Portola Pharmaceuticals, Inc. (NASDAQ:PTLA)
Q2 2016 Results Earnings Conference Call
August 9, 2016, 04:30 PM ET
Ana Kapor - Investor Relations
William Lis - Chief Executive Officer
John Curnutte - EVP, Research and Development
Tao Fu - EVP, Chief Commercial and Business Officer
Alexander Gold - SVP, Clinical Development
Phil Nadeau - Cowen & Company
Steve Seedhouse - Citi
Vamil Divan - Credit Suisse
Matthew Harrison - Morgan Stanley
Matthew Phipps - William Blair
Welcome to Portola Pharmaceuticals second quarter 2016 financial results conference call. This call is being recorded. At the end of the company’s prepared remarks, we will open the call for your questions and we’ll provide specific instructions.
I would now like to turn the call over to Ana Kapor, Investor Relations and Corporate Communications at Portola. Please go ahead.
Thank you and welcome to Portola’s second quarter 2016 financial results conference call. Joining me on the call for the prepared remarks are Bill Lis, Chief Executive Officer, and Dr. John Curnutte, Executive Vice President of Research and Development. Mardi Dier, Chief Financial Officer, is on jury duty and unavailable to join the call. Tao Fu, Chief Commercial and Business Officer, will join for the Q&A portion.
We issued our second quarter press release earlier today, a copy of which can be found on portola.com in the Investors section.
Before we begin, I would like to remind you that various remarks that we make on this call contain forward-looking statements subject to risks, uncertainties and other factors that could cause actual results to differ materially from those expressed or implied. All forward-looking statements made on this call are made based on the beliefs of Portola as of this date only. Future events or simply the passage of time may cause these beliefs to change. For a more detailed description of the risks that impact these forward-looking statements, please refer to our most recent quarterly report on Form 10-Q and our annual report on Form 10-K. Be aware that you should not place undue reliance on the forward-looking statements made today.
Finally, this conference call is the property of Portola Pharmaceuticals and any recording, other duplication or rebroadcast without the express written consent of Portola is prohibited.
With that, I will turn the call over to Bill Liss, CEO of Portola.
Thank you, Ana. Good afternoon and thanks everybody for joining us. So during the second quarter, we made significant progress toward our goal of launching our first product this year that the FDA designated breakthrough therapy, AndexXa, and our second product next year, the fast-track-designated betrixaban.
It’s important that these medicines have potential to significantly advance the fields of thrombosis for the benefit of patients and the potential to become the new standards of care. We expect even more momentum in the remainder of this year and into next year.
It’s an exciting time for Portola as we continue to prepare for the anticipated US approval and commercial launch of AndexXa. Our PDUFA date is August 17. AndexXa, if approved, will become the first universal antidote for Factor Xa inhibitors, filling a critical unmet medical need for Factor Xa inhibitor treated patients who are hospitalized with a life-threatening bleeding event.
For betrixaban, we presented and published full results from our pivotal Phase III APEX study in May. We believe these data support its potential approval in use of the first anticoagulant for extended-duration prevention of VTE in acute medically ill patients. We’re on track to submit a New Drug Application based on the APEX data this year.
Also, this quarter, we initiated enrollment in our Phase IIa study of cerdulatinib, which is our novel dual Syk/JAK inhibitor in development for relapsed and refractory B-cell cancer. We anticipate presenting data in this promising compound at medical meetings later this year.
So I'll now provide details about each one of these proprietary programs, beginning with AndexXa. With respect to our upcoming PDUFA date, we will not speculate upon FDA’s final decision. However, we can say we’re confident that we met the obligations on the accelerated approval pathway and we’re confident in the data that we have submitted to support its approval.
John will provide an update on enrollment in the Phase IIIb/IV ANNEXA-4 study. This is our study of acute major bleeding. We will be presenting an interim analysis of ANNEXA-4 at the European Society of Cardiology Congress on August 30. These data have also been accepted for simultaneous publication at a prestigious peer-reviewed journal. Following the presentation at ESC, we will host a webcast with Dr. Stuart Connolly who is the Executive Chairman for the ANNEXA-4 study. He will present the data. We’ll also have Dr. Michael Gibson who is an executive committee member of ANNEXA-4.
Because ANNEXA is an unprecedented program, we will continue to highlight its remarkable potential, but we also recognize that there are potential regulatory and manufacturing risks. We will answer questions, as we always do, related to these areas later in the broadcast.
