Seeking Alpha
We cover over 5K calls/quarter
Profile| Send Message|
( followers)  

BioCryst Pharmaceuticals, Inc. (NASDAQ:BCRX)

July 22, 2013 8:30 am ET

Executives

Robert Bennett - Executive Director of Investor Relations & Operations

Jon P. Stonehouse - Chief Executive Officer, President and Executive Director

William P. Sheridan - Chief Medical Officer and Senior Vice President

Analysts

Liisa A. Bayko - JMP Securities LLC, Research Division

Rahul Jasuja - Noble Financial Group, Inc., Research Division

Steve Byrne - BofA Merrill Lynch, Research Division

Anupam Dalal

Thomas Wei - Jefferies & Company, Inc., Research Division

Operator

Good day, ladies and gentlemen, and welcome to the BioCryst BCX4161 Phase I Results and HAE Update Conference Call. [Operator Instructions] As a reminder, today's conference call is being recorded. I'd now like to turn the conference over to your host, Mr. Robert Bennett, Executive Director of Investor Relations. Please go ahead.

Robert Bennett

Thanks, Allie. Good morning, and welcome, everybody, to BioCryst's BCX4161 Phase I Results and HAE Program Update Conference Call. Today's press release and accompanying slides for this call are available on our website, biocryst.com. [Operator Instructions] Joining me on the call today are Jon Stonehouse, Chief Executive Officer; Doctor Bill Sheridan, Chief Medical Officer; and Tom Staab, Chief Financial Officer.

Before I begin, I will read the 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 the company website.

With that, I will turn the call over to Jon.

Jon P. Stonehouse

Thank you, Rob. Good morning, and thanks, everyone, for joining us today. I'm very pleased to once again be sharing encouraging news about the progress of our programs.

Before we get to the Phase I results of BCX4161, I wanted to take a moment to remind everyone of what we're focused on and where we're heading. The core value in our company is in the HAE program, and our goal is to be a leader in the prevention of HAE attacks. Today, we will share results of our successful Phase I BCX4161 trial in healthy volunteers, preview our Phase II development plan and update you regarding the progress in our second generation kallikrein inhibitor program. Our focus for the remainder of this year is to move into Phase IIa in high attack rate patients with 4161 and select the lead and start preclinical development for our second generation kallikrein inhibitor.

In addition, we are in the process of working to complete the new drug application for peramivir. This is being funded predominantly by HHS/BARDA and will be BioCryst's first NDA filed in the U.S. We intend to file by the end of the year.

Lastly, we continue to make progress towards securing government funding for our broad-spectrum antiviral program, BCX4430.

Our strategy in HAE is to create value from our oral kallikrein inhibitors by developing and commercializing them independently. This creates the most value for shareholders and is something we can manage given this is a rare disease. We couldn't be more excited about our first generation molecule 4161. The second generation kallikrein inhibitor will now have a high bar to get over but our goal is to further improve oral therapy. If we continue to be successful in advancing our program, we have a game changer for HAE patients and their physicians.

Our strategy for peramivir and 4430 is to use the revenue from these assets to help fund our HAE efforts. Peramivir revenue could help fund an HAE clinical trial and revenue from 4430 stockpiling could help fund the commercial launch of our HAE assets. This puts us in a unique position to have non-dilutive financing for activities that are typically expensive and burdensome for biotech companies.

So with this context, I will now turn it over to Bill to share the results of our Phase I trial. Bill?

William P. Sheridan

Thanks, Jon, and good morning, everyone.

I'm very excited to be able to share with you the results from our Phase I study of 4161 in healthy subjects. As the study met all of its goals, enabling this program to move forward into Phase II development. In my remarks, I will address the validity of kallikrein as a drug target for HAE, describe the potency of 4161, estimated target drug levels efficacy, go through the safety, PK and PD findings from the Phase 1, and provide an update on the second generation discovery program.

Slide 3 summarizes a compelling clinical and animal model evidence, validating plasma kallikrein as a drug target for HAE. This enzyme is formed during contact activation, amplified with inflammatory pathway and produces bradykinin, which causes the swelling characteristic of HAE attacks. Kallikrein's main natural inhibitor is a plasma protein called serpin peptidase inhibitor or C1 inhibitor. HAE is caused by disruption of the genes to C1 inhibitor. Reduced levels of this protein allow for uncontrolled kallikrein formation, resulting in acute episode of swelling caused by excess bradykinin. The discovery of high levels of bradykinin in the blood of HAE patients during attacks was an important finding. These high levels fall quickly after IV infusions of Cinryze, a C1 inhibitor product purified from plasma.

