Below is the transcript of the corporate presentation of Portola Pharmaceuticals, Inc. (NASDAQ:PTLA) held on Monday, January 12, 2015, 12:00 p.m. PT. The company presented the results from the first part of the Phase 3 ANNEXA study, which is evaluating the safety and efficacy of Andexanet Alfa with the Factor Xa inhibitor Xarelto (Rivaroxaban). They also announced the start of the ongoing second part of the confirmatory clinical trial.
Portola Pharmaceuticals, Inc. (NASDAQ:PTLA)is a bio pharmaceutical company operating in the United States. The company develops therapeutic products in the fields of thrombosis, hematologic disorders, and inflammation. It is developing andexanet alfa for patients who are on Factor Xa inhibitors who are having major bleeding episodes or would require immediate surgery.
Company Representatives:
William Lis – Chief Executive Officer,Portola Pharmaceuticals, Inc.
Alexander Gold – Senior Vice President, Clinical Development, Portola Pharmaceuticals, Inc.
Operator
Thank you for joining the Portola Pharmaceuticals conference call. I will now pass the call to Bill Lis, CEO of Portola.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
Good afternoon and thank you to what we are calling our second annual off Broadway presentation at J.P. Morgan. I am going to go through slides and then we will have a question-and-answer following.
Here is our forward-looking statement. Where were we at Portola? We are continued to be excited about the ability to advance this company’s breakthrough products, specifically in the area of blood clot and blood cancers. We expect to advance them to the market independently. We have three wholly-owned potentially ground breaking products that focused on hospital and specialty-based markets discovered by Portola scientists. The management team which continues to grow in building our capabilities to build an enduring company is proven. We have done this before.
What is exciting is there is near-term pivotal data some of which we have presented over the last week and what we expect over 2015 and 2016 in preparation for a number of FDA filings of these products over the next few years.
Here are the slides. I will say what I have continued to say about this slide. It is late stage. It is unique because we have taken a biomarker, a genetic approach for the clinical development of all of our programs. Betrixaban, our oral Factor Xa inhibitor is now 65% enrolled in its pivotal Phase 3 clinical trial. We expect to report data early next year and file the NDA for this drug if successful next year. Andexanet Alfa, our FDA-designated breakthrough therapy has now completed and reported two of a series of Phase 3 clinical trials designed for conditional approval.
Also, just today, we announced the start and the design of the confirmatory Phase 4 clinical trial in agreement with the FDA. Now, we have a total package for the filing for the accelerated approval. We expect to file a BLA this year and launch this drug next year as our first product.
Cerdulatinib, our compound that targets B-cell pathway of blood cancers is unique. The mechanism of action of this drug is unique. We think we are starting to see some of the clinical activity that we projected we would see by targeting two important stimulating pathways in many of these hematologic cancers. We just announced that we are advancing this into the expansion phase of the clinical trial. As you look at this, you could start to see the setup of a series of commercially improved products. One in 2016, one in 2017 and then potentially one very soon thereafter. We also have the Syk-selective partnership with Biogen Idec that continues at a very slow phase.
What is going to drive value for us? It is the continued execution on our milestones. We demonstrated a significant number of achievements in 2015. Betrixaban with its enrollment. We had three positive safety reviews. The FDA has allowed us to amend the protocol to increase the probability of success based on using a bio marker for the primary analysis, patients that are enrolled based on a bio marker. In February, we will do a futility analysis on this clinical trial. If successful, we believe that will give us momentum towards the completion and the read out of the clinical trial.
Andexanet Alfa last year, not only positive Phase 3 data for submission of the conditional approval but additional Phase 2 data with edoxaban and enoxaparin, and now, we see the initiation and agreement with the FDA on the Phase 4 trial was a significant accomplishment.
Cerdulatinib, you will see even more data today of the positive responses we are starting to accumulate as we increase the dose. From a corporate standpoint, we are very successful with an additional follow-on last year and the indefinite commercial manufacturing agreements that we did with both CMC Biologics and Lonza, taking a dual-source approach to not only mitigate risk but allow us to launch on time and then extend the product globally. This is an important slide because it talks about the amount of leverage we have in the thrombosis space with our oral factor Xa inhibitor and andexanet.