We are ready to launch AndexXa shortly after approval to address the urgent needs for Factor Xa inhibitor bleeding. The market is defined by the great success and the increasing use of Factor Xa inhibitors and the associated number of hospital admissions due to bleeding. It is estimated that more than 80,000 patients treated with oral Factor Xa inhibitors were admitted to the hospital due to bleeding in the United States in 2015. And taking enoxaparin into account and those on oral Factor Xa inhibitors requiring emergency surgery, the number of these patients exceeded 100,000. These numbers are expected to grow significantly in the next decade with the increasing use of Factor Xa inhibitors.
So although the incidence of Factor Xa inhibitor related bleeding is low, the consequences can be fatal. Large randomized trials with 30-day mortality rate in patients with intracranial hemorrhage exceeds 40% and in non-ICH related bleeding it approaches 15% at 30 days. These bleeding events are associated with high morbidity and mortality, but also they are costly for hospitals to treat, ranging anywhere from $59,000 to over $154,000 for the top 20% of these patients. As a result of this critical need for an antidote, AndexXa has the potential to serve this need.
Based on research we’ve conducted with physicians across various specialties and clinical pharmacists, awareness of AndexXa is very high and the drug is highly anticipated by the medical community.
The majority of those we’ve talked to see a few important therapeutic advantages for treating bleeding patients. They cited product features such as efficacy, safety, rapid onset of action and short half-life as attractive product features.
In preparation for commercial launch, we have hired a sales and national accounts management team, medical science liaison teams. We’ve also recruited a field of 35 sales representatives on a contingency basis. All of our AndexXa medical affairs and sales teams has a successful track record of launching thrombosis and hospital-based therapeutics.
We have communicated over the last two years our initial supply will be limited as manufacturing continues to scale-up on time over the next 12 to 18 months. This lag is because andexanet is expected to come to the market much faster than a traditional program due to its breakthrough designation and accelerated approval pathway. It’s only four years from the IND filing to a potential approval.
In order to ensure that we have sufficient product for long-term, we’re partnering with two manufacturers, CMC Biologics for the initial US commercial supply and Lonza for long-term use and worldwide supply.
Moving on to some strategy. There are three major elements to our commercial launch strategy. First, to gain stocking and formulary approval in the hospitals that treat the largest number of Factor Xa inhibitor bleeds, including patients who were transferred to these hospitals from outlying community-based hospitals. These hospitals are comprehensive stroke centers, level 1 and level 2 trauma centers.
Second part of our strategy is to focus on the highest risk patients, who are also the most costly for hospitals to treat. These include patients with intracranial hemorrhages, bleeding into critical organs and severe unstable GI bleeds.
And thirdly, we plan to execute on our plan for the hospitals to incorporate AndexXa into their existing protocols to treat anticoagulation-related bleeding. We will provide details of our commercial plans on a conference call when we receive FDA approval.
I’ll now turn to betrixaban. As many of you know, betrixaban is our oral, unique, once-daily Factor Xa inhibitor anticoagulant which has fast-track designation from the FDA. In March, we reported topline results from the pivotal 7,500-patients APEX trial. And in May, we presented full results in the study in a late-breaking session at the ISTH scientific congress. The data was simultaneously published online in the New England Journal of Medicine.
The APEX study evaluated the superiority of extended-duration betrixaban compared to standard-duration injectable enoxaparin for the prevention of venous thromboembolism, or VTE, in high risk acute medically ill patients. Currently, there is no proved or guideline-recommended anticoagulant for this indication. The APEX population represents a significant unmet medical need for an estimated 15 million patients at extended risk for VTE in G7 countries.
As we communicated previously, the APEX results show that an extended-duration betrixaban reduced the incidence of VTE compared to standard duration enoxaparin at a p-value approaching statistical significance of 0.054 in the primary analysis subgroup of D-Dimer positive patients and with increasing significance in several pre-specified analyses, including the overall study population at a p-value of 0.006.
In addition, betrixaban reduced the incidence of symptomatic events in D-Dimer positive patients and in overall population at a p-value of less than 0.05. And importantly, betrixaban was not associated with an increase in major bleeding.
Based on these results, we plan to pursue a label for the overall study population which includes D-Dimer positive patients, those greater than 875 and those with additional risk factors. This is consistent with our goal that we had at the outset of the APEX trial.
