BioCryst Pharmaceuticals Inc (BCRX) 2014 Q3 法說會逐字稿

Good day, ladies and gentlemen and welcome to the BioCryst Third Quarter 2014 Conference Call.

At this time, all participants are in a listen-only mode. Later, we'll conduct a question-and-answer session and instructions will follow at that time. (Operator Instructions) As a reminder, this conference call is being recorded.

I would now like to introduce your host for today's conference, Rob Bennett. Sir, you may begin.

Good morning and welcome to BioCryst third quarter 2014 corporate update and financial results 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, but we will open up the call later for your questions and instructions for Q&A will be provided then. 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'll 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 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 the forward-looking statements. For additional information, including important risk factors, please refer to BioCryst's 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.

The BioCryst team remains committed to building the small molecule rare disease company and changing patient lives with oral drugs for the treatment of their disease. The majority of our efforts are around the advancement of our oral small molecule kallikrein inhibitors for the prevention of HAE attacks with the goal of bringing normalcy to the lives of HAE patients and transforming the treatment of HAE. Activities are underway to get the OPuS-2 trial of 4161 up and running, and we expect to dose the first patient before the end of this year. Bill will summarize the OPuS-2 trial design shortly.

In addition, we remain on track to commence Phase 1 trials of our second generation kallikrein inhibitors during the second quarter of 2015. We have also made significant progress toward improving the 4161 formulation. At this stage, we are becoming increasingly confident that we can reduce the pill burden per dose as we move toward the commercial formulation.

Regarding BCX4430, the strategic value of this program is US government stockpiling as a broad spectrum anti-viral medical countermeasure. The Ebola epidemic in West Africa has shifted our focus to Ebola virus disease. We are currently pursuing three important goals. First, determine if 4430 provides any antiviral effects or survival benefits in non-human primates infected with Ebola. Second, determine human safety and drug exposure in Phase 1 healthy volunteer studies. Third, increase production of drug supply. As Bill will describe in more detail momentarily, the first study of 4430 in non-human primates infected with Ebola virus showed a prolongation of median survival with 4430, but no improvement in overall survival. A second study in a different non-human primate model will commence in November. The IND submission remains on track for this month and we are producing more drug to support the program.

Finally, turning to our anti-viral RAPIVAB for flu, there has been a lot of activity to be in a position to make RAPIVAB available in the US during the upcoming influenza season, pending FDA approval. At this time, the status of our contract manufacturer has not changed; they continue to remain under a Warning Letter. An important next step is a successful general inspection of the plant as this must be conducted in order to remove the Warning Letter status. It's our understanding that the FDA inspection process is underway.

That's it for our general update and now, I'll turn it over to Bill who will discuss our programs in more detail.

Thanks, Jon.

In July, we presented the top line results of our OPuS-1 trial in hereditary angioedema. We are very pleased that this study was selected for oral presentation at the EADV conference in Amsterdam. Slide 6 provides more granularity around patient reported attack rates by the study period and randomization sequence, and was included in the presentation by the study PI, Marcus Maurer. His analysis supports the robustness of the primary outcome in the study.

We are pleased to note that the design of our OPuS-2 study in HAE has been finalized following regulatory discussions and the protocol has now received US central IRB approval. Slides will be opened for screening subjects in coming weeks in the United States. In the next few months, we expect that competent authority approvals, ethics committee approvals and site initiations will follow in the European countries targeted for the study.

As shown on Slide 6, OPuS-2 is designed as a randomized parallel cohort placebo-controlled trial taking two dose regimens of 4161 namely 300 milligrams three-times a day and 500 milligrams three-times a day. We planned to enroll approximately 100 subjects with HAE randomized one to one to one across the three study arms. Each subject will receive 12 weeks of blinded study drug. The qualifying minimum attack rate has been liberalized compared to OPuS-1 but in other respects, the entry criteria are similar. OPuS-2 is powered at 90% to detect benefit in reduction in angioedema attack rate as similar in magnitude to the proportional reduction seen in the OPuS-1 study. A full range of secondary efficacy measures will also be studied including quality of life and utility measures. We anticipate the trial will take about one year to complete through to reporting top line results.