On the left hand side of the slide on Slide 6 is the current projections for the novel oral anticoagulant, now expected to achieve $13 billion as a franchise. We see the market in two spheres, from two sides. One, how do we compete in the oral factor Xa inhibitor market with our differentiated oral factor Xa and the betrixaban? We see that opportunity by going into a specific indication, being the first into that market and being standard of care, that is acute medically ill. A $3 billion to $4 billion indication in and of itself and then also the antidote. The antidote is an important component of the anticoagulant market. At this point, we are ahead of the competition and have the potential and have the only and first true antidote onto the market next year.
To give you a better sense of where this market is going, and again, it drives both the opportunity for betrixaban and the antidote, we look on the side of the screen here. Currently, a drug like Xarelto has five indications already.Pradaxa,edoxaban, and apixaban of BMS Pfizer are looking to catch up to that. There are future indications as well. All this evolves into the future, but there are additional indications that our competitors are pursuing as well. Again, we are wellahead by years of our competitors in acute medically ill. At this point, only J&J and Bayer have made an indication that they are going continue to pursue this indication.
Again, what do we talk about when we say acute medically ill? We are really talking about 24 million patients in the G7 that currently have an indication in the hospital or prevention of VTEs, where the medical need is pretty simple. Despite the use of Lovenox and injectable agents this year in those territories, there will be over one million blood clots and 150,000 death, just in this patient population.
We start to accumulate this amount of deaths on an annual basis and then you start to put even now in the G7. That is more death than you see in the combined hepatitis, AIDS, and the combination of all the cancer indications. That is a pretty big human health issue that we are tackling in acute medically ill.
Why do we think we will succeed? The properties of betrixaban are unique. This is not just from a clinical standpoint, from a commercial standpoint if we do get there first with differentiating outcomes. This drug really has the only true once-daily half-life. That is very, very important from an efficacy and safety standpoint. Lowest renal clearance and not metabolized by CYP3A4. It is just a more stable drug when you talk about blood concentration as being an important parameter of defining or determining efficacy and safety. These three characteristics are clearly differentiated from all of the other agents.
We think it goes well from a clinical but also commercial standpoint. What are trying to accomplish? I mean really what is the goal? I think the goal is there are some limitations for the injectable agents. There are some limitations in the hospital. We mean to address those. High renal clearance, injectable agents that cause hematomas, excess bleeding, high cost, we mean to address those limitations. The real goal is to address the fact that nothing is approved once the patient if discharged from the hospital. I mentioned those million VTEs in this population, the 150,000 deaths in this population. The majority of that are happening in this time period where there is nothing approved.
That goal just sets up the design of the clinical trial which is you randomize patients to either the injectable agent standard of care, Lovenox, or betrixaban for the hospital period, so head-to-head during that period and then, betrixaban versus placebo for the remaining time period. That is why we say that 75% or 80% of the duration of this trial is really placebo-controlled trial.
Driving the value or the likelihood of success, is really using a D-dimer blood mark to identify the most high-risk patient population and then studying versus placebo.We know we are going to see effect based on what we see in the clinical trials. The question is, are you going to see an off effect and/or you are not going to see the excess of bleeding that was seen previously with drugs such as Xarelto. Good thing is we are over 65% enrolled. We are enrolling on a very brisk pace at this point. Each month now, the enrollment is higher than the last. What is most important is we have been very open and transparent. We look at pooled, blinded aggregate data. Right now, we are on target. We do not know if the drug is having effect but we look at pooled blinded aggregate data.
We set up to do, which again, was something unique and different. When we say we are going to look at higher event rate, we are tracking towards that. We have been tracking towards that for a long period of time and so the arrow bars around that are starting to narrow a little bit. We do not know what will happen in the remaining 35%, but if we stay where we are, we will hit the target at least of event rate.
What does that mean? What we intended to do is real simple. We took for example Magellan. What did J&J do in their first trial? That was partially successful, but not enough to give them an FDA approval. You got 5%, somewhat 6% event rate in the control arm, 4.4%, almost a 25% relative risk reduction. What we said is that in the patient population, if you look at the analysis that has higher events and higher magnitude of benefit from the drug – and that is this patient population primarily based on D-dimer or age – if you take a look at what we are trying to accomplish and what we are seeing, I already told you, on the pooled blinded aggregated event rate, the aggregated event rate is higher. We are not seeing this. We are seeing this. The question I think that we have right now is if we continue to see that, are we going to have this magnitude of benefit and are we not going to see the excess of bleeding. That is really what we are looking at here.