Ecallantide is a designer biologic kallikrein inhibitor given by subcutaneous injection and is approved for use in HAE. Animal models in C1 inhibitor knockout mice and C1 inhibitor knockdown mice have fully corroborated a critical and central role of kallikrein in HAE attacks. For example, infusion of ecallantide in mice that are totally deficient in C1 inhibitor restores a normal phenotype. There is really no doubt that kallikrein qualifies as a fully validated target in HAE.

Some of the major papers on these topics are listed on Slide 4. For those of you who want to review the peer review literature.

We have determined the potency of 4161 against kallikrein in plasma-based inhibition assays and compared its potency to that of C1 inhibitor using plasma samples donated by HAE patients during a period between attacks. In this assay, first, contact activation is triggered. And then, the resulting kallikrein activity is quantified by measuring fluorescence of the specific artificial substrate claved by kallikrein. We added by the 4161 was C1 inhibitor to the samples and compared kallikrein activity to parallel samples with no inhibitor present. The highest concentration of C1 inhibitor that we tested was equivalent to low limit of normal in healthy people and the highest concentration of 4161 tested was 1,000, nanomolar about 530 nanograms per mil.

Slide 5 shows the results in inhibition curve. It is obvious that 4161 is more potent than a C1 inhibitor. And when we do the calculations, the potency difference is about 15-fold. We can use this ratio to estimate the level of 4161 in the blood after oral dosing that should be effective in preventing HAE attacks.

Slide 6 overlays in the pink vertical bar the trough concentrations in the blood of HAE patients, those with IV Cinryze every 3 or 4 days. These concentrations of C1 inhibitor reduced kallikrein activity to about 10% to 20% of maximum seen in the assay. The concentrations of 4161 that produce equivalent inhibition of kallikrein are between 50 to 80 nanomolar or about 25 to 40 nanograms per mil, and are shown in the blue vertical bar. This gives us a conservative target for blood levels to shoot for in human studies of 4161, levels that should work in treatment of HAE.

Now let's turn to the results of the Phase I study. This study is the first ever for a small molecule plasma kallikrein inhibitor. As the first-in-human study of a new molecular entity, our goals, were to understand the preliminary short-term safety and tolerability of orally administered 4161, describe its pharmacokinetic profiles and assess whether there were measurable effects on the therapeutic target in HAE, namely plasma kallikrein.

The design of the trial is depicted in Slide 7. 87 healthy subjects completed the study. 30 subjects received a single dose of 4161. 40 were dosed with 4161 every 8 hours for 7 days and 17 received placebo. In a single dose cohorts, we studied 50 through 1,000 milligrams. And in the multiple dose cohorts, we studied 100 through 800 milligrams every 8 hours. We also completed a pilot food effect evaluation. The demographic characteristics were typical of healthy subjects in Phase I clinical studies.

Our administration of 4161 was generally safe and well tolerated as summarized on Slide 8. There were no adverse events that led to discontinuation of study drug, no serious adverse events, no dose limiting adverse events, no effects on coagulation assays, and no grade 3 or 4 clinical ECG adverse events, all of our 3 adverse events. The great majority of the adverse events were mild. There was 1 mild AE of elevation of liver enzymes, predominantly ALT with no elevation of bilirubin and no effect on Prothrombin time. The lab chemistry patent in this subject is commonly seen in placebo Phase I subjects in Phase I studies and has not caused us any concern.

Slide 9 tabulates the adverse events in subjects in the 7-day cohorts that occurred more than once, summing across cohorts.

Mild gastrointestinal AEs occurred more frequently in the highest dose cohort. In the 4161 preclinical toxicology program, we saw similar GI effects in vehicle control animals in nonhuman primates treated at high dose levels. This finding suggests that these mild events may be due to excipients in the formulation.

Exposure to 4161 was assessed in a traditional way. In a single dose cohort shown in Slide 10, exposure with dose proportional up to approximately 500 milligrams. Maximal drug concentrations were achieved approximately 2 hours post dose and terminal half life was about 10 to 12 hours. Food effect was modest, with evidence of some delay in absorption, and on average, lower peak levels. However, trough levels were maintained.

In the 7-day cohorts shown in Slide 11, steady state exposure was dose proportional through 400 milligrams every 8 hours with little additional exposure at the 800-milligram dose level. Steady state PK parameters showed minimal accumulation with geometric main accumulation ratio of approximately 1.3 followed by the Cmax and AUC. At the 400-milligram dose level, steady state Cmax was 152 nanograms per mil and C tel[ph] was 28.6 nanograms per mil. Coefficient variation were approximately 50% to 80%, which are within the range seen for marketed orally administered drugs given in fixed doses.

Slide 12 overlays the target range of blood levels for 4161 that we discussed earlier, shown in the blue horizontal bar on the actual PK results obtained after oral dosing.