OPuS-2 will use a soft gel product presentation of 4161 with a new liquid formulation, which has superior stability compared to the previous hard gel dosage form. In a formal relative bioequivalent study in healthy subjects, this new soft gel liquid formulation showed about 20% less exposure compared with the hard gel liquid formulation used in the Phase 1 and OPuS-1 studies. Therefore, we've adjusted the dose [regimen] in the top dose group in OPuS-2 500 milligrams three-times a day to provide similar exposure to 400 milligrams three-times a day of hard gel formulations in OPuS-1. Our formulation development research program is continuing with the goal of minimizing the number of capsules to the dose of 4161. The most advanced approaches include more concentrated liquid formulations in a soft gel format. These approaches to reducing the number of capsules per dose [short of] promise and should be ready to evaluate in future clinical studies. The chronic toxicology program required to support chronic administration of 4161 in HAE patients is now underway with results expected late in 2015.

As Jon mentioned, the non-clinical research program for BCX4430 under the NIH, NIAID contract is currently focused on studies of non-human primates infected with Ebola virus. The first NHP experiment was conducted at the US Army Medical Research Institute of Infectious Diseases and evaluated four dose levels of intramuscular 4430 versus vehicle in cynomolgus macaques infected with Ebola virus. With the top dose of 16 milligrams per kilogram twice a day by IM injections. Dosing commenced 48 hours after infection in most study groups with [1,000 platforming units of Ebola virus with by] IM injection. There was an additional cohort that was dosed after detection of viral RNA in the blood. This experiment has been completed and the survival outcomes are summarized on Slide 7 and displayed in [FMI] plots on Slide 8.

For all BCX4430 dose groups combined, there was a significant prolongation of median survival with a p value of 0.009. Median survival in the highest dose group was 12 days with a range of 8 to 21 days compared with median of 7 days, ranged 6 to 9 days in vehicle controls. No animals survived past 21 days of the study. Preliminary analysis of the number of final genome copies per mill in the blood shown approximately [1 lone] reduction in viral titer in the highest dose group compared to controls. The survival and virology results in this experiment are consistent with an antiviral effect of 4430 against Ebola virus in this model. We look forward to learning more once the full set of virology, clinical chemistry, hematology, coagulation and PK analysis are completed.

An additional NIAID funded NHP experiment will evaluate the antiviral activity of 4430 in Rhesus macaques infected with Ebola virus and will include a higher-dose regimen. This study is expected to start in [December] and we expect their results before the New Year. BioCryst anticipates filing an Investigational New Drug Application with the FDA in November to support first in human Phase 1, evaluation of safety, tolerability and drug exposure after single and multiple doses of 4430 administered IM in healthy subjects.

Lastly, we are finalizing a protocol for evaluation of the safety, tolerability, effectiveness and PK of intravenous RAPIVAB in children with acute and complicated influenza in the US. This study is intended to support a supplemental NDA for RAPIVAB injection for pediatric indications.

Tom will now review the financial results.

Thank you, Bill and good morning.

Today, I'd like to summarize the key elements of our third quarter and nine months 2014 financial results. As mentioned in prior quarters, our financial focus is on a single guiding principle, focusing our cash resources on the advancement of our core development programs to value creating milestones and prudently managing expenses. Following our successful $107 million capital raise, I am pleased to report our balance sheet is in a strong position and that we will remain very disciplined in deploying our cash.

On Slide 10, you see that revenue for the third quarter of 2014 was $3.2 million, reflecting an increase from $2.4 million recorded in the third quarter of 2013. This increase is the result of higher collaborative revenue from our BCX4430 development contract with NIAID which has recently increased in value to approximately $29 million. The NIAID related collaborative revenue more than offsets the decreased level of collaborative revenue under our BARDA RAPIVAB development contract as compared to 2013 following the conclusion of development activity in the June 30, 2014 expiration of that contract.

Third quarter 2014 R&D expense was $13 million from $7.7 million in the third quarter of 2013. This increase was primarily associated with our HAE and 4430 programs, but was partially offset by decreased expenditures for RAPIVAB development due to the completion of development activity.

