it's a more particular issue, or it was a more particular issue for Firazyr, which blocks the bradykinin B2-receptor antagonist -- receptor, I should say. And in the nonclinical program, which you can read in the FDA's and the EMEA's public approval documents, had pretty extensive cardiovascular safety testing because of that. So, because it is blocking the receptor from bradykinin, you are going to interject bradykinin, whether it's made by tissue kallikrein digesting low molecular weight kininogens or plasma kallikrein digesting high molecular weight kininogens. So, that's the first thing to say.

The second thing to say is we know about the early steps in the contact activation pathway and that they involve Factor XII and prekallikrein. And it just so happens that there is a trait called Hageman trait where individuals have lower than normal levels of Factor XII. And there is another trait called Fletcher trait, which is a prekallikrein deficiency state, and those individuals are otherwise normal, so hypertension is not an issue or doesn't appear to be a issue in those individuals.

We certainly monitor vital signs, including blood pressure, as a matter of routine in all of our clinical studies, whether it's this or any other compound. And the Phase 1 showed no indication of any dose-related effects on blood pressure. In addition, in the nonclinical development of both 4161 and the next-gen compounds, part of the standard safety pharmacology package includes finding out whether there are any effects on the cardiovascular system. So, all of that is negative and the fundamental biology would support the conclusion that a specific kallikrein, plasma kallikrein inhibitor is not going to have a risk related to the role of bradykinin in the cardiovascular system.

Great. That's helpful for me, and I can see that you have been very diligent about addressing that issue. So, one last question I have, and it's probably for Jon. It's sort of a big picture question. So, Jon, looking at the broader view of the future prophylactic HAE market, given the convenient dosing that 4161 and the second generation, or even less frequent injection approaches are going to be on the market, how do you see in your view five years from now an interplay between different kinds of patients, oral versus injection, are the better dosing? And then, more importantly, how does that relate to expanding the market? You see about a thousand patients or more on Cinryze. It's not really all the market, but they are the more acute [class]. Could you put some actual color on that for us, Jon?

Yes, I think it's going to be increments. So, let's take 4161 first. Having an oral that has efficacy and an impact on attack rate for patients is going to two things. One, it's going to give patients a more convenient option, and I think it's going to have some of those people that don't like getting injections to start to get prophylactic treatment. So, I think it's going to do both. It could cut into other products and it could expand the market.

An antibody given twice a month or once a month on kallikrein we think is a good approach.. And certainly when it comes to market with good efficacy it could take even more market share and expand the market further. One pill once a day, wipe out attacks, who wouldn't be on it? That's about all I can say. I mean, that is so convenient, in our minds it's equivalent to a cure. The feedback we've gotten from physicians who treat and patients with the disease is -- that is what they are looking for. So, we think that massively expands the population of patients for prophylaxis and certainly takes a lot of market share.

Yes, I just add one other thought, and this relates to interpreting the PK second-gen compounds and the opportunities. Why do normal people not get attacks of angioedema except under very rare circumstances as a side effect of ACE inhibitors? ACE inhibitors block the metabolism of bradykinin, so that's why you get it under those circumstances. But if you're not taking an ACE inhibitor, you don't get these things. The reason is because of the normal kallikrein inhibitory levels in the blood. And the opportunity here, given the PK in the rats and the monkeys that we talked about today, is to restore the normal phenotype by restoring normal levels of kallikrein inhibitory activity in the blood. If we do that, then as a physician I would think about that as a functional cure of the disease.

Yes, you can have all the contact activation you want and you [won't have edema], so we're really excited about, as I said before, the suite of molecules that we have and our opportunity to really have an impact on HAE patients' lives.

That is very helpful. Thank you guys, and congrats on a good quarter.

(Operator Instructions) Our next question comes from Christopher James of Brinson Patrick Securities. Your line is open.

I just have a really quick follow-up, Jon, to your discussion about your orphan disease strategy. So, when you look at this new rare disease target, which one of those two sort of buckets does it fall into? Are you looking at one where you already have a biologic approved or one where you have nothing approved?

We are actually looking at both. So, we are pursuing two different targets, both validated. One is in a disease where there is a biologic, and the other is where there is nothing. So, we are pursuing two.