As we go on, we believe again, we start to build momentum and see that the probability of succeeding continues to move incrementally higher. We are going to do a futility analysis in February. If we’re wrong, we are going to know. If we are successful in the futility analysis, I think it is going to give us momentum to the finish line.
I told you how we think we figured out how to get efficacy greater than what has been seen before and really identify the patients who truly need the medication or extended duration prophylaxis. There is the important side of it. It is not only patient selection, it is always dose.
This is the model data. When we did our Phase 2 clinical trial, what we did is we tried to analyze a really important PD market to pick our dose. You know we did is we modeled or we assessed thrombin generation inhibition, so all these drugs inhibit. They all inhibit the generation of thrombin. We took what is currently a very well-established standard by warfarin. Warfarin was used in our Phase 2 clinical trial. Simply what you want to do is you want to get a level of inhibition of thrombin generation, above that which can be measured by an INR which is well-established with warfarin. You want to get more than two from an INR reading because that is what allows you to prevent clot, but you do not want to exceed three because that is when you get bleeding.
When we had our 80 mg dose in our Phase 2 trial – this is the PDcurve right here –we wanted to kind of stay within that range. We wanted to get a lot of it early on, a nice bolus of it because we are in the acute setting and then we wanted to sustain that with once-daily dosing. How is that different than an apixaban dose or a Xarelto dose in this indication? Here is the Xarelto dose. It has a wide variation in fluctuation, has a very high concentration very early on because that is a short half-life. You got to give a lot of it. You got to give a lot of it for it to be around for 24 hours. Then you see the apixaban dose. It has got a BID profile. If you start to administer it without a good bolus in the beginning, you start to see you have a little bit less, maybe, of where you want to be.We think, in this indication previously, it is our hypothesis. It is our hypothesis that Xarelto is a little bit overdosed and apixaban was a little longer dosed. What we said is we picked a better patient population for having higher events and we think we got the dose a little bit better.
If we are successful, this is the… boy, there is just not too many value proposition throughout there in the pharmaceutical business or biotech business right now. We can build a billion dollar franchise with a clear value proposition that says we prevent clots and deaths associated with these blood clots. We can reduce hospitalization, readmission costs, and we can do it at an acquisition cost that is lower in the United States than the generic price of the standard of care. There are not too many drugs that can say that. That is why we think it is such a compelling value driver for this company over the longterm.
Andexanet alfa, this is the antidote. It is real clear now that what we had projected many years ago is starting to happen and Jason, you asked about it. The hospital admissions due to bleeding, they are going to up. If you look at the 12 months, September-to-September of 2013, March-to-March of ‘12 to ‘13, the hospital admissions in factor Xa inhibitor-treated patients went from about 17,000 to 30,000 and that is just Xarelto and Eliquis, just those two. Lovenox is staying about the same because itsuse is kind of flattening out. As the use grows, so does this piece of the pie.
That 30% of all the hospital admission bleeds on anticoagulants now are associated with a factor Xa inhibitor, low-molecular-weight heparin injectable, or the orals and that is going to continue to grow. That is going to continue to grow. It is growing at a rate that we would have predicted from the Phase 3 clinical trials. It is not just the rate at which they are being admitted, but who are these patients? What is the morbidity? Jason, you asked about how you are going to profile these patients to determine who really needs it?
We are going to start to understand a little bit more about the morbidity of these patients, mortality of these patients. We are just learning about it. The costs associated with these patients. The top tier of about 15% of patients, cost of $100,000 to treat these patients. These are expensive patients for a hospital and it causes morbidity and mortality. That is what we are trying to address. We believe we are really setup to monetize around 500,000 patients who may benefit from an antidote by 2020.
The question for us is do we target all 500,000 of those or do we target a narrower group? Because we have more benefit, there is more urgency, we can get more adaption. We have more pricing leverage. Those decisions we will make over the next 12 to 18 months. I think most of you know the mechanism of action modified a version of human factor Xa; two modifications made to it primarily to render it not procoagulant or anticoagulant. The good thing is that it is very, very specific – very, very specific –it is different than anything else that is being developed, not only based on its specificity as a recombinant protein but also its half-life. You basically can turn this on and turn it off. We think that is really, really important because of its onset of action which is immediate and its pharmacodynamic half-life which is fairly short. You can almost turn it on and off. In the acute setting, that is all clinicians want, a little bit of control. I think it is specificity and it is on-and-off rate or something unique to anything being developed. I think it is one of the reasons we were granted breakthrough status by the FDA.