General and administrative expenses for the third quarter of 2014 increased to $1.8 million compared to $1.6 million in 2013. The increase was due primarily to additional costs associated with RAPIVAB commercialization in order to make the drug available in the upcoming influenza season should it receive FDA approval.

Moving below the operating line, we incurred $1.2 million of non-cash interest expense in the third quarter of 2014 and 2013. We also recorded a mark-to-market hedge gain of $4.1 million in the third quarter of 2014 as compared to a gain of $97,000 in 2013. These gains resulted from changes in the yen-US dollar exchange rate. Both interest expense and the hedge mark-to-market adjustments relate to our non-recourse notes and hedge arrangement enacted in conjunction with our RAPIACTA royalty monetization.

Our net loss per share was $0.12 for the third quarter of 2014 and $0.14 for the third quarter of 2013.

Slide 11 summarizes our nine-month financial results for 2014 and 2013. Revenue for 2014 was $8.2 million, an increase from $6.8 million recorded in 2013. The increase was primarily due to higher collaborative revenue associated with 4430 development activities under our NIAID contract. This increase was partially offset by lower collaborative revenue associated with the reduction in reimbursable RAPIVAB development expenses.

Nine month 2014 R&D expense increased to [$13.3 million] from $26.5 million in 2013. The increase was primarily due to increased spending associated with our HAE and 4430 programs as well as compensation charges associated with achieving positive OPuS-1 results including the vesting of performance-based stock options. Both these items were offset by an asset write-off that occurred in 2013, but did not recur in 2014.

General and administrative expenses for the nine-month period increased to $5.4 million in 2014, as compared to $4.6 million in 2013. The increase was due primarily to grants provided to the US and international HAE societies as well as costs associated with RAPIVAB commercialization.

Moving below the operating line, in the first nine months of 2014 and 2013, we incurred $3.7 million and $3.5 million of non-cash interest expense respectively. We also recorded a mark-to-market hedge gain of $732,000 in 2014 as compared to $3.2 million in 2013.

Moving on to Slide 12, I'd like to discuss our cash balance and cash usage. We ended the quarter with cash and investments of $127.6 million following a successful public equity raise, which closed in early June. Based upon current plans and expectations, we expect our existing cash to provide us liquidity into fiscal 2016. Our operating cash usage in the first nine months of 2014 was $19.8 million reflecting a small increase from the $18.4 million utilized in the same period in 2013. As a reminder, operating cash use excludes any hedge collateral posted or returned and any other non-routine cash flows.

In regards to financial guidance, our 2014 ranges remain unchanged. Accordingly, we continue to anticipate operating cash usage to be in the $35 million to $43 million range with the expectation that we would be in the lower end of this range. We do expect our usage to increase in the fourth quarter as compared to previous quarters in 2014 primarily due to HAE program activities especially with the expected initiation of OPuS-2 prior to the end of the year. In addition, we continue to expect our operating expenses to be in the range of $48 million to $59 million.

Now, I'd like to turn the call back over to Jon for some closing remarks.

Thank you, Tom.

So in summary, what should you take away from today's call? We're well positioned to reach important milestones from now to the end of next year. Specifically before year-end, we expect to initiate the OpuS-2 trial in HAE patients, to start a second non-human primate study and a Phase 1 human safety study for 4430. And finally, we expect a decision by the FDA regarding our NDA for RAPIVAB by the PDUFA date.

Looking out to next year, we plan to complete the pre-clinical development of our second gen HAE compounds, file an IND and move into Phase 1 safety studies during the second quarter of 2015. And finally and perhaps most importantly, we plan on reporting our results of the second gen Phase 1 in the third quarter and OPuS-2 by the end of 2015. We look forward to providing you with further updates as we reach these important milestones.

So that concludes our prepared remarks and we are now ready to take your questions.

(Operator Instructions) Brian Abrahams, Wells Fargo Securities.

I wanted to drill down a little bit more on the OPuS-2 trial design. I was wondering if you could maybe talk a little bit about the rationale for using two different doses in that study. When I circle back and look at the prior data, I guess the 300 mg -- the lower dose would equate to about 240 mg, our prior formulation and I guess you tested a 200 milligram dose that -- where the -- the target concentrations were -- I guess the concentrations were above your target range for substantially shorter period of time as compared to the 400 mg and 800 mg doses. And so, just wondering the rationale for testing that dose and what gives you confidence that using 300 mg TID will enable substantial sustained kallikrein inhibition?

