BioCryst Pharmaceuticals, Inc. (BCRX) Q4 2016 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen, and welcome to the APeX-1 Interim Results Call. At this time, all participant lines are in a listen-only mode. Later, there will be 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 turn the conference over to Robert Bennett, Vice President, Investor Relations. Sir, you may begin.

Thank you, Shannon. Good morning and welcome to BioCryst APeX-1 Part 1 trial results 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; Tom Staab, Chief Financial Officer; Dr. Bill Sheridan, 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 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 may be found on our company website. With that, I will turn it over to Jon.

Thank you, Rob. Good morning and thanks for joining us today. We are extremely excited with the interim results from our APeX-1 Phase 2 trial in patients with HAE in which we evaluated our oral kallikrein inhibitor BCX7353 versus placebo in reducing HAE attacks. We have a specifically significant and clinically meaningful result in patients with severe disease as measured by the baseline attack rate of approximately one attack per week. When planning and designing APeX-1 it was critically important for us to show this drug works, the interim analysis clearly does this. That's why we chose to start with the 350 milligram dose. Based on the PK data from our Phase 1 healthy volunteer trial, we anticipated we would over scoop the target range of the drug trough levels we are aiming for, and the PK and the interim analysis confirms this too. Our Phase 1 trial results also showed there is a likelihood of GI adverse events at this dose. Not surprisingly we see some GI adverse events in the interim analysis of patients on the 350 milligram dose. What is surprising, when you look deeper into the efficacy results is the difference in attacks by anatomical region. 7353 has a dramatic impact on reduction of peripheral attacks, triggers an 80% reduction. We did not see the same effect on abdominal attacks. We believe this is due to patients reporting transient abdominal adverse events as attacks. Bill will go into much more detail with the data to explain it further. The interim results also show that over a four week dosing intervals 7353 is generally safe and well tolerated. Bill will go into the detail on the safety and tolerability as a Part 1 of his review of the interim results. Lastly, as I already mentioned, the PK and PD results from the interim analysis confirms what we saw in healthy subjects in Phase 1 for both 24-hour drug level in kallikrein inhibition. On average, the results show that we far exceeded our target range for drug exposure levels during the entire 24-hour dosing interval. With trough levels between 11 and 32 times to EC50, this is very encouraging because it suggests to us that we can get to similar or better results at lower doses. That's because the 250 milligram and 125 milligram doses we still exceed the target range and in the Phase 1 study we saw less GI adverse events at both dose. Bill will explain the rationale and planned changes at APeX-1 to further explore the dose response in this study. Let me conclude my introduction by saying what this means for HAE patients. We now have proof-of-concept for once a day oral therapy to prevent HAE attacks. Patients all over the world tell us over and over again that this is what they're waiting for, the dream of being able to live a normal life. Now I'd like to turn it over to Bill to go over the results.