This is the conditional, when you say pivotal trials for conditional approval. Right now, we completed two of them, Eliquis and Xarelto, randomized patients who are in steady state, not patients but healthy volunteers who are on steady-state factor Xa inhibitor to andexanet or placebo and measure its ability to reverse the anticoagulant activity measured by primarily factor Xa inhibitor units and also on a secondary basis, normalization of thrombin generation. We do a short duration and a longer duration. Just to mirror what we think is going to be needed in the clinical practice.
This is the data from what was called ANNEXA-A. This is the reversal of Andexanet on the left hand margin. These are anti-Xa units. This is the validated enzymatic activity of the factor Xa inhibitors. This is concentration that is of the atrial fibrillation dose of apixaban at steady-state. You can see at the first time, you measured after the completion of the infusion. It is roughly to well below 90%. All 24 of 24 subjects are greater than 90% reversal. The consistency, look at the arrow bars around that. That is important because you are going to look at some other agents that are being used. What is important is look at the margin of arrow around this drug given as a bolus followed by infusion.
The important thing is I think the specificity of this compound is really well-tolerated, and I think that is going to be important when we get to the market because we are going to be there without having a lot of data in patients, so the safety profiles I think are just going to be very, very important for its adoption. This is what we announced last Friday, that the results of the ANNEXA-R, which is the reversal of rivaroxaban with the bolus only, so the short duration, was very consistent. We met all the primary efficacy endpoints, met all the secondary endpoints, high statistical significance and again, welltolerated, no SAEs, important antibodies to factor X or factor Xa. One of those things we continue to watch, if you say, where is the Achilles heel maybe. These are the things we continue to watch.Thus far, we have got a pretty good profile. I am not going to say anything more because the results are going to be presented in oral presentation at the American College of Cardiology.
Here is what we announced today and that is the design and the start of our ongoing confirmatory clinical trial. This was a significant effort. The accelerated approval, we are doing something unprecedented here. We think we are doing something unprecedented with betrixaban based on the biomarker approach and the statistical analysis approach, but we are really doing something unique and groundbreaking here. It will be an accelerated approval, as we said, based on the PD data from the Phrase 3 trials and healthy volunteers and then the confirmatory trial of that is ongoing. That is the package that we agreed to with the FDA. They said, “Send us greater than 10 patients’ worth of data from this trial along with your healthy volunteer studies for approval.” That is what we intend to do.
What if it is a single-arm study, we are not required to randomize patients which we did not think was ethical and we did not think it was possible. After hard work with the FDA, they agreed. That 270 patients that are treated with a factor Xa inhibitor and come to the hospital and are admitted for major bleed. That is who these patients are. There are certain exclusion criteria. We have a co-primary endpoint, the same primary endpoint that we had in de facto Phase 2 and Phase 3 that is factor Xa levels and then the achievement of effective hemostasis. We are going publish with just what that means.
What I will tell you is this, the faster you get hemostasis, the more effective we are going to define the hemostasis. What we are trying to do is get a certain percentage of patients that all have what we call effective hemostasis. It is compared versus a historical control from the antidote, or I should say, reversal agent that is used for Warfarin. We will study during this kind of first 12-hour period and then we will do a 45-day safety followup.
I think it is important to start, we are hearing a lot about who the competition is. They are behind us but we are hearing a lot of about who they are. We are starting to define who we are versus who they are. Right now, you have andexanet which is a recombinant protein. You have a small molecule inhibitor called PER977. We are unclear of its mechanism of action. Then you have 4-Factor PCCs. These are the factor II, VII, IX and X factor replacements that are approved for warfarin, but not currently being studied in a pivotal way for factor Xa inhibitors.
All I am going to say about this slide is we are going to start to spend more time here. There are five factors that we discussed with the parameters. We discussed with the FDA to give us an accelerated approval, made them comfortable approving a drug based on healthy volunteer in an accelerated way. That is understanding of the mechanism of action. That is a clear activity against PD markers that are validated, anti-factor Xa units, normalization of thrombin generation, discussion on the half-life and adverse events. These are the five parameters that we discussed with the FDA to come up with a package for accelerated approval.