We can see that the 400-milligram dose level, blood levels meet or exceed the target range for approximately 80% to 90% of the dosing interval. As you may recall, in preclinical studies, the oral bioavailability of 4161 was low, and we put considerable asset into formulation development for this project to create a drug product that we could test in the clinic. So we are very pleased to see these PK results. We assessed the pharmacodynamic effect of 4161 after oral dosing using the plasma kallikrein activity methods that I described earlier. The amount of kallikrein activity in the plasma after dosing with 4161 was compared to the amount present in day 1 pre-dose baseline samples. By definition, since this study was done in healthy subjects, all of the plasma samples assay had completely normal levels of C1 inhibitor. This means that we are measuring the effect of the achieved drug levels over and above the kallikrein inhibitory effect of normal concentrations of C1 inhibitor.

Recall that on Slide 5, the top concentration of C1 inhibitors spiked into the HAE patient plasma samples was at the low limit of normal. Here, we are resetting the baseline of the approximately 90% inhibition seen at this concentration of C1 inhibitor in the spiking experiments to 0 and asking whether the achieved 4161 exposures resulted in additional enzyme inhibition.

Slide 13 shows the results for the 10 subjects receiving 400 milligrams of 4161 3 times a day compared to the 4 placebo subjects enrolled in cohorts 3 and 4 of 7-day dosing. The assay was conducted on samples collected at steady state on day 7. For placebo, there was no significant change from day 1 pre-dose baseline as expected. In contrast, for all the time points measured, the samples from the 4161 subjects showed additional kallikrein inhibition in a pattern replicating the pattern of absorbed drug levels. Maximum kallikrein inhibition was around the time of maximum drug concentration and enzyme inhibition was seen throughout the dosing interval.

When we compare the degree of inhibition for 4161 and placebo by analysis of variance for p-value is less than 0.0001. These data clearly show that 4161 is hitting the target enzyme after oral dosing in healthy subjects and confirm the potential of 4161 as an investigational therapeutic in HAE.

Slide 14 compares the enzyme inhibition seen in the subject dosed at 400 milligrams and 800 milligrams. The degree of enzyme inhibition at 800 milligrams was no greater than for 400 milligrams, a result that could be expected from the PK results since there was little increase in drug levels in the blood when increasing the dose from 400 milligrams to 800 milligrams. We plan to share additional details of this groundbreaking Phase I study at an upcoming scientific meeting.

In summary, as shown on Slide 15, the safety, tolerability, drug exposure and on target kallikrein inhibition results from the Phase I study of 4161 in healthy subjects successfully met all study objectives. Really, I could not ask for better or higher quality results from a Phase I study, and our team has done a great job in designing and executing the trial. The safety, tolerability, PK and PD, strongly support moving to the next step in development of this specific oral therapy for HAE, the Phase II study in HAE patients who suffer from a high attack frequency.

The results also support the selection of 400 milligrams 3 times a day as a suitable dose regimen to test. We intend to initiate the proof of concept Phase IIa study by the fourth quarter of this year. Its basic design is shown in Slide 16. This randomized, placebo-controlled 2-period crossover study will enroll HAE patients who have experienced a documented historical attack frequency of at least 1 attack per week. 4161 will be administered at a dose of 400 milligrams 3 times a day for 28 days. Study endpoints will include attack frequency, safety and tolerability, attack severity and quality of life. And the results should provide a wealth of new information on the potential of 4161 in HAE treatment. The sample size of 25 is sufficient to observe the treatment effect and also to provide the safety basis for a future Phase IIb dose ranging study.

Finally, I would like to provide an update on our discovery program for second generation kallikrein inhibitors. And our main goals for this research as shown on Slide 17 were to improve oral bioavailability, while retaining high potency and high selectivity.

BioCryst's structure-based drug design scientists have continued to make excellent progress and the project is meeting all of its goals. We now have a series of bioavailable, potent and specific compounds that we are currently working through in order to pick 1 or more to advance to the next stage. Bioavailability has been greatly improved into the range of 20% to 60% compared to low single-digit percent for 4161. Potency is in a sub-nanomolar to low nanomolar range and specificity is excellent. The starting scaffold for all the compounds, by the way, has no activity against tissue factor, Factor VIIa. We are on target to advance 1 or more of these compounds into preclinical development by year end.

I would now like to hand the call back to Jon.

Jon P. Stonehouse

Thank you, Bill.

Before we open it up for your questions, I'd like to remind you of 1 more important point. Last fall, we revised our spending plan around a focused set of assets. We did so to be able to have enough cash runway to get to important value creating milestones. These milestones include the outcome of the Phase IIa for 4161 in HAE patients, selecting the second generation HAE compound and initiating preclinical development, the peramivir NDA filing and obtaining government funding for early development of BCX4430. So while we will always maintain our flexibility in using a variety of available levers to improve our cash position, we currently have sufficient cash to reach this important milestones. That concludes our prepared remarks. We now like to open it up for your questions.