Hi, this is Bill. I'll start with a few points. Thanks for the question. So I think, let's frame-up the study first. So this is a study that tests two doses. The study will be successful if the 500 milligram three-times a day dose shows a statistically significant improvement compared to placebo, regardless of what the 300 milligram three-times a day dose arm shows. If the 300 milligram three-times a day arm also shows an improvement, that's very important to know. And it's very helpful to understand what proportion of patients might benefit from a lower dose. So obviously regulatory agencies are very interested and sponsors evaluating more than one dose. That's written into the guidance documents in fact. And I think that as we got a market, it's helpful for us to know what's the distribution response look like.

We are expanding the patient population and liberalizing the entry criteria. So the 24 subjects we had in OPuS-1 had very high attack rates that are not typical of HIV patients. And as Dr. Maurer explained in our call discussing the OPuS-1 results as we go into a broader patient population, we may actually need less drug to get to enough total kallikrein inhibition level in the drug to be of benefit. So I think there are good drug development reasons to study a lower dose and it's a sensible thing to do at this stage.

Yes, I think from a commercial perspective, it would be good to know if a lower dose is effective in some patients because we know with the other prophylactic agents that are out there that both physicians and patients play around with dosing. So from a commercial perspective, that would be very, very important to know.

That's very helpful. That makes sense. And then, did you get any feedback from the FDA as to whether OPuS-2 could potentially be part of a regulatory -- registrational package, could OPuS-1 and OPuS-2 serve as two randomized studies sufficient for approval or did you get any clarity or that really wait until we see results, and then you can go from there?

I think in general, it's always good to see results as you're making those decisions. But we did get feedback that two adequate and well controlled studies would be necessary for licensure. And so we're designing OPuS-2 in a way that it -- that would be one and for conservative planning purposes, we believe that there will be another that will be necessary. Depending on what we see (technical difficulty) we may go back to the agency and bring forward if it's really robust results, we may say that this plus OPuS-1 could be adequate for filing. But again, we'll have to see that. I think, if you want to try to set expectations before that this is a division that follows the guidance very carefully and so therefore, I think for realistic purposes, we should assume that it's OPuS-2 and another study.

Makes sense. And I assume that that's nothing specific to 4161 and that's really their view on the development for any new HAE drugs?

Yes. That's correct.

Okay, great. I'll hop back in the queue. Thanks again.

Charles Duncan, Piper Jaffray.

Congrats on the progress. I wanted to ask you a little bit more about OPuS-2 in part to get better understanding of the design. Bill, you said approximately 100 patients, 32 patients per arm. Can you share with us a little bit more color on what your baseline expectation is in terms of attack rate, but also in terms of the magnitude of benefit I think you've referred to it, but I didn't catch an actual number. How did you power this study?

Alright. If we go back to the results of OPuS-1, the primary endpoint was adjudicated attack rates and we had an attack rate of 0.82 in the 4161 period compared to 1.27. We discussed that in the previous call. So the difference was 0.45. So if you think about that in (technical difficulty) it's 0.45 divided by 1.27, that gives you a percentage. So we're also able to look at the standard deviation of the attack rate in that study and think about what's a reasonable thing to plan for power assumptions. And if you then go to Slide 5, you can see that the standard deviation in the first period, which is if you like that can be viewed as a parallel design segment of OPuS-1, you can see the standard deviation on both placebo and 4161 was 0.7 and you can do the math and see what the proportion of that is.

So I think what we're doing with the power calculations here is despite the fact that we are expanding the population into a less severely affected group, if you like, and we may -- we're hoping Dr. Maurer is correct and that the benefit will be even better than we saw in OPuS-1, but we're not counting on that. So we are planning to have enough patients in the study that we will hit an appropriate p value if we see a similar proportional effect comparing a drug arm to the placebo and with a pretty substantial standard deviation.

Okay. And that's helpful and then with regard to increased number of sites and increased number of patients to be enrolled, perhaps similar variability, what steps are you taking to reduce the likelihood of potential compounding variables with regard to those patients coming in and advertising a certain attack rate or whatever?