None of the other agents have demonstrated in these areas what we have demonstrated, not this [per sphere] compound and certainly not 4-Factor PCCs. As far as we know, the companies are not even running trials with 4-Factor PCCs, the company that manufactures this. What we do know as our colleagues, the manufacturers of the factor Xa inhibitors are conducting some things, trying to look for some things here. What is important is if you look at 4-Factor PCCs, there is a poor biological rationale for why this could reverse factor Xa inhibitors if you use these parameters. There is clear in the label, warning for the downside of using factor replacement to restore hemostasis. That is the blackbox warning for strokes and myocardial infarction. What was interesting is it was just data presented on the ability of this drug or this drug not to reverse anti-factor Xa inhibitors and that was just done at ASH in December.
What they found is there was no measurable effect on anti-factor Xa inhibitor activity. When they looked at normalization of thrombin generation, it did some, but it did not achieve the statistical significance or the primary endpoints that were defined by the company who ran the trial. I believe BMS run the trial. There is some information out there in a press release and other that is a little bit misleading because it suggests that there was normalization of thrombin generation. There was, but it did not achieve statistical significance and it did not do it early. It did it late, mostly when the drug was starting to be eliminated.
We just want to clear the air and make sure you folks understand that the 4-Factor PCCs, they not only have a poor biological rationale but the data that is coming out does not meet the criteria that we have started to establish with the FDA that would grant this or definitive demonstration of activity or a reversal because people use the word reversal interchangeably. We think this is what defines reversal, not what we have seen with 4-Factor PCC in the reversal of Eliquis. We will continue to educate around that fact.
We have been asked a lot of about when are you going to give us more information and more data? It is going to continue to come out. It is moving forward at a pretty significant pace. I know everybody want to know is more clinical data and more importantly manufacturing data and then commercial data pricing, cost of goods.
This slide is what we promise to you and it is kind of a timeline of when we are going to present this information. We just gave you Phase 4 study design, we gave you Phase 3 data in the last few weeks. In the first half of 2015, what other data are you going to have? Bolus plus infusion longer duration from both the Xarelto and Eliquis trials; Phase 2 betrixaban data, which is important to us; and then very important, a larger scale and advanced scale production of andexanet at the Lonza facility which is our long-term commercial supplier. That is very important. That is what will give you in the first half of 2015.
What about the second half of 2015? Very, very important. This is the 2500 leader validation of what we are doing at CMC Biologics. This is the first commercial product for the BLA. That is what you have in the second half of 2015. All important, how much supply and what is the productivity at Lonza’s 10,000 liter tanks and facility that will produce commercial products? These are very important because this is your launched product and that is your long-term solution, so that is important.
What about our commercial strategies, specifically how are you going to target this, what is your label going to look like? What is your cost of goods? What is your supply? What is your pricing? When is that going to come? It is going to come in the first half of 2016. There are a lot of factors that factor into this. Our supply, what the market looks like, and what our data looks like and our discussions are with the FDA. That is what we promise to you and that is the timeline.
Our product that we think is the next wave of innovation for Portola. It is very, very exciting because we are starting to see clinical activity in patients that are very sick and have real end-stage cancer and some of this hematologic cancer. Two signaling pathways. We know that there are tumor progression cells and tumors that progressso these pathways of B-cell or cytokines are really the basis for some of these hard-to-treat hematologic cancers CLL, DLBCL, folliculars. This drug is unique. It is the only drug. It is in a class we believe by itself that targets both in a single pill, targets both the B-cell side of signaling pathway and also the JAK-STAT or cytokine pathway.
We are starting to understand the molecular basis by which some of these patients are either resistant or relapsed. This is a data point we have been showing for a while. We are understanding the resistant mutation associated with patients who relapsed on ibrutinib, at least in vitro. We have shown that if you take those cells that relapsed and progress, that if you treat them with cerdulatinib that you can stop the progression.
Perhaps, this is some of what we are seeing in our Phase 1 trial. We do not know. We are starting to get the genetic footprint of somebody’s patients. We have now escalated – how many doses John?
John Curnutte, Executive Vice President of Research and Development, Portola Pharmaceuticals, Inc.
Seven.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc
Were up to seven and we have gone past this. What unique about this drug is that the targeting is highly specific. We are seeing it at a high level, both Sykand JAK and we are still escalating because the tolerability of this drug thus far has been somewhat remarkable.We have not MTD yet. We expect to soon, but in the meantime, we think we are comfortable listing some of the cohorts for expansion that we are going to move forward.