Question-and-Answer Session

Operator

[Operator Instructions] Our first question comes from Liisa Bayko of JMP Securities.

Liisa A. Bayko - JMP Securities LLC, Research Division

I just wanted to kind of sort of better understand the level of inhibition that you're seeing. So could you maybe talk about in patients, what sort of kallikrein levels increase over healthy long periods you would see, what happens during attacks? And then for any other drugs that treat HAE, what sort of percent inhibition seems to be sufficient, if that makes sense? Because I know you're kind of -- it looks like right now, you're getting in a range of, let's say, 40% to 75%, so what are we seeing for maybe some of the other drugs?

William P. Sheridan

Lisa, thanks for the question. So the literature on kallikrein inhibition assays is pretty thin. In fact, we're not aware of other companies having developed these assays. So my remarks are really based on the evidence that we presented today and the work we've done at BioCryst. And it's very important to remember that in the healthy subjects in a Phase I study, they have completely normal levels of C1 inhibitor. And they're not patients with the hereditary angioedema. They're never going to have an attack, and so they have normal levels of kallikrein inhibition by definition. So having additional kallikrein inhibition is what you're seeing on that chart where we show the kallikrein inhibition results from the Phase I study. So you can think about it in a geometric way. So you get 90% of the possible inhibition in HAE subjects at the drug levels we're seeing in HAE patient plasma when you spike the drug in, and then when you give the drug to normal subjects, you get an additional 40% to 70% of whatever is less that is possible to inhibit. So there is no data out there that takes patients with HAE, given either C1 inhibitor or ecallantide, and then measures kallikrein inhibition in a contact activation stimulation assay of the sort that we described today. That data doesn't exist. So I think in summary, I think we're extremely pleased with the levels of inhibition we are seeing. And as noted on the chart, we're seeing that right throughout the dosing interval when we get to steady state, so that's very encouraging.

Liisa A. Bayko - JMP Securities LLC, Research Division

So if I could just clarify to make sure I understand. If a patient starts at a higher background level of kallikrein, would you expect then -- expect more inhibition than what you would see in healthy volunteers?

William P. Sheridan

So the -- maybe I can -- I very much appreciate the question. Maybe I can address it just by also pointing out that what we're doing in the assay is like artillery barrage of contact activation, using huge amounts of ammunition to stimulate it. That's not what's happening in hereditary angioedema. So these attacks are slowing on sets, slow to peak and they're not over and done within a few minutes. And I'm quite sure that in those circumstances, the circulating prekallikrein is not all getting activated to kallikrein. The assay is a totally different situation. It's a worst-case scenario where we're dumping in the contact activator ellagic acid in converting all of the prekallikrein to kallikrein within a couple of minutes and then measuring its activity. So I think in patients with HAE in between attacks, the bradykinin level is actually just at the upper limit of normal. So it's a traumatic trigger or an infection or having a period or some other trigger can locally stimulate more kallikrein production. So it's a much milder degree of kallikrein production in patients with HAE than what we're representing here in the assay. So for that reason, I think we can be pretty confident that the drug, given its characteristics has an excellent chance of working in studies in HAE patients. I think that's probably the best way to think about it. I wouldn't be -- focusing on the percentage inhibition in the assay in normal subjects, is a potentially -- you can't extrapolate that to how successful is the drug going to be in HAE patients. I think that the fact that we're seeing an on-target effect is the point.

Liisa A. Bayko - JMP Securities LLC, Research Division

Great, that's helpful. And then just 1 more question if I may. Kallikrein, is it stable throughout the day in sort of normal people?

William P. Sheridan

So the normal situation is you're not going to be measuring any kallikrein in the blood because you don't have ongoing contact activation in the fluid phase of the blood. There's a minor amount of contact activation from trivial trauma to the endothelial surface of blood vessels, and that's where the action is normally, so, the prekallikrein, which is not active, circulates with the kininogen, and it's like a part of the inflammatory cascade waiting for something to happen. So normally, in normal people, you're not going to see any kallikrein. And you have to do special assays in the lab to stimulate contact activation to even measure it. You can measure its precursor, prekallikrein, and that's stable throughout the day.

Liisa A. Bayko - JMP Securities LLC, Research Division

Okay, that's helpful. And then actually, just 1 more question. For Phase IIa, where are you going to be doing the studies?

William P. Sheridan

Well, we're very excited about the study. Planning is well-advanced and protocols finalized. We submitted the regulatory documentation. The study will be done in Germany. And Germany has an extremely well-organized medical system for treatment of HAE patients. So essentially every patient is managed out of 1 or 5 centers, and we have targeted several of those centers to complete the study. Some of the world experts in hereditary angioedema are the physicians who account for those patients and we are thrilled to be able to work with them on this study.