Right. It's a good question, it reminds me of the old sour about if -- why did bank robbers rob banks, because that's where the money is. So I think that with regard to setting up clinical trials you have to have patients with disease with regard to get the events that you need to measure. So we were very successful at doing that in OPuS-1. I think that there were two reasons for that. One is we were strict about the eligibility requirements and strict about documenting that the patients actually had that attack rate. So we're taking the same type of approach in OPuS-2, it's more diverse because we are doing the study in both United States and we're also expanding the number of countries in Europe, it was just Germany and the UK in OPuS-1, we're going into more countries.

So patients will be able to qualify for the study either by having great medical records that really do tell us just like they did in OPuS-1 that the patient has the qualifying attack rate. Or if they are not adequate or don't exist, then the patient will enter a screening running period and we'll prospectively document if they're having the attack rate to qualify for the study. So I think that, that's the number one thing that you have to have in order to run a study like this.

The other aspects of operational execution, we're going to pay just as much attention as we did in OPuS-1 with regard to education of investigators and site personnel, site initiation visits and hands-on management of the study. So that will be to the same high standard.

Okay. And then my final question is regarding the duration of dosing, 12 weeks versus four seems like a good thing in terms of signal to noise. But I'm wondering if you have detected or have any reason to believe that there could be a difference in sensitivity to the drug over time, what do you anticipate in terms of the duration of treatment?

So we didn't -- yes, it's an interesting question and we -- I absolutely agree that 12 weeks gives you more opportunity to see the attacks you need in order to detect the treatment effects or longer duration studies are very helpful in that regard. I think that in the biology of kallikrein, pre-kallikrein and contact activation in the way our drug works, we don't see any reason to think that there would be a loss of effect over time or an improvement in sensitivity to the drug at a time.

I think that what we try to do here is to restore the normal phenotype of kallikrein inhibitory content in the blood and I think we've made progress with the first generation content 4161 and it looks like a real drug to us and we have actually very excited about implementing OPuS-2. But I -- we are not counting on an improvement in why we power the study.

Thanks for the added color, Bill. I'll hop back in the queue.

Mario Corso, Mizuho.

A couple of things I wanted to ask about. In terms of the pill burden, the 4161 I know there is no certainty yet, but if you could talk a little bit about how you see that looking or even a range of how that might look. And then in terms of OPuS-2, will there be an extension? Is there a design to get some longer term exposure from the study? And then thirdly on peramivir, has there been any substantive FDA interaction besides waiting for an inspection that potentially could push the PDUFA out say 90 days or do you feel very certain that you're going to see a decision in the next month. Thank you.

So I'll take the pill burden one, Bill, you take the second one, and then I'll come back to the FDA RAPIVAB question.

So on the pill burden front, so it'll be five capsules three-times a day for the 500 milligram and three capsules three-times a day for the 300 milligram. As Bill mentioned, we have formulations where we have higher concentrations of liquid being able to be put into the capsule. And so, getting back to the four capsules for the 500 milligram, I'm very, very confident we'll get to that point and I think we can get even lower with that approach. And then we're also exploring other technologies that could bring it down even further. They're too early to talk about at this point in time. But, stay tuned. But we are really committed to bringing the capsule count down and so far so good.

Yes. So with regard to the ability to have a rollover study, not at this stage because the chronic toxicology to support that isn't completed. It'll be completed by the end of next year, assuming that supports the safety of chronic administration in people. Then we will be able to start a long-term safety study. The opportunity for a rollover probably isn't there, that would require a [waiver of] some type from the regulatory agencies.

So with regard to your question about the interactions with the FDA, there have been a bunch. And as you probably know, I think it's from PDUFA 5, we now have a mid-cycle interaction -- formal interaction with the FDA and then a late cycle, both of those have been completed. We've largely negotiated the labeling for the drug and so the big remaining issue is the manufacturing that we've been communicating all long. And as I said in my prepared comments, the inspection process is underway with our plant in our CMO, but we're not in control of either the process or the timing. So I can't give you a whole lot of insight beyond that. I mean the good news is, with the amount of time left between now and our PDUFA date, at least the processes, [they are at in-process] in terms of inspection.