We continue to recognize that the statistical and clinical results will be subject to interpretation by regulatory agencies. We, and the APEX study academic leadership, believe the overall robustness of the efficacy and safety results in this very high risk patient population, including the positive net clinical benefit, provides ample evidence and support for submission of an NDA.
At our ISTH investor call in May, we communicated that we will review full comprehensive data set with the FDA at a formal pre-NDA meeting. Based on that meeting, we plan to submit an NDA. We have had additional dialogue with the FDA and we’re on track to submit the NDA in early fall.
We plan to meet with EU regulatory officials soon and submit for marketing authorization in the EU by the end of the year. We will continue via press release to update you on our NDA and EU marketing authorization submissions. And we will also update you via press release on subsequent decisions by these agencies on the acceptance of these filings.
Now on to our third proprietary program, cerdulatinib. It’s an oral, dual Syk/JAK kinase inhibitor in development to treat patients with resistant and relapsed hematologic cancers. In our recently completed a Phase I trial, cerdulatinib demonstrated clinical activity in patients with relapsed/refractory B-cell malignancies, including chronic lymphocytic leukemia. We recently began enrollment of patients in three cohorts in a Phase IIa study. That study is progressing well and we expect to have data from those initial cohorts by the end of this year.
I will now turn it over to John Curnutte, our Head of R&D, for additional comments on the progress.
Good. Thank you, Bill. I’ll focus my comments today on AndexXa. In the second quarter, we kept enrollment on track for ANNEXA-4, our global Phase IIIb/IV single-arm, open label study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin who present with an acute major bleed.
We have enrolled over 130 patients to-date in five countries and are about halfway to our goal of enrolling 270 patients. The Data and Safety Monitoring Board will be conducting its third review of the study before the end of year.
Now, the ANNEXA-4 interim results will be presented at ESC on August 30 and will include results from the first 67 fully-adjudicated patients receiving AndexXa. These patients were on apixaban, rivaroxaban or enoxaparin and experienced major, potentially life-threatening bleeding, including gastrointestinal bleeding, intracranial hemorrhage and bleeding in other sites.
Changes in anti-Factor Xa activity with AndexXa and fully-adjudicated efficacy and safety outcomes will be presented. As Bill mentioned, these data have also been accepted for simultaneous publication in a prestigious peer-reviewed journal.
We've also submitted a day-180 update to the BLA on our ANNEXA-4 results to the FDA in June. Bill provided an overview of the size of the market for patients hospitalized for Factor Xa inhibitor associated bleeding who could benefit from an antidote.
It's important to note that in the absence of an FDA approved antidote, some patients who require anticoagulation reversal are treated off-label with four-factor Pectates plasma-derived products are indicated for the reversal of warfarin, not Factor Xa inhibitors. Importantly, there is not a strong biologic rationale for their use for Factor Xa inhibitors, consistent with the failure to demonstrate reversal Factor Xa inhibition in clinical studies.
Moreover, no well-controlled or label-enabling clinical studies are being conducted with these agents. And finally, they carry a black box warning for fatal and non-fatal blood clots for their approved indication to reverse warfarin.
We're working to address this significant unmet medical with our commercial supply of AndexXa. We continue to make progress with manufacturing, with Generation 1 process at CMC Biologics and the Generation 2 process at Lonza. Two manufacturing lines are being used for Generation 1, one using a pair of 2,500-liter stainless steel tanks and another using single-use bioreactor technology at the 6x2,000-liter scale. The Generation 2 supply of Lonza is intended to increase drug supply for a broader US, EU and worldwide launch planned for late 2017 or early 2018 using larger 10,000 liter bioreactors and incorporating multiple process improvements to enhance yield.
During the second quarter, we continued to advance both processes. The Generation 1 2,500-liter scale process is on track for launch, having successfully completed its validation runs for drug substance and drug product, as well as its pre-approval inspection in April.
In addition, we have completed validation runs for the Gen 1 6x2000 liter process for both drug substance and drug product and successfully manufacture drug for commercial use. This process is on schedule to submit to the FDA right around the time of our US launch using a CBE30 submission pathway rapid approval.
Now, with regard to the Generation 2 process, we're initiating this week the process validation campaign at Lonza as planned. This process, as I mentioned above, will generate commercial material in late 2017.