Operator

Our next question comes from Rahul Jasuja of Noble Capital Markets.

Rahul Jasuja - Noble Financial Group, Inc., Research Division

A few questions. So let me start with sort of looking -- I'm looking in my notes here and looking at the preclinical studies. So Bill -- and you didn't talk about it directly but I assume the answer is yes. The high concentrations of 4161 that you're seeing in your studies or high plasma concentrations without any safety issues and so on, so this will extrapolate to the EC 50 that's needed for bradykinin suppression, is that kind of how you saw in the preclinical studies?

William P. Sheridan

Yes. I think that all of the data is lining up very well. And you might recall that I think we had it on our website or on the poster at [indiscernible] when we did the PK, PD studies in rats, we saw the drug levels go up and down, and we saw the kallikrein inhibition have the same pattern in the rats, and we've replicated that now more importantly in healthy subjects with the drug levels going up and down, and the kallikrein inhibition exactly mirroring that pattern. So that's a very satisfying result.

Rahul Jasuja - Noble Financial Group, Inc., Research Division

Okay, good. And then the other point I wanted to ask is -- and I think looking at the quality of data you've got today, the answer probably here is yes as well. But just sort of to dot the I and cross the Ts here, so the inhibition of bradykinin that you're seeing or the inhibition of kallikrein, and I guess the inhibition of bradykinin subsequently would be much less than the prolongation of the Prothrombin time that is kind of all of the concern with this kind of therapy, so that's not an issue given the therapeutic window that you're seeing. Is that right?

William P. Sheridan

That is correct. So I think we're in the fortunate situation that the drug target is in the blood and also the potential adverse event target is in the blood. And we can -- we've got a lot of mileage in understanding what our therapeutic window was by measuring the Prothrombin time after spiking in 4161 into normal human plasma, and that data is in our poster. And the concentrations you need in order to cause any coagulation using that test are in the range of about 2,000 to 5,000 nanomols, and you take that line of thought 1 step further, and you can run studies in rats where you get very high doses of the drug IV and do bleeding time and we have that data on the poster as well. And in that case, you need at the order of 20,000 to 30,000 nanomols of the drug to have that toxic effect. So we're nowhere near those levels. And as you pointed out, the levels of drug needed to successfully inhibit the disease targets are much, much, much lower and we're achieving those levels very well in our clinical trial.

Rahul Jasuja - Noble Financial Group, Inc., Research Division

Okay. And just a couple sort of more questions on safety and tolerability here. Now number one, is there any relevance to patient-to-patient variation that needs to be tweaked as you go forward? What about the liver enzyme, you saw I guess 1 patient? And is there any effect with food -- I guess you said there's no effect with food intake?

William P. Sheridan

There's a modest effect with food intake. I think for the purposes of clinical research in the next study, we'll encourage patients to take the drug on an empty stomach. However, if the drug is taken after food, we get absorption, and the trough levels at the end of the dosing interval is still very good. So I think in the long run, it's likely not to be a concern. With regard to the liver enzyme, there is a very nice publication in British Journal of Clinical Pharmacology in 1999 looking at a whole series of placebo subjects in Phase I studies, in Phase I drug studies. So of course, none of them got the drug and there's about a 7.5% incidence of the type of liver enzyme changes that we saw in this particular individual treated at 100-milligram dose level. So we've reviewed that with some outside experts that are familiar with these type of safety interpretations and evaluations. And the conclusion that we are drawing right now is that it's a spurious random finding. Our first priority of course in all our clinical research is, patient safety, in this case, healthy subject safety. And we will continue, of course, through the development program to have very close safety monitoring, and we'll learn more about the drug. But right now, we're not worried about that. And I think I've forgotten your first question now.

Rahul Jasuja - Noble Financial Group, Inc., Research Division

Yes. Maybe I'm putting the cart before the horse here, but just basically, patient-to-patient variability [indiscernible]

William P. Sheridan

Right. I think that the degree of variation -- so there, I think there are a couple of different points to make at the variation. One is variation in exposure with the drug. I think we're quite comfortable with the degree of variation that we're seeing with the drug is perfectly acceptable. There are marketed drugs out there that have way higher variation and drug exposure than this some of the AIDS drugs, for example, that have been very successful, protease inhibitors, for example. And second source of variation, I'm not worried about at all, which is variation in the amount of residual C1 inhibitor in patient plasma, in patients with HAE. That's not going to make any difference to how well our drug works.

Rahul Jasuja - Noble Financial Group, Inc., Research Division

Okay. And then the next generation of 4161, I figured with this call, but this is going to be at 400 mgs for starting from now 3 times a day, where do you envision the next generation being in terms of dosing and frequency given the fact that it's dramatically superior than in terms of PK, PD?