Thanks, Jon. I'm very excited discuss the results of our interim analysis. I'd like to start by thanking the patients, site staff, investigators, and their teams here at BioCryst for their commitment and dedication with this important research. In recent days, we've had the opportunity to work through the analyses with our principal investigator, Dr. Emel Aygören, who is joining us on this call and discuss the findings with other leading HAE experts and their patients' advisors. The feedback has been very positive. Before we get into the results, let's go over the design of this placebo controlled clinical trial. The trial has been conducted in sites in several European countries Australia and Canada. Despite two trial was designed to test several doses in two stages, with study drug dose for 28 days. In Part 1, we wanted to look at 350 milligram once daily and in Part 2 which is currently enrolling, we are looking at 250 milligrams and 125 milligrams daily. The key elements of any HAE study is the qualifying rates with angioedema attacks, for this study we selected a minimum range of two attacks per month or 0.45 per week and we expected to see an average qualifying rate about twice that. Another key element is have the data collected on our test symptomses reviewed as in our previous studies, we had an expert panel of three independent HAE physicians adjudicate the attack diary. Also as in our previous studies subject head to head access to specific medicines to treat HAE attacks hugely either a C1 inhibitor given intravenously or a CAT event given subcutaneously. The most common management strategy for HAE patient in the countries where we conducted the trial is on demand treatment with acute attacks. Other prophylaxis treatments such as Amgen or C1 inhibitor IV were not allowed during the study. The main goal of Phase 2 clinical research is to understand dose response and for the full study, we will be able to look at several doses for efficacy and safety profile what sort of drug levels we get and the degree of target enzyme inefficient with those doses. With that information, we will be in good shape to select dose levels for Phase 3 trial. We look forward to those analyses once the study is completed. With the interim analysis of Part 1, it was very important to see if we could establish this drug works to prevent HAE attacks and then estimate the magnitude of benefit. That information and the pharmacokinetics and pharmacodynamic measurements could help us understand if any changes might be helpful for the rest of the study. Turning now to the analysis results, the first question relates to the demographic and disease characteristics of the subject with hereditary angioedema who enrolled in the trial. We had 28 subjects randomized and treated 14H for 7353 and placebo and this defines the intent-to-treat population. Although subjects have to have a medical record documenting mostly one inhibitor levels to support the diagnosis of Type 1 or Type 2 HAE and indeed full 28 subjects satisfied that requirement, we could not confirm low levels by Central Reference Laboratory testing for one subject on each arm. In addition, two subjects in the 7353 group which I will describe in more detail later discontinued study drugs early. So that leaves 11 active and 13 placebo for a total of 24 subjects with Type 1 or Type 2 HAE completing 28 days of treatment for the third protocol assessments of efficacy. We are very pleased to see the compliance with once-daily study medicine with near perfect with 98% and 99% compliance in the 7353 and placebo groups. Subject to demographic characteristics, we are generally well-balanced across the two groups with the exception that more subjects on active drugs 11 out of 14 had prior androgen exposure compared to six out of 14 on placebo. Talking about eight subjects had alanine aminotransferase level or ALT above the upper limit of normal at baseline prior to any study drug exposure. This is likely a reflection of their prior end use for the treatment of HAE. As in all cases, these baseline elevations were seeing exclusively in subjects with that treatment history. The average qualifying attack rate was about one per week as we expected and very similar in each arm. This high rate and the low C1 inhibitor level with an average level of less than 20% of the normal mean are both good indicators that the population study in this trial represents a severely affected group with patients with HAE. The statistical analysis plan laid out a series of pre-planned analyses of efficacy, safety, drug levels and PD effects on the target enzymes as indicated in the top box on this slide. One of our goals in this analysis was to help us think about selection of the primary endpoint for a Phase 3 trial. So we looked at the clinical disease outcome with interest namely angioedema attacks in a number of ways including attack rates, counts, and proportion of subjects with Type 3. Similarly we knew the steady state trough levels of this drug are not reached for about six to seven days, so we pre-specified two analysis periods weeks two to four can be effective dosing periods and weeks one to four the entire dosing period. As already noted, we also have third protocol and intent-to-treat population, so we analyze efficacy using both of those definitions. The attack rate and proportionate attack free analyses that we present are based on adjudicated attacks. The results presented are based -- we also reviewed analyses of all patient reported attacks to check the consistency of the set, with or without attacks adjudication. The usual clinical characteristics and time course of abdominal and peripheral angioedema attacks are different. So we also wanted to see what efficacy looked like if attacks were categorized that way. An important point of interim analysis of Phase 2 study is to learn as much as possible from the data. We did in fact see a difference based on anatomical locations. So we also looked closely at the abdominal attacks and sorted them into those that also had peripheral symptoms and those that did not, as indicated in the lower box on the slide. This classification was done with blinded data and we conduct a post-hoc analysis with number of attacks in each of those categories. Now turning to the efficacy results, we were very pleased to see a strong and highly statistically significant treatment benefit and this is just a great slide to spend a couple of minutes on. On this slide, we provide the details of attack rates for the effective dosing period for both the PP and ITT population. For all the right analyses is an analysis of an covariance model with qualifying attack rate as the covariate. For the per-protocol analysis, the placebo attack rate was 0.915 per week and on BCX7353 was 0.343 per week, a reduction of 63% with a P value of 0.006. Looking at the intent-to-treat analysis, the results are very similar with a reduction in attack rate in favor of 7353 with 52%. The strength of this effect is reinforced by the small sample size in this interim analysis. These results are displayed graphically on Slide 9. Together with the results, the entire dosing period in each panel, the left peer is placebo and 7353 weeks two to four and the right peer is weeks one to four. The protocol analyses are on the left side of the slide and ITT analyses are on the right side. As you can see, the benefit from 7353 in reducing attack rates is very consistent across each analysis duration and each analysis population whether per-protocol or ITT. Sensitivity analyses were also conducted. The first approach we took was to set the small amount of missing diary data as a failure i.e. as an attack. The second approach was to impute the attack rate for those missing days using the baseline attack rate. Neither of those sensitivity analyses affected the magnitude of benefit indicating a statistically robust treatment effect. These analyses confirm that 7353 is a safety that's been preventing angioedema attacks in patients with HAE who are severely affected by their disease. The second step pre-specified analyses was to look at attack rates by anatomical location divided into peripherals and abdominal. In these panels we have also indicated the overall results for weeks two to four in the left hand peer bars in each panel that were shown on the previous slide. Per-protocol analysis is on the left and ITT is on the right, as is obvious the benefit from 7353 is much greater in peripheral attacks compared to abdominal attacks, for example with an 88% reduction for peripheral attacks compared to 24% for abdominal attacks in the per-protocol analysis. This is a rather curious difference. The third phase of pre-specified analysis was to look at proportionate subjects of Type 3 and we displayed here the results for all attacks and also by anatomical location divided into peripheral and abdominal and exactly the same sort of format as the last slide. Again as it's obvious the benefit from 7353 is much greater in peripheral attacks compared to abdominal attacks, 81.8% of subjects for pre-peripheral attacks by per-protocol and 78.6% by ITT. Compared to placebo, there was a 51% improvement in the percentage of subjects peripheral attacks compared to 7% improvement for abdominal attacks in the per-protocol analysis. These observations with a parent differential efficacy based on location of attacks together with the blinded adjudicated notes indicating that many of the abdominal attacks appear to be atypical prompted a post-hoc analysis of attack counts and characteristics to try to understand if this observation was really true and why it not be so. Patients who provided an angioedema attack diary and asked to record the anatomical side of the HAE symptoms as well as check off what the symptoms were each time they had an attack. That patient diary data allowed us to split up the attacks that had any component of abdominal symptoms into two groups, attacks with no other part of the body affected i.e. abdominal only attacks and attacks that these include other body sites in terms of mixed attacks. The counts of attacks with peripheral, mixed size and abdominal only symptoms show striking pattern here which has the same direction and similar magnitude in both the per-protocol and ITT population. For example for per-protocol there were two, two, and seven attacks in 7353 treated subjects for fewer peripheral mixed and fewer abdominal attacks respectively compared to 22, 12, and 2 for placebo. The 7353 subjects had counts of peripheral on mixed attack categories, 91% and 83% less than placebo and in both cases there is no doubt that the attacks are unequivocally angioedema because the patient can see the event of swelling or specific pink greenness on the skin that heralds an attack. In contrast, the counts of attacks with symptoms were confined to the abdomen showed the exactness reverse pattern with for the per-protocol analysis seven on 7353 and two on placebo, this reversal makes no sense at all. There is no reason that a kallikrein inhibitor circulating plasma would not work in all locations in the body. We also noted the atypical nature of many of the attacks for example symptoms lasting several days not changing after a single dose of HAE medicine and not interfering with continued study drug administration. That really isn't compatible