Our expectation is that the initial label will be for Factor Xa inhibitor-related bleeding. Later this year, we will initiate a surgical cohort as part of the ANNEXA-4 study to expand the label for this patient population. And as we had communicated previously, we also plan to start a prospective exploratory cohort, looking at Factor Xa inhibitor patients experiencing a major bleed, but who are not administered Andexanet alfa.
With regard to betrixaban, I'll briefly expand on Bill’s comments. We believe we have a compelling dossier of clinical data to support FDA approval. Based on the totality of evidence from the primary efficacy analysis as well as numerous pre-specified supporting analysis, all including the overall study population results, the data show a clear clinical benefit with betrixaban in preventing VTE in acute medically ill patients without an increased risk of major bleeding. We plan to present and publish additional findings from the APEX study later this year and next.
I would like to remind you why the acute medically ill population is important. These are patients who are hospitalized for serious common medical conditions such as heart failure, stroke, infection, pulmonary disease. Each year, more than 1 million VTEs and 150,000 VTE-related deaths occur in this patient population in the G7 countries. All of this despite the standard use of injectable enoxaparin and other aparins in the hospital.
More than a half of these VTEs events occur after the patient is discharged from the hospital. Yet no anticoagulant, including enoxaparin or any of the marketed oral Factor Xa inhibitors, is approved for extended VTE prophylaxis in the more than 24 million medically ill patients hospitalized in the G7 countries annually.
Our goal is to bring betrixaban to market as the first and only Factor Xa inhibitor approved for in-hospital and extended-duration prevention of VTE.
Finally, turning to cerdulatinib. We have continued to make significant progress with this program. We presented the final results of the Phase I study at ASCO and EHA showing that cerdulatinib demonstrated clinical activity in heavily pre-treated patients with CLL and B-cell non-Hodgkin's lymphoma and was generally well tolerated. We observed partial responses in six of these patients and multiple additional patients have demonstrated reductions in nodal disease and maintain clinical benefit for over a year.
Based on the Phase I data, we selected 35 mg twice daily as the Phase IIa dose. To-date, we have enrolled 12 patients in the study in three cohorts that include aggressive lymphoma, indolent lymphoma and CLL and SLL. We expect to add 20 to 40 patients in each cohort and plan to present data on a portion of these at a major medical congress later this year.
I will now turn the call back over to Bill who will review the financial results for the second quarter of 2016.
Thank you, John. For the second quarter of 2016, collaboration revenue earned on our agreements with BMS, Pfizer, Bayer, Janssen, Daiichi Sankyo was $4.2 million compared to $2.4 million for the second quarter of 2015. The increase in revenue was primarily due to collaboration and license agreements. These included development and commercialization agreement with BMS/Pfizer for AndexXa also in Japan and clinical collaboration agreements with Bayer and Daiichi Sankyo to include the Factor Xa inhibitors in the development program for Japan.
Total operating expenses for second quarter 2016, $61.9 million compared to $61.2 million for the same period in 2015. Total operating expenses in second quarter 2016, $7.6 million in stock-based compensation expense compared to $4.8 million for the same period in 2015.
Research and development expenses were $44.8 million for the second quarter of 2016 compared with $52.3 million for the second quarter of 2015. The decrease in R&D expenses was primarily due to lower development costs, following completion of the APEX study and also lower development costs related to cerdulatinib due to timing of activities. These decreased costs were partially offset by an increase in costs in the development of AndexXa.
Selling, general and administrative expenses for the second quarter of 2016 were $17 million compared to $8.9 million for the same period in 2015. We increased headcount to support our growth and to support the commercial launch activity for AndexXa.
For the second quarter of 2016, we reported a net loss of $57.3 million or a net loss per share of $1.02 compared with a net loss of $58.3 million or net loss per share of $1.12 for the same period in 2015.
Shares used to compute net loss per share attributable to common stockholders were approximately 56.4 million for the second quarter of 2016 compared with approximately 52.1 million for same period in 2015.
As of June 30, 2016, cash, cash equivalents and investments totaled $353.6 million compared with cash, cash equivalents and investments of $468.2 million as of December 31, 2015.
In conclusion, this is a very exciting time for Portola. We continue to execute and make progress towards our goal of launching our first product this year, the FDA designated breakthrough therapy AndexXa and our second product next year, the fast-track-designated betrixaban.
With that, I will now open questions. Operator?
[Operator Instructions] Thank you. Our first question, I’ll turn the line now to Phil Nadeau of Cowen & Company. Your line is open.