Jon P. Stonehouse

So Rahul, this is Jon. It's hard to predict when you're still in the discovery phase. But with the oral bioavailability that Bill presented today, in the 20% to 60% range, that's multifold higher than 4161. And so the goal would be if you can get there, and again, I want to stress that we're still in the discovery phase. The goal would be 1 tablet once a day. But we're so excited about the 4161 results that as I said in the prepared remarks, the second gen has got a higher hurdle to jump over now because we're so pleased with the results we got with 4161.

Operator

Our next question comes from Steve Byrne of Bank of America.

Steve Byrne - BofA Merrill Lynch, Research Division

Bill, can you talk a little bit about the mechanism action here and how that differs from plasma derived, the kallikrein inhibitors that leads to the increased potency on a malaria basis?

William P. Sheridan

Sure. So I think let's start with the natural C1 inhibitor first, the natural kallikrein inhibitor. So it's a protein. And the way it works is by actually forming a bond, a covalent bond with the target, in this case kallikrein. And it flips the target over and makes a confirmational change in the target and stop the active site from working. And then that complex, that 1:1 molar complex is cleared from the circulation. So each time a molecule of C1 inhibitor inactivates kallikrein, that's 1 less molecule of C1 inhibitor that you've got circulating. So that's very interesting sort of mechanism. The 4161 molecule is a traditional pharmaceutical small molecule drug. And it's a traditional competitive enzyme inhibitor that binds with very high affinity to the enzyme active site. So it's a little bit different than the -- quite different than the way the C1 inhibitors works on kallikrein. So as a drug, it binds very tightly. It's not a covalent bond. It's competitive and it simply stops kallikrein from accessing its target. So the targets for kallikrein is kininogen. So the kallikrein target to its targets, because it can't make bradykinin.

Steve Byrne - BofA Merrill Lynch, Research Division

So if a C1 inhibitors have a 1:1 relationship with kallikrein, would your molecule be able to improve upon that?

William P. Sheridan

So I think the potency difference simply is the way of figuring out how much of our drug we need. I wouldn't read too much into that, honestly. I mean if it was equally potent, then we need just as much on a molar basis. If it was 100 times more potent, we need 100 less on a molar basis. So I think the most important point here is that we achieve the drug levels that we need.

Steve Byrne - BofA Merrill Lynch, Research Division

Okay. And is 4161 cleared to deliver and do you think that you would need to do an ADME study to determine what the fate is?

William P. Sheridan

So the preclinical information that we currently have is that we have no evidence of metabolism in liver microsome tests. And as you say, the next step is our ADME studies. The next step, in fact, it would be an ADME study in animals. And then we'll complete drug transporter studies and the like before we determine whether a human ADME study is going to be necessary. And as a small molecule, with the information we currently have, I would expect that it's probably cleared predominantly through renal filtration and excretion in the urine, but we don't currently have evidence to support that.

Steve Byrne - BofA Merrill Lynch, Research Division

Okay. And for the next generation molecules you're looking at, as you commented, they clearly have increased bioavailability, but do some of them also have an extended PK profile?

William P. Sheridan

So I think that we'll select 1 or more to move into preclinical development, and we'll pick the ones with the best PK profile as you suggest.

Jon P. Stonehouse

Yes. That's an important piece, right. It's not just how orally bioavailable they are, but do they have the half-life that allows for once a day dosing.

William P. Sheridan

I think in increased bioavailability gives you much greater flexibility in dosing.

Jon P. Stonehouse

Yes.

Operator

Our next question comes from Anup Dalal of KVP.

Anupam Dalal

I wanted to ask a question about the population variability you're seeing with respect to kallikrein inhibition. On Slide 13, Bill, you put an estimate of error and I just want to see if you could comment on sort of the population in a deviation. My calculations is about 15% [ph] to 20% is that what you have?

William P. Sheridan

Yes. I couldn't quite hear everything you said, but I think the variability is pretty modest.

Anupam Dalal

Okay. And then the next question is from a profile perspective in Phase II, can you give us any color on -- so instead of mean inhibition, another way to think about is proportion of the target population on desired threshold inhibition, for example, 50% inhibition. What about what you'd like to see in Phase II and how that compares with what we're seeing in Phase I, for example, at hour 8?

William P. Sheridan

So I think we'll learn a lot in the Phase II. At this stage, the goal of this small Phase IIa experiment will be to estimate the treatment effect, so we'll measure all the things we can measure. And I think we'll consider doing selected kallikrein inhibition assays during that study just to learn more. But the real important information is going to be to what extent can we reduce attack frequency because that's the way we'd like to use the drug. So I think that these assays are helpful at this stage of development. Once we start to get clinical data in HAE patients and measure attack frequency, my goal will be to transition away from this assay actually because it's a lot of effort. And on the other hand, measuring drug level is easy. So now being able to correlate, as you are saying, the drug levels with the reduction in attack frequency would be very helpful as we design the Phase IIb and the Phase III studies.