What do we see?We showed that we had a response at ASH. Now, we are starting to see a number of responses as we dose-escalate. The good thing is we are still seeing the tolerability that we saw at the lower doses with this drug. I mentioned the expansions. Where we do we go look at? We look at CLL, certainly follicular lymphoma. We are looking specifically now at DDK and PI3-kinase failures. We have seen activity in this study now in some of these patients. Certainly, we want to continue because of the cytokine activity of this drug. We think DLBCL is still a target of us and we just like to maybe understand genetically where we want to go. We are going probably look at combinations because of the tolerability of this drug and unique… both the tolerability and the unique mechanism probably give us a fabulous chance to assess this drug in combination with other compound.
This is the year and two years ahead. Again, we are talking BLA submission, potential product launches, topline data, another NDA. You are looking at 16 submissions and as this drug progresses as well, we are going to try to find a path to accelerate its approval to the market as well.
It is a pretty exciting time. It is really just about execution for us. Thus far, we have been pretty good and we hope to do it for the next few years as well. Mardi, you can answer questions on cash, 437 million in cash equivalent in investments as of 10/03/14. That is the Q3 performance. Yes, the Q3. We are doing Q4 March 10. Questions?
Male
Bill, could you go back to the pricing argument, you said lower than generic cost? Can you define…
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
For betrixaban?
Male
Yes.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
Right now, Mark, what is the generic? We are on $20 something for a 40 mg injection of Lovenox which is normally given for somewhere between six to ten days in acute medically ill patient. It is in the $20 range. That is the generic. The branded is still higher than this in the United States. In Europe, it is somewhere in the $6 to $12 range. We expect to price betrixaban at an equivalent to the other oral factor Xa inhibitors, which right now is with AWP 850 and then you can say you can figure price increases somewhere north of that. We are in a pretty good position from a pricing standpoint.
At that price that we say it is an addressable $3 to $4 billion market. Whether we will have more pricing leverage, we will wait to see where the market plays out, how far ahead we are of the competition and what our clinical data looks like. Yeah, Jason?
Jason
Yes. Can we talk a little bit about the futility analysis and what exactly are you looking at and what can you tell us about what we can learn or infer if we get the announcement, trial continues as planned? What have we learned?
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
Yes. That is exactly what you are going to get. Well, there is one of three outcomes. Continued trial as plan, stop trial due to futility or something in the middle which says, you might want to consider or some indications of increasing the sample size. Because there are statisticians that are taking a look at the probability of success. We set a bar and our guidance to the folks that are going to look at this is that we want to see activity. We want to see activity and a probability that we can succeed.
Alex is our head of clinical research here, Alex Gold. Alex, do you want to maybe give a comment just at a high level from a precedent standpoint and how this is similar to or what has been done?
Alexander Gold, Senior Vice President, Clinical Development, Portola Pharmaceuticals, Inc.
Yes, Bill. As Bill mentioned, this is something,[that cap] is commonly in the clinical trial, as you know. We have planned that into the design and the purpose is really to ensure that there is not a high probability that there is not efficacy. We do not think that this will happen because we have previously established that the drug works in Phase 2, etcetera. As Bill mentioned, there is indication that the trial design has worked so we are treating the right patients.
Bill told you about what the scenarios are and how we would interpret it. It looks very positive based on the indicators that we are able to follow. The only negative scenario is when they see no activity which appears unlikely based on everything we know about the drug and also we have no so far indication of unexpected safety signals. We look forward to the result, which will tell us to either move on or will give us some useful information if that is not the case, but we are positive about the outcome.
This is not an interim analysis so it does not have a pre-specified stopping rule, so what actually is used is a conditional probability as a concept. Really again, the purpose here is to not continue the trial if there is clearly a very low chance of success. In that case, we would get guidance not to continue. I think it is low probability based on everything we know and they indicated so far but those are kind of the scenarios, just to be differentiated.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
It is still meaningful. I mean the drug has to show activity, all indications is that it should. We have the events. The events are occurring, so you know if the drug is dosed appropriately. We should see activity. I think again, it just puts more wind in our sales to push to the finish line if it is successful.
These trials build overtime. The momentum, either positive or negative, builds overtime because they are so large. They are big moving aircraft carriers and now it seems to be building in the positive direction. We can still fail from our operation standpoint or from a clinical standpoint. We could still fail, but certainly, we are building momentum. We are right where we want to be. We could not ask for anything more at this stage but we still have 35% of the way go and we are still in 32 countries and 450 sites. Believe me, it is a bear to manage but so far so good.