with an abdominal attack of angioedema. The likely explanation is quite simple and that is with patients that are so used to abdominal pain or nausea or vomiting being part of their disease that they assume that that's the case whenever those symptoms happen and record those symptoms as an attack and some subjects may not have been able to distinguish drug related GI upswift from early signs of an attack. We then looked at the counter events of adverse events for abdominal pain, nausea, and vomiting. That fibrillation is in the left hand column on Slide 15 and shows only one event in each category on 7353 and none on placebo. We would have expected to see more GI adverse event in the active arm based on the event rates recorded in the Phase I study in healthy subjects at this dose. If we tabulate the same symptoms recorded on the HAE attack diary page for all the attacks that had any abdominal symptom and using the same classification into abdominal only versus mix as on the previous slide, we have for example, one and six events of abdominal pain of 7353 and placebo in mixed attacks and the reverse pattern in the abdominal only attacks seven for 7353 and three for placebo. The excess in the 7353 arm for symptom count in the abdominal only group are more in line with drugs related to AE than with angioedema attacks. To understand the potential impact of any misclassification of abdominal pain, nausea, and vomiting as an HAE attack instead of a study drug related adverse event, we can look at all of the days that patients in the ITT population recorded any symptoms of HAE in their diary which is represented on the slide. I compare that to what happened when we strip out days in both the 7353 and placebo groups on which there were only one of those symptoms. Each row in this table represents one study subject and each column one study day, one through 29, the top half are 7353 subjects and the bottom half are placebo. Each color square indicate days with symptoms recorded. The white squares indicate no symptoms on that day. This snapshot gives visual sense to the overall benefit in the 7353 subject compared to placebo. These two slides are a good example of the pictures being worth a thousand words stripping out the days in both the 7353 and placebo groups on which there were only the three GI symptoms from both groups makes clear that this likely degree of benefit that we can see with 7353 with now 9 of 14 subjects free of symptoms for the entire study compared to one placebo subject. I would now like to turn to the pharmacokinetics and pharmacodynamic results. We had a very good PK profile in our Phase 1 trial in healthy subjects and we expected to see similar drug exposure in HAE patients as you can see we did. The left hand panel shows the serial blood drug levels on a clinic visit day at steady state and the inset shows serial trough levels. This interim PK analysis has summary PK parameters that are very similar to the healthy subjects with no evidence of having hereditary angioedema effects either absorption or clearance of 7353. The trough levels in other words 24-hours after the previous dose far exceeded the proposed target range for efficacy with values from 11 to 32 times with 50% inhibitory concentration on plasma kallikrein contact activation assay. At the same time point, we also measured kallikrein inhibition; in this assay kallikrein enzyme velocity measured in the post-dosing sample is compared to that in baseline pre-dosing samples. We made sure to activate this plasma to the contact activator to ensure that all of the pre-kallikrein present is compared to kallikrein. Again the results are very similar to those we saw in our Phase 1 study in healthy subjects at the 350 milligram once daily dose level. Turning now to a summary of the safety profile that we saw in the interim analysis. There were no serious adverse events and no severe drug related adverse events. As mentioned previously, two subjects discontinued 7353 study drugs early; one subject discontinued because of persistence of the pre-existing liver disorder. The other subject who discontinued study drug had intercurrent Gastroenteritis and developed abnormal liver function, these abnormalities result. The treatment emerging adverse events seen at least twice in the interim analysis are listed and included the common cold, diarrhea, flatulence, and fatigue. There were no clinically significant clinical examination findings and no clinically significant abnormalities of renal function test and electrolytes, hematology panels or year analysis. One subject, the completed treatment was noted to have an ILT level more than three times the upper limit of normal on the day 29 clinic visit. This subject had a complex medical history with colitis, fatty liver with baseline LSTs above the upper limit of normal and had been treated for more than 20 years with androgens with hereditary angioedema up until three years prior to study. In this population based on abnormalities of liver function are common, we will continue to carefully monitor all safety parameters as our clinical programs continues and look forward to seeing safety profile of 7353 in full study analysis. In summary, the interim analysis achieved all of its objectives. First and most important we saw a large treatment effect that was clinically meaningful, statistically significant, and statistically robust with 64% reduction in overall attack rate compared to placebo in the per-protocol analysis with a P value of 0.006 and 52% in the ITT analysis with a P value of 0.035. These results aren't particularly impressive given the relatively small Phase 2 interim analysis sample size. When we looked at angioedema attacks they were unequivocal and characterized by cripple swelling or the cutaneous ignosure of the disease including those that also had abdominal symptoms the reduction in attack rate was even more striking. Our analyses strongly suggest that some GI symptoms that are being recorded on the HAE diary when subjects have only those types of GI symptoms and not other symptoms with angioedema are in fact related to study drugs. Second, the observed safety and tolerability profile supports continued clinical trial of 7353. Third the drug levels that we achieved with once daily oral dosing of 350 milligrams greatly exceeded the proposed target range of efficacy supporting the study of lower dose levels. To help us think about those dose levels we review the available information on trough levels in dose ranging and Phase 3 trials of another kallikrein inhibitor namely CSL830 subcutaneous form of C1 inhibitor and compare those to trough levels of their drug. To do that, the levels of C1 inhibitor were compared to multiples of its 50% effective inhibitory concentration for kallikrein i.e. with EC50 and we did the same thing for BCX7353 levels using EC50. The left panel is the CSL830 data and the middle panel is 7353 plotted on the same scale. For 7353, we showed both the interim results of 350 milligram in this analysis and the levels of the indicated doses in the Phase 1 healthy subject trial. We have indicated our proposed effective target range of four to eight times the EC50 in the blue bar in each panel. The average level for C1 inhibitor in CSL Phase 3 study were approximately five to six times the EC50. The average baseline level without twice weekly CSL830 was about three times this EC50. So in other words twice weekly subcutaneous dosing of that drug on study increased the levels of that kallikrein inhibitor by two to three EC50 units. With the measured trough levels of 7353 in the APeX-1 interim analysis over 11 to 32 times with EC50, clearly we have plenty of room to lower the dose. As you know, we are already starting 250 milligrams and 125 milligram dose levels in APeX-1 Part 2. The right hand panel updates our previous stimulations of the proportionate subject that we expect to exceed different target levels of trough concentrations. What we do see is to add stimulations for target level of two times EC50 and we can see that with the dose of 62.5 milligrams once a day we would expect more than 50% of subject to exceed that target trough level and might expect to see benefit based on the CSL data. So with this said the interim analyses and reflections on the emerging dose response data from CSL, our confidence in the efficacy potential of lower doses of 7353 has increased. We have decided to expand the evaluation of the 125 milligrams and 250 milligrams dose cohorts and also evaluate some subjects at 62.5 milligrams. We are doing this by adding an additional double-blind placebo controlled Part 3 element to the APeX-1 trial. This path add six subjects each to the 125 milligrams and 250 milligram cohorts and six subjects at 62.5 milligram QD and two additional placebo subjects. At this stage, we have fully enrolled Part 1 and Part 2 is currently recruiting with eight randomized and six on screening. We very much look forward to seeing the results of Part 2 expected in the second quarter and then completing the trial. I could not be more pleased we had such strong results in this interim analysis of the APeX-1 trial. In all of our interactions with patients and expert physicians we are constantly reminded how this almost seriously impacts patients and that there is a strong medical need when all prophylaxis treatment. I would very much like to thank Dr. Emel Aygören, the principal investigator for the trial who helped us in fully announces you have seen today and encapsulate a special trip for several days from Frankfurt to the United States away from her duty clinic in order to help us go through the data. Emel is Head of the Centre for Hereditary Angioedema and a specialist in Internal Medicine and Hemostaseology in the Department of Child and Adolescent Medicine at Goethe University Hospital in Frankfurt, Germany. This clinic is very famous and cares for one of the largest cohort of patients with hereditary angioedema anywhere in the world. I would now like to invite Dr. Aygören to provide her perspectives on the interim analysis findings. Emel Aygören-Pürsün: Well thank you for the introduction. I want to draw your attention to the fact that the disorder that we are dealing with is a lifelong disorder that is very severe in many cases and is connected with episodic swelling of various body parts and one of the biggest limitations of that disease is that the tests are unpredictable and maybe even life threatening. The scientific literature has shown that in the patient population quality of life is significantly decreased and that many patients are hindered in their academic and professional lives. So when we look at that setting, we can only estimate what any reduction of the attack rates needs to patients especially if we look at the severely affected patients with a high attack frequency. And so the result of the interim analysis of our study are really striking given that we've had severe population in that study and that we have seen significant and pronounced therapeutic or rather prophylactic effect that was achieved by as a great class by an early nanostep [ph] medication given once daily. So from the patient perspective a further success of that prospect will have begun to grow with the pursuit really have made a benefit. For some patients may be even that's changing.