Anupam Dalal

Okay, good point. And let me just clarify. In the Phase I data that we have in front of us, what was at hour 8, what was the proportion of patients who had inhibition greater than 50%?

William P. Sheridan

That I can't read from the chart. I think what you can -- the way -- I would strongly caution against using the percentage inhibitions in healthy subjects and trying to extrapolate what does that mean. Does it mean it's only going to be 50% effective in HAE? That's not the right conclusion to draw. So I think the way to think about the question you're getting at would be to look at the PK on Slide 12. And for the vast majority of the dosing interval, you're going to get all of the subjects well above the target range. So another important point to make here is to ask the question, does it really matter if for a few hours a day that you're below the target range. And we've discussed that with our leading advisors who treat these patients. And they pointed out to us that when you're giving Cinryze, if somebody doesn't take their next dose, that doesn't mean they're immediately going to get an attack. They could go days or longer without getting an attack. And by definition, they're well below the target level that you need or that you achieve with the regular dosing of Cinryze and prophylaxis of HAE. So I think that our clinician expert advisors are quite excited by the data, and they can't wait to start the next study.

Jon P. Stonehouse

Yes. So we're pretty confident that if you've got coverage of 80% to 90% over the course of the day that you're going to likely have a good effect on reducing attack rates.

William P. Sheridan

Just remember that it's impossible to get 100% inhibition of any enzyme with any drug, right? So that's not the point. The point is in normal individuals, we can take that plasma and make it produce kallikrein, and that's what we are testing here. So that's a tough test, right.

Operator

[Operator Instructions] Our next question comes from Liisa Bayko with JMP Securities.

Liisa A. Bayko - JMP Securities LLC, Research Division

Just a follow-up on the last comment about Slide 12. So I understand that when you take -- there's not necessarily big difference 400 and 800 as you run it through the assay, but actually, if you look at just the levels, you get -- you seem to get greater inhibition or greater coverage over time with 800. Why not take 800 forward?

William P. Sheridan

So I think our logic in selecting the dose to test in the Phase IIa was, first of all, when we look at the safety, we did have 10 out of 12 subjects in the 800 milligram dose level who had 1 or other type of gastrointestinal adverse event. And looking at the pattern in total, it's similar to the pattern of a G.I. event that we saw in the monkeys treated at very high doses preclinically and it's likely related to vehicle. So we could be collecting some vehicle related adverse events at 800 milligrams. But it really is we didn't see that at the lower dose ranges. And when we're thinking about longer-term therapy, we want to keep patients on the drug, not have them go off the drug because of gastrointestinal intolerance so that's the fact that are considered. The second is that when you look at the activity of the drug as measured by the kallikrein inhibition assay, there was absolutely no difference between 800 and 400. And finally, the PK for 400 we think is quite acceptable. And so we don't see really much in the way of an advantage in pushing to 800 and it's a potential downside with the GI.

Liisa A. Bayko - JMP Securities LLC, Research Division

Okay, fair enough. And then 1 final question. I just want to ask about accumulation. Do you expect further accumulation beyond 7 days?

William P. Sheridan

No. We're at steady state. So with a half-life of 10 to 12 hours, you would reach steady-state within 40 to 50 hours. So certainly, by day 7, what you see in the PK profiles represent steady-state, and we've got 30% accumulation, which is actually very helpful for this drug. That's very helpful because at the start of the dosing interval and at the end of the dosing interval when you're taking it regularly, you have residual drug that is having an effect on the enzyme.

Operator

Our next question comes from Thomas Wei from Jefferies.

Thomas Wei - Jefferies & Company, Inc., Research Division

I'm sorry if you had already addressed this at some point on the call. But could you just talk about the number of pills that you think might need to be given at 400 milligrams?

Jon P. Stonehouse

So in the Phase IIa, it will be 4 capsules 3 times a day. Obviously, we're going to work to reduce that over time, and there's plenty of work that we can do to accomplish that, but for the Phase IIa, it will be 4 capsules 3 times a day.

Thomas Wei - Jefferies & Company, Inc., Research Division

And how large are these capsules?

Jon P. Stonehouse

I would say, there are 100-milligram obviously, and they're about the size of a Tylenol liquid gel. So very easy from a size perspective to swallow. They're not horse pills.

Thomas Wei - Jefferies & Company, Inc., Research Division

And the liver enzyme elevation case, could you just go through what is mild ALT elevation? What's a fold higher than the upper limit of normal? And was that, is that something -- could you just talk about how did it resolve? Was it just single measurement or was it repeated?