That answered your question, Mario?

Yes, thank you.

Steve Byrne, Bank of America.

Hey, Bill, I was wondering if you thought the reduction in bioavailability of the capsule formulation could have an increasing effect on the standard deviation of responses.

No. We are going to hit the sign exposure because we're giving more milligrams, and the PK data from the relative bioavailability study supports that approach. So I'm not anticipating that would have an influence on the standard deviation response, I mean it's certainly possible, but I'm not anticipating that.

Okay. And what are your thoughts about or at least considerations of perhaps a higher dose rather than a lower dose? Is that something that you consider notwithstanding the pill burden, but your comments on that and whether you think maybe a dose escalation study might also be worthy given the variability in responses maybe some individuals just need a higher dose because the -- their particular bioavailability is lower?

Yes, so we thought about that, Steve, after OPuS-1 and we beat that around quite a bit internally and with our experts and key opinion leaders and the decision was given the robustness of the results and this just crazy high attack rate frequency population that we felt that the profile looked pretty good with the dose that we had. You know from the Phase 1 that when you get up to much, much higher doses, I believe it was 800 milligrams that you start to see some of the side effects from the excipients and the formulations. So I don't want to go to that and then there is a saturable absorption mechanism. So I think we're at the point where we're real comfortable that from the efficacy profile where we've got the high dose that we need and at the end of the day, as I said earlier, physicians and patients may play around with dose again but I'm less concerned about it on the upside than I am on the downside.

And then I had a question on the 4430 data in these macaques. Do you have any view on what might be limiting the efficacy and whether you just simply need to go higher doses or is it a dose frequency issue?

Yes, thanks for the question. I think it's worth keeping in mind that this is just the first experiment. There is a nice review paper that came out this year that lists all of the monkey experiments published for all of the things that have been tried in either Marburg virus disease or Ebola virus disease models in monkeys. And for example, the monoclonal antibody campaigns -- this is a total of six experiments trained cynomolgus monkeys and trained Rhesus monkeys. So it's hard to answer every question in a single experiment in the space of four facilities, the number of animals that you can put in those facilities is quite limited, to the huge amount of work to do to each one of these studies. So I think we're happy that we've learned something from the first study, which is, it does appear to be an effect statistically significant prolongation in survival and an anti-viral effect. You could be right that it may simply be a matter of being on the cusp of getting the right dose to maybe a higher dose will result in survivors, so that's a testable hypothesis. So we'll be putting a higher dose regimen into the next study.

The other interesting thing is these models are really very aggressive and up to the introduction of the monoclonal antibodies and 4430, there were no examples of experiments with survivors when the interventions were introduced more than after the first date. So I think that they're very aggressive models. The Rhesus model seems to have slightly slower progression than the cyno model that in both cases, the rapidity of the disease is way faster than it is in humans. That's -- that handy to get an answer that I think that there is having a result with a solid anti-viral effect and some survivors I think would give people grounds for hoping that there would be a treatment effect in humans, the human disease is most slowly evolving, there is more time for the immune system to kick in.

And the mortality rate is different.

Yes, that's right. So it's very, very rare to get a surviving monkey in the control groups in these experiments and as you know the -- obviously it's a very bad outbreak. Fortunately, I guess there are survivors and the survival rate in Africa is about, it has been quoted at about 30%. So I think that they're very, very high stress models and we have taken the first step and we look forward to getting a lot more information from the study and also from completing the next study and let's try to move forward and the goal here is to do better obviously.

And just one more from me on OPuS-2, what's your (inaudible) where you think the average attack frequency might be given the relaxed entry criteria?

We are not going to be very specific about the entry criterion, because I think just like (inaudible) we don't want to have people try to gain the system in terms of getting into a study. But I think in 12 weeks you can look back at the synchronized data and you could imagine that that [led] study in the New England Journal would have had fine results even if the attack rate had been quite a bit lower than what was reported. So there is a good opportunity to see attacks. I mean you could take the example of OPuS-1. If we see a similar number of attacks spread out over 12 weeks that's probably just fine, right?

Okay, thank you.