Good afternoon. Thanks for taking my questions. I guess, first, Bill, a kind of broad question. In your prepared remarks, at one point, you mentioned that there is regulatory and manufacturing risks for AndexXa. And then at another point, you said you weren't going to speculate on the prospects or approval around the PDUFA. I guess with the PDUFA eight days or so away, that type of hedging language makes me somewhat nervous. I guess, could you maybe talk a bit more about what you see are those regulatory and manufacturing risks? And how are you feeling about the PDUFA?
Yeah, I think, Phil, we do this every call. I think you should know me by now. I do this every call where we try to be measured and say we are really confident about where we are, what we’re doing moving forward, but we recognize the regulatory and manufacturing risks. We do it every time. And I just think it’s wise for us to continue to do it. We’re kind of in a quiet period here. We think we’ve done our part. As I said, we’ve met our obligations. And we provided the data that we think support approval. And now, we’ll wait to see the FDA decision next week.
Okay, fair enough. I guess, on the label, there was a brief comment made, I think it may have been, John, where your initial label expectations are. And I think you said Factor Xa inhibitor bleeding. Will that be – could that be all Factor Xa inhibitor bleeding or would it likely to be limited to rivaroxaban and Eliquis where you have the pivotal data?
Yeah, it’s a good question, Phil. It’s Bill. I think it’s a very fair question. I think, at the end of the day, the goal is for a broad label. I think [that probably the] [ph] FDA supports that as well. I think they probably – my sense, they want to be able to give guidance for where the drug will be used. That said, sometimes the label does reflect specifically what you’re studying. So I think, in that case, you could probably make the case for it. I don’t think we have any particular insight at this time, although we know the FDA – based on what we know, the FDA’s goal is to have it as broad as possible, so that there is guidance for use of the drug.
Okay. And on the accounting for AndexXa sales, will you – do you know if your book sales when the product is shipped from your warehouse? Or in the past, we've seen some products that have a similar use pattern as we'd expect here, had their revenue actually booked on pull-through to the patient. Do you know which of those two alternatives is likely to be used?
Well, I’ll tell you, we’re going to communicate that. We’re going to have a press conference upon approval, Phil. And I think that’s the time we’re going to communicate that. But it’s a very fair question. At the day of approval, when we have our – or the day or day after, whatever, we have our press conference, we’ll be sure to communicate that.
Okay. Just last question, the R&D expense was down quite a bit. As you mentioned, the APEX trial is over. Should we use this quarter as the run rate off which to base H2 R&D or are there any other elements in the R&D spend that we should take into account as we model forward?
Let’s see. Mardi is not here. I’m trying to think how he’d react to this question, Phil. As you mentioned, the operating expenses have come down. We’ll probably see a continuation at least through next year due to manufacturing of AndexXa and then following approval of Gen 2 based on what we’re doing today unless – that could change based on what we’re doing today which we plan to continue moving forward it probably will come down following the Gen 2 approval, which is scheduled for the end of 2017/2018.
Okay, great. Yeah, makes sense. Thanks for taking my questions and congratulations on the progress.
Thank you. Our next question is from the line of Yigal Nochomovitz of Citi. Your line is open.
Yes, hi. It's Steve Seedhouse on for Yigal. Could you talk a bit more about the APEX data you plan to present at medical conferences later this year? What will that include beyond what you've already shown at ISTH and are these analyses that FDA requested in your discussions with them? Thanks.
Yeah, I think we presented at – we presented every analysis that the FDA has requested. That wasn’t all presented at ISTH. So it would be fair to say some [indiscernible] and then kind of more comprehensive meeting presentations around the individual…
Yeah, individual cohorts and contribution of individual components as well as we’re looking at closer results by dose in the trial.
Yeah, we haven’t presented the PKPD. I think we’ve indicated that we have, just call it, results in patients who got the higher dose versus the adjusted dose. I think we have indicated that there is an exposure that explains that. We haven’t presented that specific data. We’re still crunching through it. But my sense is it will be data like this. We will present additional data around D-Dimer with some clarity, trying to think what else, a lot of the…
Yeah, more around symptomatic events. Likewise, on some of the subgroups, we may present some of the data as well, including whether there is anything we can discern in the 1. And only, out of hundreds of subgroups, where there was an interaction that was the male/female bleeding. So it would be more of that. And that’s fairly traditional. We have an interest in producing more of these because they all support the approval. So we’re probably generating them faster than is traditional. So I would say, starting in the fall of next year, you should start seeing these.