William P. Sheridan

If you look at -- you may not have heard my comments on the publication earlier. There's a publication in the British Journal of Clinical Pharmacology in 1999 that has a nice chart in it that shows the pattern of rise and fall in the ALT in placebo subjects in Phase I studies and a type of an event that happens in that series, about 7.5% at the time. It was very similar to that in terms of onset. So the onset was on day 7, and then it rose and fell and recovered spontaneously. The mild moderate severe type of classification, mild was the investigator's overall assessment of the AE. So twice the upper limit of normal or something like that. And as I mentioned earlier, there were no changes in Prothrombin time or in bilirubin in this patient, and the enzyme abnormality were focused around ALT predominantly. So I think that when we discussed this case with experts in the field, their assessment is that it follows the type of random event thing that you can see when you put people in the Phase I unit, change their diet and they eat different things, and you can get a liver enzyme abnormality happening spuriously in these types of studies. So does that mean that we can rule out a drug effect? Well, no, you can never do that. But it doesn't have the hallmarks of a drug effect. We certainly will continue to collect blood chemistries, hematology, ECGs and clinical adverse events in urinalysis throughout our clinical studies with the compound, and we'll learn more about the safety. But right now, on the basis of what I described, we're not viewing this as a concern.

Thomas Wei - Jefferies & Company, Inc., Research Division

And then just lastly. What about the dizziness, lightheadedness, seen in both in the single dose and in the multi-dose study? Is that like a first dose effect? Is that something that persisted for these patients? Can you describe a little bit more about that?

William P. Sheridan

Sure. In each case, it was -- there were faced with vasovagal symptoms that any of us can get if we lie down for a while and then stand up quickly. And in 1 case, it was related to such as if we take [ph] a look at the PK samples and this type of study, you leave an indwelling IV cannula and cap it off with a little lock or something like that. The subject bumped the indwelling cannula and having a vasovagal response with disturbance of the vein is commonly reported. In fact, in the old days when IVs got first introduced, people had fresh cuts as in putting in an IV because they were worried about causing a vasovagal reaction. So these things are highly likely to be unrelated to study drugs.

Jon P. Stonehouse

They're pretty common.

William P. Sheridan

Very common, yes. And you've got people resting all day and if they get up quickly, they feel a bit lightheaded for a second.

Operator

I'm showing no further questions at this time. I'd like to turn the conference back over to Mr. Jon Stonehouse for any closing remarks.

Jon P. Stonehouse

Thank you. So it's really nice to have some wind in our sail again. And I just like to thank, first off, our employees for staying very diligent and focused, and doing a fantastic job of executing against this trial. It's the focus that we're working in the clinical development group, the CMC group and also people running the samples in our biology labs, so just a great, great effort overall. And then lastly, I'd like to thank those investors that hung with us through the tough period. It's an exciting period for us now. And we really appreciate those investors that stuck with us through the tough times. And we look forward to continuing to update you as we progress through the course of the remainder of this year. Thank you very much, and have a great day.

Operator

Ladies and gentlemen, this does conclude today's conference. You may all disconnect, and have a wonderful day.

Copyright policy: All transcripts on this site are the copyright of Seeking Alpha. However, we view them as an important resource for bloggers and journalists, and are excited to contribute to the democratization of financial information on the Internet. (Until now investors have had to pay thousands of dollars in subscription fees for transcripts.) So our reproduction policy is as follows: You may quote up to 400 words of any transcript on the condition that you attribute the transcript to Seeking Alpha and either link to the original transcript or to www.SeekingAlpha.com. All other use is prohibited.

THE INFORMATION CONTAINED HERE IS A TEXTUAL REPRESENTATION OF THE APPLICABLE COMPANY'S CONFERENCE CALL, CONFERENCE PRESENTATION OR OTHER AUDIO PRESENTATION, AND WHILE EFFORTS ARE MADE TO PROVIDE AN ACCURATE TRANSCRIPTION, THERE MAY BE MATERIAL ERRORS, OMISSIONS, OR INACCURACIES IN THE REPORTING OF THE SUBSTANCE OF THE AUDIO PRESENTATIONS. IN NO WAY DOES SEEKING ALPHA ASSUME ANY RESPONSIBILITY FOR ANY INVESTMENT OR OTHER DECISIONS MADE BASED UPON THE INFORMATION PROVIDED ON THIS WEB SITE OR IN ANY TRANSCRIPT. USERS ARE ADVISED TO REVIEW THE APPLICABLE COMPANY'S AUDIO PRESENTATION ITSELF AND THE APPLICABLE COMPANY'S SEC FILINGS BEFORE MAKING ANY INVESTMENT OR OTHER DECISIONS.

If you have any additional questions about our online transcripts, please contact us at: transcripts@seekingalpha.com. Thank you!

Source: BioCryst Pharmaceuticals, Inc. (BCRX) Discusses BCX4161 Phase I Results and HAE Update (Transcript)
This Transcript
All Transcripts