Thank you, Emel. It is now my pleasure to introduce Professor Bruce Zuraw, who is Division Chief and Professor of Medicine at the University of California, San Diego School of Medicine and Director of the United States Hereditary Angioedema Association, Angioedema Center. We have been privileged to had Professor Zuraw advice us on our HAEA program since it's inception and I would now like to invite Mr. Zuraw to provide his comments on the interim analysis findings.

Thank you, Bill. Let me also echo what Emel said I think that these are very encouraging exciting results. I'd also like to comment that I see a lot of patients with Hereditary Angioedema both at UCSD but as well in terms of meetings with the Hereditary Angioedema Association where we have patient summits and there is a lot of excitement about the possibility of an oral prophylactic treatment so, lot of patients are looking forward to a successful drug. My last comment relates to the difference between peripheral and abdominal attacks where I would agree with your comment that we have no basis for expecting that this, that there should be a real difference in terms of the pathophysiology of the disease and I think that the data for clear absorbable attacks really speaks to where the data lies and how this drug works so as the doses lowered in that Part 2 and 3 I expect that we're going to continued to see excellent and even better results. Thank you.

Great, thanks Bruce. Bruce and Emel will both the continuing on to answer questions that you may have. So let me wrap up the summary from this interim analysis is the drug works and we look forward to completing APeX-1 and moving on to Phase 3. As I said earlier patients have been patiently waiting for such a therapy. We will work very hard and go as fast as possible to get this drug to market so there waiting will be over. Let me wrap up by thanking all employees of BioCryst for their hard work and perseverance and commitment to taking us to a successful future and particular a special thanks to Bill and his team for the great work that they did on APeX-1. Thanks also to our investigators starting with the principle investigator Dr. Aygören and all the other investigators and their teams for the superb execution of this trial. I want to thank the patients and physicians like Professor Zuraw and many, many more who have been encouraging and reminding us of the importance of what we're working on. That completes our prepared remarks. We will now open it up for your questions.

Thank you. [Operator Instructions]. Our first question is from Jessica Fye with JPMorgan. You may begin.

Hey guys good morning. Thanks for taking my question. ApEX-1 Part 2 which sounds like it's underway do you have any indication of GI effects are reduced at the 125 milligram and 250 milligram doses in patients or should we take the evaluation of the 62.5 milligram dose as some indication that you're still team GI events that could be kind of misinterpreted as attacks?

Thanks for the question. The unblinded safety data that we have is what I presented today so everything else is blinded so we really can't comment on any ongoing safety. I think that as you've seen in the previous presentations over the last few months since Protected Zero in fact presented the CSL study data at the Allergy Accounting Meeting in November we have been thinking a lot about whether the trough levels support lower doses and we have really come to that conclusion and I think the interim analysis efficacy here is encouraging us to do that.

And just we added a slide at the very back after the Q&A headline slide that is actually a slide taken from our Phase 1 presentation that looks at the adverse events and so you can see very clearly the difference between the 350 milligram group and the 250 milligram and the 125 milligram in terms of GI events.

Okay, yes understood. I wasn't sure if there was any kind of fold of blinded from Part 2 that would give you kind of some optimism by looking at those lower doses definitely do have in the patients. And also curious if the evaluation of the 62.5 milligram dose are you trying to find ineffective dose or do you believe that that will have some more efficacy of the higher doses?

Again thanks for question in Phase 2 drug development, it's very important to try to demonstrate dose response because regulators and obviously the sponsor in five in this case really need to understand whether you can show that. And so with the dose range we are studying here once the study is completed with 350 milligrams, 250 milligrams, 125 milligrams, and 62.5 milligrams we will have the rich dataset of efficacy, safety, PK and PD and we will be looking for dose response in that. So I think that if everything looks great even at that dose that will be a good outcome. If some patients benefited 62.5 milligram that will be a good outcome and we will have the data we need to select doses for Phase 3.

Thank you. Our next question comes from Charles Duncan with Piper Jaffray. You may begin.

Hi guys, good morning first of all, congrats on these data especially the roughly 50% peripheral I can't for even rates. And thanks for taking my question; I guess I had a question first of all for one or both of the KOLs and then just a couple of questions for management. For the investigators, I'm wondering if you could provide a perspective, how often it seems like its not frequent but how often could you see clearly an abdominal attack without peripheral symptoms, do you see that at all?

Emel let me give it to you and we will pass it to Bruce. Emel Aygören-Pürsün: Yes, thank you. Thank you for that question, it is important to know that really about one-third of the attacks account for purely abdominal attacks and about one-third may be mixed attacks. According to how you look at the attacks this would be data from cross-sectional views. So these attacks will exist purely abdominal attacks and will curtail.