Okay, thanks for all that detail. And we have a question also about the AndexXa launch. What is your expected average order for hospitals at launch in terms of number of vials that each hospital will stock? Is it one vial, is it ten vials? Any way you can help us narrow down our expectations there?
Well, we haven’t given out specifics. I think what we said is, we’ve said that probably two to three patients most hospitals. Based on what we know, the rate of hospital admissions and then given our supply, we are trying to target those, what we call, at most need, highest risk, morbidity/mortality, cost, and so that’s where we’ve come up with that number. I think we’re going to have track it and see if that is the case. But that’s our guess right now based on what we have seen in the ANNEXA-4 study, which gives us a little bit of a window, some of the institutions based on screening logs and consenting. And then also based on the number of quantitative and qualitative market research that’s been done and then maybe some of the precedence. So I think that’s how I’ll answer today. Again, as we said, as soon as we get approval, within days, we will have a pretty comprehensive conference call. We’ll go through more of this in detail.
Okay. And last question, you've previously, last year, I think in your company presentation given wide price range for comparable drugs from a couple of thousand all the way up to $100,000. Understand you can’t provide exact price detail right now, are you able to book-end in any way that range and narrow it down at all? Thanks.
Yeah. I think we’ve given a little bit more guidance. What we’ve said is we will definitely be at a premium to where Praxbind, the BI folks price there as we think theirs is a different business model where they are trying to sell in and gain market share of their product. So it’s not a – they are not trying to build a profitable business there. And then we also said we’d be at a premium to Kcentra for its use in reversal of warfarin and for Factor Xa inhibitors. We don’t know what the dose is. It could be higher, but at least for warfarin. We said there’s really three factors. We said the value that this drug presents, especially as a universal antidote, and the data that we presented thus far and will be presenting more at ESC on the ANNEXA-4 trial, we said the other factors we’re targeting at a very narrow group of patients at highest risk and because of the complexity and costly nature of the manufacturing, that will drive the price as well. So that’s the guidance that we’ve given thus far. And again, I think when we have a conference call assuming approval, we’ll be giving specifics.
All right, great. Thanks for taking the question.
Thank you. Our next question is from Vamil Divan of Credit Suisse. Your line is open.
Great. Afternoon, everyone. Thanks for taking the question. I guess, maybe just one more if I could ask on the antidote, and I assume some of this will get more color post the approval. But just say – we've been getting a lot of questions in discussions with investors around how the drug will actually be dosed, given that people would be coming from maybe different anticoagulants and have had their last dose of those drugs at different times. Can you just provide a little more color? I know we've seen, obviously, what's been done in the clinical trials. But how do you envision sort of in the real world, how this will be laid out so physicians can sort of clearly understand the best way to dose the product? Thanks.
I’ll let John answer that, but I'll just make this comment. The ANNEXA-4 study, we believe, has given us a window into what’s going to happen in the real world regardless of – because we’ve got patients that are shipped in, we’ve got patients all across agents, Factor Xa inhibitors – across the doses of Factor Xa inhibitors at different times and including enoxaparin. So we set up a pretty nice algorithm in the study and my guess it’s going to – we were fortunate – these patients, probably because they are on – they are sick patients. They are on concomitant medications. These are the pill watchers, right? These are the people that have – they come to the hospital – their caregiver comes to the hospital, they know what they are on, when they are on it, when they last took it and that’s really going to help the algorithm. But, John, if you want to go through some of the specifics on the algorithm, what we think is going to be in play.
It’s a great question. And as we have talked about previously, based on all of the Phase II and Phase III data, it’s clear that we can cover all of the direct and the enoxaparin class of drugs with just two dosing regimens, a high dose and a low dose. And we have also been able to construct a very detailed pharmacokinetic, pharmacodynamic model relating doses, time from dose, plasma levels, effects on ANI [ph] Xa and, as I said, time from the last dose. In order to guide how the drug should be worked, as Bill said, we have adopted that into the ANNEXA-4 study. With over 130 patients enrolled thus far, we are now beginning to get a very good handle on this. And what we’re seeing is that the modeling that we did is really beautifully borne out in the Phase IIIb/IV study that we actually – even though patients are having, some of them quite large and significant, bleeds, the properties of the Andexanet, its relationship to the anticoagulant and its behavior in these acute bleeding patients all seem to conform to the model. Thus, I think as we begin to share the data with you later this month and going forward, I think what you’ll see is that we are very much on the right track with the kind of dosing regimen we used in Phase III – that is, a high and a low dose regimen. It fits apixaban, riva, edoxaban and enoxaparin and it also fits with the time since the last dose.