Female
Can you help us understand how to understand a concept of conditional probability, where it would be in certain range, you would think you would have to increase the effect size? I mean because you are powered for a certain effect size with the numbers that you are having, right?That is why I am having a little bit of trouble driving why it is not to just a yes-no scenario.
Alexander Gold, Senior Vice President, Clinical Development, Portola Pharmaceuticals, Inc.
Sure. We are not getting too much of the statics. The concept of the conditional probability has to do with, again, this concept of ruling out a low probability of success. What we do is we define what low probability of success means. Our executive committee which is composed of leading academics in the areas – you probably know if you look at our papers – including Bob Harrington, Mike Gibson,Andy Cohen. What they do is they sit down and say, “What is clinically meaningful for patients to prevent their thrombotic events from happening?” Based on that, they define a threshold below which it is really not clinical significant or the probability of success which is something that we would like to not rule out. What I mean by that is not to continue the trial in case there are still possibilities clinically meaningful, if that makes sense to you.
That is really the main concept. If it is beyond that threshold and it is really futile, hence the concept, then do not go on. If there is still a possibility, probability that this drug will prevent VTEs from happening at a reasonable, clinical rate, then that is something we would like to continue and complete the trial.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
Let me answer that differently. Again, we are not breaking any new ground here. For 25 years that I am seeing this clinical trial, we have been doing the same thing. To put in terms of what you said, you are expecting a certain relative risk reduction. We are powered 95% to see a 35% relative risk reduction, but that is not what the DS&D is looking at. They are not looking to see a 35% relative risk reduction to say yes or no. We are looking to see some clinical activity that suggests halfway through the trials, but this is only done with 50% of the patients that you are on target to show a clinical benefit and that there is a probability that you can kind of get there. If they see that there is a probability that you cannot get there as Alex, that is really what they are focused on. There is not a probability that can get there within a range, not 35%. There is not a probability that they can get there. That is really what they are looking at. Does that make sense?
Female
We have to guess in part, but under what [off mic] would they say, “You should increase your [off mic].”The probability will be…
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
Yes. It is not precise, just to let you know. We have been doing this for a long time. It is not precise. It is a little bit of a dialogue that goes in with our executive committee and the folks who read this beforehand. It is that kind of what range is it. That is what you are talking about here as you said. You are talking about ranges here and that is the discussion that will happen. I think that is really what we can say at this point and I really think that is what we can say at this point.
We wish we could give more specificity to it. I think if you want, you can really dig in and take a look at other trials and which ones may have been stopped, which ones have not. You can start to get a sense of it. I think there is a history. There is a rich history of this in the area of thrombosis early in factor Xa inhibitors. The Magellan, adopt. I was involved in some of these trials, Rocket. All had futility analysis associated with them.The ACS clinical trials. The only one I know that was stopped was the BMS Pfizer Eliquis study. It was stopped for futility and safety. That was what? APPRAISE? That was APPRAISE.
Yes. Of all the factor Xa inhibitor trials and there is probably over 20, there is one that has been stopped. It is the BMS Pfizer’s APPRAISE study in acute coronary syndromes. Did that help at all? I know you want detail, but it is not done at that level.
Alexander Gold, Senior Vice President, Clinical Development, Portola Pharmaceuticals, Inc.
That is why to differentiate with the interim analysis, so you were looking for some pre-specified guidance probably and ther1e isn’t such because really the question is, is there enough reason to believe it is futile or not. That is the main question that they are answering. They choose to provide different guidance, as Bill said, but that is not something that is the primary goal of the futility analysis.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
They will look at net clinical benefit per se as well. Again, when we get through all these safety checks and we get comfortable or at our bleeding effect. That also makes us comfortable and confident, too, going into futility analysis. We will see. We got more months to wait.
Jason
Can I ask one more question?
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
Sure, Jason.
Jason
Will you provide some indication of what the parameters were after you passed it? The DSMB says to continue and we now can rule out some effect size after the fact.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
We probably will not have enough information to determine that. Again, we are giving them guidance like this. It is going to be difficult to us. We are probably going to be saying the same thing. We passed the first hurdle, we have some win in ourselves and we could still fail but we are feeling positive about moving forward. Maybe I should give some thought to that, too. That is a good question. Maybe I should give some thoughts to that.
Female
Thanks, everybody.
William Lis, Chief Executive Officer, Portola Pharmaceuticals, Inc.
Yes. Great to see everybody. Yeah. Enjoy the rest of your time. We are having a nice weather here, although Jason, you see it all the time.