Thanks, Emel. Bruce?

I guess I would agree with what Emel said in terms of the frequency of the abdominal only attacks. I would also add that we are used to evaluating or trying to guess whether an attack is real or not and some of the parameters that Bill mentioned like response time, demand therapy if the attack doesn't respond that's often an indicator that maybe we are dealing with another cause for the abdominal distress but in general yes we do see these purely abdominal things.

Thanks, Bruce. Go ahead.

I was going to also ask the investigators whether or not the symptoms that they saw the AEs that were observed, I understand that you may be able show efficacy with improved tolerability but with the AEC could cause them to setting guess whether or not they want to use the drug in their patients?

So may be start again with Emel. Emel Aygören-Pürsün: I'm afraid I did not -- I missed the part of the question, could you maybe repeat the question, it is pretty difficult to hear for me.

Yes, would the tolerability profile cause you to wonder whether or not institute the drug with the patients? Understanding that of course you are going to study a lower dose in tolerability profile could improve.

I think what he is asking Emel is the safety and tolerability profile so far, is this the drug that you think you use in your patients? Emel Aygören-Pürsün: Yes we're all looking forward to the further part of the study with lower dosing on, especially in view of the fact that we know that the toxic effect of mostly dose related, so I think this would -- we would expect to be that less important in further study stages and we also have even the hope that may be that the attack or the efficacy would be increased by decreasing gastrointestinal side effect of the drug that might affect the efficacy of the prophylaxis drug.

Okay, thank you. Emel Aygören-Pürsün: I'm really optimistic about that.

Great, thank you. And Bruce your thoughts on the safety and tolerability profile?

I would say that from what we saw in this limited amount of data that I wouldn't be hesitant to use the drug. I think that we're all cognizant that it's a short exposure in a small group of patients in a scenario that we have always pay a lot of attention to, so as we get more data if it continues like this, I wouldn't be -- I would be happy to use the drug.

Great, thank you. Charles anything else?

And then just quick question for you or Bill, the trough level seemed high relative to say what we would predicate from the PK wondering if you have perspective on this and maybe what's going on with the drug. It seems positive that you could reduce the dosing and get more tolerability but I'm wondering about that? And then my second or last question is in terms of future study are you just relying on the improved dose response in terms of efficacy versus tolerability or are you going to improve the recording of GI symptoms through possibly reduce this potential compounding variable?

So let me start with the last part first. We also had the opportunity to talk with the couple of senior patient advisors about that data and they made a couple of interesting points along the lines of first of all the degree of anxiety and fear that patients have and their commitment to entering clinical studies like this. But you can imagine doing so, you don't know with your own placebo or active drug, you're wondering whether or not things will go well. I think that their point was that with the drug used chronically you learn how to take the drug and you learn how to take on systemic for example. So because we absolutely needed to have serial PK done in a rigorous way in APeX-1 the data has been attended to clinic, we wanted to dose it in the morning, so to get accurate data all of the drug administration is in the morning in this study. And we did instruct them to try to take the drug after food but what you have to -- what is real life, real life is these days, most people skip breakfast or grab [indiscernible] here in Europe or a Chile and may be once a week in the United States on the way to work with your favorite Starbucks or your favorite Sprint or something. So I think there's definitely an opportunity in the future study where we don't need that serial PK and all we need is population PK that can be taken at anytime to instruct subject to take the medicine after a full meal and do it at the same time every day, I think that that's the most obvious. Now we talked about those and as Emel pointed out and Bruce, I mean you would expect all adverse events, whatever they are to the list with lower doses. With regards to pharmacokinetics, it's actually right on target and in the slide where we lay out the three panels the middle panel shows you the mean and standard deviations for the 350 milligram dose level in the Phase 1 study and the data from APeX-1 and they are completely overlapping and providing us, I would say the APeX-1 trough levels are right in line with what we saw before. What we didn't have when we started the study was evidence of efficacy. Well now we have the evidence of efficacy and so I think that that plus to our analysis that I talked about in some detail give us confidence that we've only struck by a long way and we have plenty of room to lower the dose. Bruce one other comment I will make and I couldn't quite heave but I think you mentioned 50% reduction in peripheral attack three population it's actually better than that. So if you strip out the abdominal only and just look at the mixed and peripheral you end up with nine out of 14 attack free. Another way of looking at it is if you look at Slide 12 and look at -- we will go through both analyses, so two peripheral attacks versus 22 that's 91% difference in weeks two to four and to a protocol is six versus 25 weeks two to four in ITT. So that was an interesting how it helps generating analysis and let's say what we get with lot of doses.

And I just reinforce what Bill is saying; when we started with 350 milligram we are going all the way down to 62.5 milligram that's how we definitely believe we overshot.

Thank you. Our next question comes from Liisa Bayko with JMP Securities. You may begin.

Hi guys. Thanks for taking the question. Just to drill into the abdominal attacks a little bit more. Can you may be talk about little bit more about the timing of the attacks and that first period of time when you are trying to get up to steady state versus the sort of two to four weeks from off steady state. And then also just maybe a little more color on the kind of quality of the attacks, was it kind of obvious that maybe it was pain, was it relieved by a bound, I'm just giving an example versus something that really was more reminiscent to that or should you attack?

Sure. Yes thanks for the question Liisa. I think if you go to Slide 14 and 15 you can see the pattern of attacks by study day, so the first seven days is the first week obviously and there abdominal, if you look at the differences in just the overall pattern, the abdominal symptoms do happen in all the weeks of the study. To give you some color and why did the adjudicators note that these things are atypical. In some occasions there was a record an attack not being treated and lasting an extremely short amount of time and that's really compatible with the real abdominal attack of hereditary angioedema. So somebody would record I had swelling and pain but I didn't treated in vein an hour. And for example another example is the other extreme is here are symptoms recorded for four days in a row with abdominal symptoms only and the subject reach for their attack medicine which is perfectly reasonable ahead of dose didn't do anything. The symptoms persisted and they keep taking the study drugs. So those types of atypical features are really not compatible with angioedema and may be Emel and Bruce might like to comment on that. Emel Aygören-Pürsün: Yes I can only agree with what you said, Bill. They are attacks that aren't unanimously recognized as abdominal attacks and the differentiation is you're really done by either patient or giving acute therapy and seeing more of the therapeutic factor. So the differentiation is not always very easy that's what I can just say from clinical life.