Christopher James, Brinson Patrick Securities.

Thanks for taking my questions and congrats on the progress this quarter. My first couple of questions relate to OPuS-2. Just given the longer duration the 12 week versus four week, do you anticipate any issues with off-target effects, how do you think about the effects on bleeding time with the longer duration and new formulation?

Thanks for the question. Sorry, I think we've answered the anticoagulant off-target effect question definitively already. As a former practicing hematologist, prothrombin time is a very valuable assay. We know from the accumulated non-clinical and clinical data now that the concentrations of drug that we need to affect the prothrombin time is so far above what's achievable with oral dosing of this drug in humans, so that's a non-issue. And we've got hundreds of prothrombin time evaluations from the Phase 1 and OPuS-1. Obviously, we'll continue to do them, but I'm very, very confident that continued administration for any period whatsoever is going to be safe from the perspective of anticoagulant off-target effects.

One of the reasons you go progressively from short duration to longer duration studies obviously is because you can't predict the other potential off-target effects of new drugs that's part of the testing paradigm. So we've built in comprehensive safety evaluations, of course, but there is nothing in the Phase 1 or the OPuS-1 data that makes us worry.

Again, we've done the 13-week talks to allow us to be able to do the 12-week study and as Bill said in his remarks, we're starting a six and nine months.

Great. That's really helpful. I know you will comment on the minimum attack rate for your entry criteria, but maybe can you discuss the distribution of patients, maybe with respect to the lower attack rate that you're targeting I guess from the literature, what proportion of patients with a JED, I think fall within that range that you're going to be targeting?

So, I think in that I don't know the answer to that question. I think that what I can tell you is that we anticipate that finding patients for the study proportionally will be less of a chore than it was for OPuS-1. On the other hand, it's still going to be a chore because it always is. So it's always a challenge to recruit patients into any sort of orphan disease indication study. Sometimes by the way, it's a challenge even in run of the mill [conversations]. So we are putting a lot of effort into identifying the sites that have the patients that are enthusiastic about the study. In the US, we've worked very closely with patient efficacy groups to understand how they might be able to help recruitment for the study and the like. So, I think that like last year at this time when we're about to getting to OPuS-1 it's always hard to predict exactly how enrollment will go. But we will put our best effort behind it and I -- we feel comfortable in setting out the timeline that we did on the call.

And Bill, isn't it safe to say that as our clinical program progresses, we're going to move closer and closer to the general population of HAE patients.

Clearly, I think your average patient out there in the community, they might or might not qualify for the study, there are plenty of patients out there who had very, very infrequent attacks that -- way less frequent than an attack every three months, clearly they're not going to be eligible for the study.

Great, that's really helpful. Thanks for the clarity on that and congrats again on your progress.

Thank you.

Rahul Jasuja, Noble Life Science Partners.

My first question really is a clarification probably stemming from my ignorance here. So when moving from the hard gel to the soft gel capsules, was there an expectation that the bioavailability could be that much lower? Could you sort of explain that and what were the advantages you were expecting going to the soft gel?

So the hard gel thing was really only a temporary maneuver to enable us to do the OPuS-1 study. And so we've been developed -- working on soft gel formulations and succeeded. So I think that in order to get the stability we need, there were certain changes we had to make into the excipients in liquid formulation. Whenever you do that you can't predict the result of sense of bioavailability and you need to do a related bioavailability study. So I'm not sure I was anticipating one direction or the other. You'd just have to do the experiment and find out the answer. I'm not worried about 20% difference in bioavailability, that's easy to fix by just by giving more milligrams.

Yes. The important thing is that we know that we're getting similar exposure to OPuS-1. That would have been a disaster if we went into the study not knowing that and then we found out that we had less exposure.

If that's the -- if that excipient makes soft gel type of combination progresses and we can make it more concentrated and we'll continue to pay close attention to those types of issues to make sure that whatever the final dosage form is that we're getting the exposure we need.

Okay, that's fair. And then the other question I had was, the upcoming trial compared to the OPuS-1 study obviously has patients that have a lower attack rate, and then potentially we had discussed that population versus the high attack rate could do better given the low bioavailability with 4161. But then facing the fact that compliance was really excellent in the 28-day study with the higher attack rate patients. How would you sort of address the issue of compliance with patients that may be a less driven, have less attack rates, and also heterogeneity in the population given the low bioavailability?