So I’ll leave it at that, but, again, I would encourage you to take a close look at the report that we will release later this month.
Okay. All right. That's great. Maybe just one follow-up, if I could, just on cerdulatinib. I know, obviously, much more focused on the antidote and betrixaban right now. But just given the way that product is already emerging here and also, obviously, the competitive dynamics in that space, can you just maybe give us your views at this point, how you see that sort of fitting in given all the competition we're seeing in these types of tumors?
Well, so John again. A good question. We think about this a lot. Really, we are very excited about our Phase IIa. This is the first time that we have had a chance to study the drug at our optimized dose in patients who have not been so heavily pre-treated, many of them who were refractory to therapy. So this is, I think, our next real shot to really see what the drug can do. We continue to collect pharmacodynamic data, molecular pathway data, and what we’re seeing is that the original hypotheses based on cell lines that guided this work are now being borne out as we get into these earlier line patients with endolin or aggressive lymphoma or CLL.
Now, in terms of – so that’s I think overall – it’s clear that the drug works. And maybe the competitive question is, how well does it work versus the others. Obviously, that we’ll need to see in the Phase II study that’s ongoing. But I think one of the things, as I look at it, as both an oncologist and a biochemist, is I continue to be struck by the molecular diversity of the diseases that we are seeing and particularly the diversity that begins to occur after people have been on other types of therapy and the way various sub-clones of the original disease have been selected for.
So I think as we look at these drugs, none of which are curative, what we’re looking at is a way to manage patients chronically with these disease, perhaps using non-cross-resistant sequences of therapy, which cerdulatinib is likely to be an important element of it. It is unique among all of the drugs that are out there right now. And I think it will find its role if it continues to demonstrate the kind of activity that we think it has and that we have seen extrapolated from the Phase I. I think it will be part of an overall management regimen. And that is leaving still uncovered, really, its potential in our action or use in combination therapy where we may see additive or even synergistic effects with some other types of drugs. And we have in-vitro work ongoing where we know that this is certainly at the molecular level quite possible to be demonstrated. So, again, we’re going to forge ahead. We’ll let the data guide us. We will learn more about the molecular and genetic elements of our patients and stay tuned for further developments there.
Yeah. Vamil, it’s Bill. The only thing I would say – it’s a good question. I think at the end of the day, we’re going to give it a good test. I think it’s going to have to show some time, end of the year, or early next year that there is a unique patient population for what’s there as potential differential effects or there’s potential for it in combination. But it’s one thing to show activity. We need to find a path forward now for this drug. So we’re hoping to see that by studying first three cohorts, maybe we’ll add additional cohorts to it. But that’s the goal that we determine the path forward and one that’s accelerated in nature. So stay tuned.
Okay, all right. Thanks so much.
Thank you. Our next question is from Matthew Harrison of Morgan Stanley. Your line is open.
Great. Good afternoon. Thanks for taking the questions. First one, can you just remind us, for the Gen 1 manufacturing process for Andexanet, when was the last time that plant was inspected?
This is John, Matt. I believe they were inspected approximately a little over a year ago. And then, obviously, there was an inspection for our product just recently. So this plant in Bothell, Washington is familiar to the FDA.
Okay, great. And then I’m assuming no comments related to your inspection that you can share with us at this point.
Yeah, I think that what we’ve said publicly is that it went well. Obviously, anytime the FDA comes in with a team of inspectors, there will be things that were found, but there were no really critical issues with the plant. All of the issues identified are being readily addressed. Nothing is that complex or that detailed. So I think all is well within the reach, both in time and effort, to address the findings from the FDA. Bottom line is, we were very pleased with the inspection as were the CMC senior management team.
Okay, thanks. And then just second question, on ANNEXA-4, exactly what kind of data will we be getting in ESC? And is that data similar or different from the data that you filed with the FDA from ANNEXA-4?