Bruce? Thank you, Emel. Bruce?

Yes I would add that having served on some adjudication panels that as an adjudicator we are trying to be conservative and we would perhaps if we can't rule out an attack, so we say yes it could be an attack but it doesn't mean that the adjudicators believe that nearly was a true attack. I just would make that distinction.

Thank you and I would add in talking with a patient they said you can go out to dinner, have a bad meal and start to feel something and you worry it might be an attack and so you don't want it to get worse so you grab for your medicine. So it is -- it sounds like it is hard to differentiate.

Okay, great. Thank you. And then one thing you didn't really talk about at all was rash which was seen in some of your earlier studies, could you may be comment on if you observed any frequency differences between placebo et cetera?

There were no rashes reported in this dataset.

Okay.

I don't think we can conclude that the rate is different but I think the good news is it doesn't look like it went up after four weeks of treatment right.

Yes, great. Thank you. And then just final question obviously what you are going to try to do now is lower the dose, so you can kind of maybe lower the rate of the just side effects without lowering the overall efficacy and that's what we want to see. Just curious when those data for next cohorts, I know you are unwilling but when do you expect that we might can you give us some guidance of when we need to look for that data? Thank you.

Yes so if you look at Slide 20 Bill went over that Part 1 is fully enrolled and Part 2 has eight randomized and six in screen. So our confidence level is high that we will report out the Part 1, Part 2 total in the second quarter.

And would that be like Yache or would that be just be press release or what are you thinking?

I think we would do it like we did this. That that would be my sense, yes, looking certainly presenting more data.

Two, you've the data there or just curious.

No this relates I think that comes in March and so for the interim we can certainly consider doing something for that. But we'll absolutely take advantage of medical meetings and publications because we think this data is exciting.

And then actually just one more question I do have. We've been benchmarking what our expectations are quite a bit against what we have seen for Dyax. I was looking what the data you can see that there is a difference in baseline attack rate that's fairly significant. Can you comment on how that may -- how we should be thinking about these two data sets I know that there are different studies but just as a way to kind of look at everything is that difference in baseline attack rate meaningful in you view and how that, impact of things?

No, so just to mention what they are. So the baseline of attack rate studies about one attacks per week. Kind of memory tells me correctly in the Dyax Phase 1b it's about 0.34 or something round about attacks per week and maybe we could ask our principal investor in Protected Zero to comment on whether that's a meaningful difference. Emel Aygören-Pürsün: Yes, clinically speaking it's of course clinical meaningful difference and it does make sense to assume that its yes, how to achieve prophylactic effect in more in the affected patient group. So it's hard to compare and we have to wait for the results are coming now.

Yes, thanks Emel. Bruce?

Yes, it's something that it clearly indicates this would be a more severe group. I think that's all you could conclude from that.

Okay.

Yes. Then your question back to us was this is a drug. We have in effect, I've said all along and we showed you the data that Lynne had done with her team about the desire to have an oral drug in the preference. And so this is the drug with the data that we have. If we improve the results and we start seeing the lower doses and improved efficacy, I mean sky is the limit so.

Thank you. Our next question comes from Brian Abrahams with Jefferies. You may begin.

Hi, this is Marianne [ph] for Brian. Just wondering through the GI AEs versus attacks if there is a way to help better quantify differences may be with the biomarker in a future arm or study.

Hi, that's a very interesting though. We've tried to think a something along those lines and haven't come up with anything yet. But I think that that the types of strategies that we've talked about before in future studies like taking the drug with a full meal, I think will be quite beneficial. And if you think about just a drug if you had prescribed post July even a short course of antibiotics has been tolerated on a full stomach. So I think that’s a definition element. I'm sure dosing will help, I'm sure just experience with the drug in individuals will be an important thing.

Okay.

Let me just interpret once second Hey Bruce I know that you have to leave at the hour so, just want to say thank you for your participation and appreciate you joining us such an early morning or early time this morning in the West Coast.

Okay, well yes pleasure thank you. Let me just make one comment as I leave if I could certainly to that last question I mean that's a point that as an investigator we would love to be able to look at that data but the challenge for us is getting patients when they have a symptom to come in. And so if we could measure biomarkers at the time people report a possible attack it would be fantastic but it's not very practical and in terms of doing this study at least in my experience. Okay, thank you much and look forward to future results.

Thanks Bruce. Sorry to interpret go ahead with your rest of your question.

Sure. Thanks, Bruce. Forward the ALT patient he will remain on the study I was wondering if you can provide any additional details on that patient if the ALT elevation persisted and how long it took to resolve.

So the observation was made at the day 29 clinic visit and in that particular subject as a there were elevators, levels of baseline so just by the way of explanation, this is not a normal healthy subject study. So you have to allow some little room for abnormalities in clinical chemistry in the like at the screening test otherwise you end up having no patients on the study. So we allowed up to two times the upper limit, it has been less than two times upper limit of normal at a screening visit. One of the interesting phenomenon we have in this data set is just the variation overtime which is random fluctuation in clinical chemistry parameters like liver enzymes. So we saw quite a few subjects at the sites one visit on day one. So that's two or three weeks out the screening visit actually had increase over baseline liver function test values and I think on the graphics slide we put down what proportions were something like 36%, 28% something like that. Anyway that's quite a lot so approximately a third of the people coming into the study had significantly elevated liver enzymes with baseline. In this sample size before I get on to other comments in general with would regard to the resolution yes in the cases we serve elevated liver enzymes resolved and you would typically follow that in one or two weeks and if it's still elevated follow it for another couple of weeks there was a schedule day 42 safety follow-up visit in all cases and that elevated enzymes results. I think that we have to be cautious in interrupting all of this because it's a small study and because of the confounding factors we obviously can't rule out drug affect and in our consultations with our regulatory advisors and consultants that's pointed out that these things are commonly seeing in drug development, regulators are used to seeing and knowing how to deal with them and so let's tune for a minute that isn't real drug effect provided that the nature of this is similar to what we've seen here in our full data set for an NDA including a safety study in Phase 3. And the incidence lowered, then you would expect routine with a function test monitoring that might go into the label. So maybe I could ask Emel that type of monitoring product any routine practicing, looking out the patients with HAE currently. Emel Aygören-Pürsün: Yes, Bill absolutely this is the part of our routine especially in view of the fact that most of our patient to receive plasma for them. So we do have obligations follow live enzymes and value to these parameters and this is what we do regularly, every time the patient visits our center and what we see is indeed very frequent mind elevations of liver enzymes up to 1.5 approximate of normal. So this is nothing that would and you place any concern and we see that with that is growing to normal again when we review the patients without any secular.