Great. All right, thank you.

Our next question comes from Steve Byrne of Bank of America Merrill Lynch. Your line is open.

Hi. Thank you. This line you show on the PK curves, Bill, on slide 8, the line corresponding to four times EC-50, is that essentially the same line illustrated previously for 4161, that the target range you illustrate for that PK data?

Thanks for the question, Steve. Yes, exactly, because that is -- the reason we picked on that is because it is around about in the range of the kallikrein inhibition that you get at the trough of every three days or every four days C1 inhibitor prophylactic therapy. That is about where it is. And just for clarification, the chart on page 8, the two charts express the drug concentration as multiples of EC-50, right?

Right, okay. Whereas, in the 4161 PK data it was in micrograms per milliliter.

Nanograms per milliliter, yes, that's right. So, we're not going into all of the various specifics about the two compounds right now, but I think you can get a very good sense from these two charts that we're seeing drug concentrations in rats and monkeys throughout the 24 hours that are easily above tenfold the EC-50. And if you look at the dose response, the dose ranging on the right-hand chart in the monkeys, going from 10 milligrams per kilogram to 30 to 100 milligrams per kilogram, we're getting -- at the highest dose there, we're getting 100 times the EC-50 on the enzyme. We don't need that much, right? So, the other point to make is even if the bioavailability of these compounds in man is a little bit less, with that type of scaling dose exposure relationship, if I need to get a slightly higher 24-hour drug level, I'll just increase the dose and I'll get there. So, the flexibility with these compounds because of the very good bioavailability is night-and-day different compared to 4161.

And so is there a similar binding domain between 4161 and these second gen, or is that also different?

We know a great deal about all of that but we're not going to talk about it, because that's trade secret information .

Yes, we're going for the same site but we're not going to give the details of how.

But presumably the other major differences are just functional differences that would affect absorption?

Absolutely. Well, it's really -- it's the nature of the compound. So, 4161 is a charged compound, is the way to think about it, and in general charged compounds have lower bioavailability because they have a tougher time getting across plasma membranes themselves, which are full of lipid, right? So, the new generation compounds don't have that liability. They are clearly extremely well absorbed, right, extremely well absorbed. We are targeting the same active site in the enzyme, the details of that we're not going to go into, but, yes.

And the charge is -- for 4161 is what made it bind tightly to the active site. So, what's amazing with what Babu was able to do is come up with something that you could pass through the membrane but still have the potency on the active site and the tight binding, so -- and even better specificity. So, I mean, these guys are fantastic in what they have been able to do in a couple of years with this second-gen program.

Okay. And just regarding the antiviral product, this 4430, are you getting increased interest in this one just from that Ebola virus outbreak in western Africa? Are you getting more interest in it?

Yes. I think in general, since we came out with the data that was published in Nature, I get a sense there is a lot of interest from governments, from academics, from people around the world around this drug. We are trying to go as fast as we possibly can to get an IND filed and get it into man. But, yes, there is a lot of interest.

And the way you look at it now, Jon, would you say that the commercial opportunity is still preferred to go down this path of these highly virulent virus rather than maybe a different indication that might have broader commercial potential?

I think this is pretty good commercial potential for the purposes of BioCryst, right? I mean, as you have heard at the beginning of my remarks and in that first slide, the way you want to look at peramivir and 4430 is every dollar that comes in from those programs in terms of a stockpiling order or other revenue is a dollar we don't have to use or raise to fund other activities in the Company. With 4430, if you look at some of these other stockpiling orders for one drug for a single bug, they can be as high as $700 million in stockpiling. That's a whopping amount of money into a company that you can do a lot with. So, that is absolutely the strategy.

Right. There is one other element there, and that is it is impossible to ignore 95% survival in monkeys infected with Marburg virus, a 100% lethal disease in monkeys, and the fastest path to getting the drug approved is developing it for Marburg virus infection.

Okay. Thank you very much.

I am showing no further questions. Please proceed with any closing remarks.

Yes. So, as always, we appreciate the interest in the Company and we look forward to updating you on the OPuS-1 results sometime before the end of the quarter. Thanks. Have a good day.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect. Everyone, have a great day.