Yes. I don't think you should think that people are less motivated if their frequency of attacks is less frequent. One attack is bad, really bad. And so, I would say in general, what we heard from patients, what we heard from physicians is that these are -- these patients across the board, whether it's profile of OPuS-1 or OPuS-2 or even less frequent attacks, these folks are very, very disciplined at managing their disease. I mean, think about it. The prophylaxis treatment right now is every three or four days an IV infusion. So we are not worried about the discipline of these patients managing their disease.

So I think that just to set expectations, the amazing compliance that we saw in OPuS-1 is a hard thought to meet again and again and again. So I'm not necessarily -- I'm not counting on that. But what I'm counting on is the diligences, our team and the investigators and the study staff to help drive, attention to detail around taking the medicines. So there is -- we are taking every measure that you can think of to remind a patient to graciously agreed to come into the study to take the randomized medicine and to -- and we've built into the study visits that you can see on Slide 6 to reinforce that message, as well as to do the usual safety and other required follow-up and supervision that driving, taking the medicine in any study within oral medicine is one of the top priorities in execution.

Okay. And then, the other sort of sub-question there was, I mean there was significant heterogeneity in patient response in the OPuS-1 study, and that was due to poor bioavailability. I am asking a tough question, but do you think that the response -- the heterogeneity and response in this lower attack rate population would be expected to be any different? Would there be -- would be more homogenous, I mean what are your thoughts?

Okay. So you've mentioned bioavailability a couple of times. Just to be clear, I don't know of any reason to expect any difference in the distribution of bioavailability between OPuS-1 subjects (technical difficulty) I feel very, very comfortable about getting -- targeting 32 patients per arm for statistical purposes. If we get out a blank piece of paper and cover up the right hand side of Slide 5, and look at the left-hand side, that's 12 patients per arm. And we're seeing a pretty profound difference, and we're having 3 times that many approximately. So I feel pretty good about the [same for size].

Okay, very good. Thanks, that's helpful.

Ed Arce, Roth Capital Partners.

Most of them have been asked, but I have a couple. First on, with OPuS-2, assuming that 500 milligrams three-times a day is ultimately the right dose going forward into potentially another trial or registration and assuming as you said, you're very confident in breaking down the pill burden at that dose down to four pills per day or four pills per three times a day, it seems we're back essentially the 12 dose per day that you saw in OPuS-1, and I'm wondering if that ultimately stands as the final pill burden, how do you think about that in terms of the commercial effect? I grant that this is a disciplined group of patients, but just your thoughts on that.

I think what's really important here is, this is not hypertension, this is not high cholesterol, this is not reflex or something like that, this is HAE attacks and preventing them. And I feel like sometimes I seem like a broken record, but I've talked to more patients and physicians and there are people that don't like needles, period in this space. And they are worried about vein fatigue and a whole bunch of other things and so there will be a population, even if it's five capsules three times a day, there will be a population. Now, I am confident that we're going to get that capsule count down per dose, but I just can't stress enough that the desire for an oral makes the willingness to take multiple times a day, multiple capsules much better.

Okay. One other final question I guess is, you expect OPuS-2 to run about a year. And so my question is, do you think it like the -- that we could expect top line results by the end of 2015 or would it more likely be early 2016?

We're shooting for the end of 2015.

Okay, alright. Thanks.

Yes.

(Operator Instructions) Charles Duncan, Piper Jaffray.

Sorry, guys. My questions were all answered. Thanks.

Sir, I am showing no further questions in the queue at this time. I'll turn the call back to Jon Stonehouse for closing remarks.

Great, thank you. We've been working hard over the last quarter since our last call, and I think as you look at this call, it's about how we're setting ourselves up for next year. Next year is a very exciting year with important studies and programs advancing. I mean if you think about it, we were really in one clinical trial this past year, now we'll have multiple programs in the clinic next year. So it looks like it should be a very exciting year for the Company. And so, as always, we appreciate your interest in BioCryst and have a great day. Thank you.

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