Thank you. So obviously we'll continued to do the comprehensive site monitoring that we need to do during our clinical development program and click the data we need. Emel Aygören-Pürsün: Exactly.

And one last question Joe. I just wonder if you could provide an update on the formulations work that you're doing to get to one, yes. Could you expect to do any [indiscernible] work with that?

So given the does that we're studying our expectation is that we'll able to have one capsule in the -- they of formulation that we're using in the clinical experiments, simple powdering a capsule. It will be slightly more sophisticated than that I guess so that not in a dosage form and yes, I think reaching PK study is all we need, sure that we get the exposure in a similar way.

Yes, size of a capsule is very manageable compared to our previous program, so lot of good progress there.

Thank you. Our next question comes from Tazeen Ahmad with Bank of America. You may begin.

Hi, good morning, thanks for taking my question Bill I just have one clarification question on slide 17 here. The patient that have the ALT elevation greater than three times the upper limit of normal is that the same patient that has the gastroenteritis?

No, it's not. They are two different individuals. So patients who needs more than the three times upper limit of normal noted on day 29 was a patient with rather complex medical history of colitis with unspecified nature that's been going on for some time treated with an oral medicine. Fatty liver is a common observation in the general population as well; she has that and a long history of androgen used that has stopped three years previously. No, I think that that's not a lot of literature out here on the what happens when you stop androgens. I have asked several key opinion leaders about that and obviously it's a common elevated liver enzymes or call it any people currently taking androgens, we also know that they can patients can develop structural mover abnormalities like curiosis hepatitis and [indiscernible] and in rare cases carcinoma with the liver from long-term androgen administration and she doesn’t have evidence of those particular disorders, it does have a disorder study. The case with gastroenteritis is in the -- is a different case and that discontinued patient developed typical gastroenteritis symptoms and then later on in the course of that had an elevated ALT of 1.9 times up when the normal study drug was discontinued.

Okay. Thanks for that color. And then now that you're looking at the 62.5 mixed dose when do you think we could see the Part 3 data?

I think that's one is hard to predict since we haven't even screened anybody for that yet. So I would rather give you the results of Part 2. We should be well along understanding how what the pace is for Part 3. So we will give you that update when we give you the results of Part 2.

Okay. And maybe a last question, I know one of the KOLs has left but I just wanted to get a sense, I know with just limited data of short duration but based on the evidence that you presented so far and either Jon or Bill may be you could provide some color, how are physicians kind of looking at the profile of your drug overall versus what patients get from Sunrise?

Well that is a great question for Emel; I will let you take that one Emel. Emel Aygören-Pürsün: Yes I think we cannot compare both. We have different thoughts of administration which is never important and I think we have very limited data on 7353 at the moment, it is still too early to really to compare, I think they are apples and pears, and you cannot compare them.

Is it the same profile that makes them apples and pears or is it just not enough data? Emel Aygören-Pürsün: They are contextually different. We have C1 esterase inhibitor concentrated plasma derived one in one case and we have an orally given drug small equal in the other case and we have only very limited data concerning efficacy at the moment. I think I'm really looking forward to receiving the result of the whole study to see how the lower doses work. I think we have to see it also from a practical point of view, from a patients perspective an oral drug would -- I would say of course be preferable, this is what I hear from my patients. Although we have to admit that many patients get along their thing with IV injection but I think we have people show how these patients will receive an oral drug. So it's a big chance for the patient community and as Bruce pointed out they do see it as a big chance.

Okay.

Again it's patient choice, it's patient choice at the end of the day which I think is really important.

Okay. This then in line with the patients' choice comment though the desired drug is expected to have some late stage data released later this year. So how would you kind of introduce that and for the mix relative to what you have down again I appreciate that this data is early but for example the SubQ injections are not known to have GI related side effects, how do you think that would have patient preference?

Yes, listen I think, I don't think there is a perfect drug out there and so let's see what the data show, I think we look at the CSL pivotal study as kind of the goal standard and again it's not a perfect drug. And so from Emel's point let's see how the rest of the data unfolds in APeX-1. As I said before, I think with the profile we have some interim analysis, we have a drug, it's an oral it's once a day way more convenient than anything else and clearly some patients benefit from it. If that's benefiting recently and the assay profile improves then it's going to apply to more people. And so let's see how the program unfolds before reacting to say interim data.

Thank you. Our next question comes from Christopher James with Ladenburg Thalmann. You may begin.

Hi guys. Thanks for taking my questions and congrats on completion of Part 1, just a question on Part 3 based on your previous PK work with 125 milligram dose specifically do you consider the 62.5 mgs still 2b dosing or does the exposure level you've seen 125 you thought you might do DND?

No, I'd say once daily.

Yes, I think the difference is that blue range that we have, the green what kind of endogenous C1 you have, it might be a little too high.

Got it. Okay. And I know just a follow-up on previous question about the rashes, you said no rashes but were there any hypersensitivity reactions --

No.

And if so what grades?

No, there were none.

Okay. And then I guess finally, what's the peripheral filing and abdominal attack to patients generally if doses all together or what generally happens when?

I think that's another telling point here is other than the two discontinuations with study drug was stopped at about, I think end of the second week approximately and in the other case day 23. Other than those essentially everybody took all of their capsules everyday whether or not they had abdominal symptoms. So I think that speaks to the motivation of the patients who enrolled in our study to help develop an oral medicine.

Thank you. Our next question comes from Serge Belanger with Needham & Company. You may begin.

Hi good morning. Just a couple of questions. One related to this issue with attack related symptoms and abdominal HAE attacks, is that something you saw in the overall SAP program, anything similar to that came up in that study?

So I went back and looked at the overall proportion of patients in the other two studies who reported at least one of abdominal attacks during the study it was very similar in the placebo and active. But your question is actually very interesting one because what isn't confusing to patients and we were taught that when we spoke to some leading patient association colleagues is diarrheal and flatulence. So when and that comes out straightway in adverse event title. So wasn't confusing to patients, pain, nausea and vomiting is what they perceived as heralding an attack. So to give you a bit of color on this in the old days before there were effective acute treatments and these attacks went untreated. These abdominal attacks could become very, very severe to the extent requiring OP and analgesic in the emergency room and volume replacement therapy with intravenous crystalloid fluids because they were so much leakage of fluid, angioedema fluid into the small value and into the peritoneal cavity. And they could be extremely severe and particularly life threatening and in many cases there are people you hadn't yet been diagnosed with their disease result in unnecessary surgery for what the emergency room physician talk as an acute abdomen. So once you diagnose with the disease you really don't want to have any more of those. So if you get an abdominal symptom that you think might be heralding an attack and this is the case around the world whether or not you take any cross life therapy, patients the guidelines, statements that have been written in the United States and in Europe specify and encourage patients to treat as early as possible. And we know from excellent studies that both the Emel and Bruce have been participating in and leading over the years that if you treated early that makes a big difference in both be attack. So we would expect and we saw in this interim analysis and we expect to see all of that studies and we do see that patients treated early. So if you look at peripheral symptoms on the other hand they're often perceived as especially if in the hands or feet as not so urgent, so there's bit more of a delay typically in us, in every study we've done so far the time from the first symptom of an attack the time of treatment with the medicine is longer for those types of attack than it is for an abdominal attack. We did have two laryngeal attacks on the study in the interim analysis and both of those occurred in the placebo and that's the real -- that's where the anxiety and that goes up usually for obvious reasons because you could a 68 if it goes untreated and patients are very prompt to treat any early sign of a laryngeal attack and if doesn't responds adequately instructed to get to an emergency room as fast as possible. So we had 0 and 7353 and 2 on placebo in that care group.

Okay. When you look at placebo rates in APeX-1 here any surprises obviously placebo rates are a little different for the cohorts with abdominal attacks but excluding those ones do the placebo rates are they in line what you were projecting?

Absolutely so our screening attack rate minimum was two attacks a month and we anticipated about one attack per week average qualifying attack rate which is what we got and on study we got a roughly a 0.9 attack rate per week in total, just look at the total for placebo. So it's right in line with and I think that -- this is an internally valid experiment because of the randomized blinded nature of the experiment. So no there is nothing surprising here.

Thank you. [Operator Instructions]. Our next question comes from Rahul Jasuja with FBR & Company. Your may begin.

Hi guys good morning. Just a couple clarifications and question I have so obviously going forward only to rectify the issue with the abdominal or GI safety and tolerability is lower the dose. But in the event that's not a constant and this is a patient reporting issue would you be conducting this trial any differently in terms of how patient report this issue.

Yes, I think that's a great question, Rahul, and so what will be -- the way we develop the diary is to work with HAE expert end with a patient focus group and you have to be -- I mean, there's always an urge for a desire to try to collect a mountain of information in your diary and you can't do that. It has to be user friendly and it has to be a valid instrument. So but it's a very good question and we will be reviewing that to see if we can collect a little bit more information that would treat this out, for example you could say if it's are they symptoms typical to your illness or not and if they are not typical gives a bit more information. We haven't decided what to do yet but that's something that will certainly work through to help set up that Phase 3 program.

Okay, that's great. And the question that I have I think -- I'm not sure if I this information is out or maybe I just don't know it, is there a formally data that shows that there is no food effect, there is a food effect with 7353?

Yes, so again good question. So we did do a pilot food effect evaluation in the Phase 1 at the 250 milligram dose level and it was crystal clear. So the very regulated type of studies and there is something called a standard fatty meal which you probably don't want to eat, which has a lot of fat in it and it's specified in the regulation. So we had got our fasting and then we got those subjects back and go to the standards fatty mail and did it again. And in the fasting the only real difference we saw was as you might recall there was a double peak in the fasting represented internal [indiscernible] circulation of the drug some of it coming out in the wall and getting reabsorbed. So when you eat that slows that process down. You see a single peak bit later on and overall appropriately exposure was slightly higher after fatty meal but certainly no evidence that there would be less exposure after reading.

Yes and I think that actually leads to another answer to your first question is we are really making sure that people have a full stomach when they take the drug could have some effect on the adverse event profile as well. So recognize, as Bill said, for PK sampling purposes we have to do it in the morning and you have piece of toast and coffee and that's it and that's probably not a full stomach right so, we'll see if we can make adjustment on that in future study.

Okay that make sense. And then my final question here so looking at dosing and looking at future trials and the real work so to say obviously if you got, acute patient and have to have a certain number of attacks within this 28-day period. But going forward as you look at the whole repeater of HAE patients are we looking at clinical trial down the road that goes across three or four doses and different doses with different kind of patients given that fact that you only looked at the most acute right now and the real world probably somewhere in the middle.

Yes, I think it's a very interesting question I think after we have the full results from this study we will work out our proposed Phase 3 and discuss it with regulators and it's the guidance responses on Phase 3 trials strongly encourages sponsors to have more than one dose in a Phase 3 study. And we would be quite happy to take a couple of doses into Phase 3. Another potential thing to consider is how might Doctors use the drug in the real world, we think of that too. The main job of the Phase 3 is to confirm efficacy, rigorous experiment that's negotiated with the regulators so that we can secure the efficacy plans we need in our label.

So I think you pointed good one which is the Phase 1C inhibitor level carry depending on the scenario of disease. And so this study clearly they had very little gas in the tank and so used the analogy before and somebody’s got more perhaps they need a lower dose we will explore that later and we'll certainly get more information from that part 2 and part 3.

Great, that’s all I had. I look forward to part 2.

Great. Thanks, Rahul.

Thank you. I’m showing no further questions at this time. I will turn the call back over to Jon Stonehouse for closing remarks.

Great. So Emel thank you so much both for participating in the call with us today been our principle investigator and just the extremely important study for both the company and for patients and for spending time with us last week, taking time away from your busy practice to go through the data we really, really appreciate your support, so thank you. And then lastly I'd like to say thanks to all the investors. We appreciate your interest in BioCryst and we look forward to continue in this program forward and sharing all results with you. Have a good day.

Ladies and gentlemen this concludes today's conference. Thanks for your participation. Have a wonderful day.