I’ll answer the first, Matt, and then John will. So it is different than what we initially submitted. As you know, we submitted based on – I think it was just over ten patients. We have updated the filing as we continue to adjudicate events. The last one, John, was at the base 180 in June. This one will be a portion of those patients. So it will be more than what we submitted at BLA submission. It will be less than what we submitted to the FDA as far as the day 180. It will be similar to – well, we don’t have a surgical cohort, but it will be similar to what was published for [indiscernible] with one exception – maybe two exceptions. We adjudicate our events – there’s a blinded committee that adjudicates whether we have good – excellent, good or for hemostasis. And so, there's a little bit of a benchmark of efficacy that’s established. And that’s the benchmark established by Kcentra in warfarin. So you have that. And then, we're a little bit more rigorous on how we assess mortality, thrombotic events, SAEs, and so I think you’ll get a – not any definitive picture because – in interim summaries of results. But you’ll certainly get a look at – get a fairly reasonable look at the potential activity of the drug and its potential safety given, as John said, we’re probably halfway through the trial, so that’s what we – population of less than that. So, hopefully, that gives you some sense.
John, do you want to comment?
No, I think you’ve covered most of it, Bill. I might point out – I think a feature that has really, I think, been of great interest to the medical community as people get to know about the study, and that is that on intracranial bleeds, we are assessing serial CT scans or serial MRIs at baseline and then at one in 12 hours after completion of the Andexanet using advanced quantitative software to measure hematoma volumes, thickness and subdurals as a way to really, I think, very carefully and rigorously define the level of hemostasis in these intracranial bleeds. There is also then companion clinical scoring both at the time that they are admitted to the study and then with longer-term follow-up. So I think that is an area which I think we are building on. It’s part of this rigorous adjudication by this independent adjudication committee that’s taking place. So you'll see those data and then you’ll see them broken out by excellent, good or none. You'll see a sense of the breakdown across multiple demographic groups, different anticoagulants, different types of bleed, et cetera, different age groups. And we also have, I think, very important summary data there regarding deaths in thrombotic events. So, again, for an interim look at the results, I think physicians and those in the allied medical fields are going to get a pretty good handle of the drug and its performance thus far. And I just want to echo Bill’s caution, the study is only part way through. So there is still a distance to go, many more patients that are even already enrolled that need to be adjudicated. So we have much more data coming, but I think this is a very good initial look. And I’ll just say what we will be showing is very consistent with what was in the BLA with that first handful of patients, our day 90 update and our day 180 update. So what we’re seeing is not erratic or whatnot, it is quite steady and consistent what we’re seeing at these different time cuts in the data.
Okay, perfect. Thank you. And then just one final one from me. And I’m sorry, I joined a little late, so, Bill, I don’t know if you covered this in your prepared remarks. But on betrixaban, can you just characterize what regulatory interactions you’ve had with the global regulators and if there is a time period you’re willing to point to, whether the third or fourth quarter that you plan on filing? Thanks.
Yeah. So I’ll cover and Alex if have any other comment. So we had a formal pre-NDA meeting. As we said, that was the basis for us to move forward. And then we’ve had subsequent correspondences in which we interact with them, where we give them a little bit of – just kind of outline for them how we’re approaching it and ask for a little bit of their guidance as to whether we were on track given the fact that we went through the full data set. Alex, do you want to say anything more?
So that’s the approach we had for that pre-NDA meeting and then we had some questions of clarification and had an exchange with them regarding the contents and the format of the NDA and how we’re going to present it. So taking advantage of the fact that this is a fast track development program, and so we received the answers and that will allow us to hopefully submit just like we planned according to the time lines that Bill described.
Well, so the goal, as we said [indiscernible] we said early fall for the submission. And then what I said, Matt, is we’re going to tell you when we are submitting. We know that some people believe that – when talking to investors, they believe that the acceptance of a filing is an important milestone. So we’ll communicate it. We’ll communicate it the day we submit. We’ll communicate it the day we find out whether the filing is accepted or not. So that’s what we plan to do. Because after the filing, and we’re going to assume acceptance, but after that, then the next major milestone clearly would be some type of advisory panel thereafter. So those are the type of milestones we are looking to continue to gain momentum behind the results.
Okay, perfect. Thank you very much.
Thank you. Our next question is from Matt Phipps of William Blair. Your line is open.
Hi there. Thanks for taking my question. Just one quick one, kind of following up on these regulatory discussions. When you’re meeting with the FDA, are you really making the case for them to look at the center lab D-Dimer test versus the local lab or is it really more looking at the overall patient population, the totality of the data?
Yeah. It’s all of the above. The nice thing is with this study is we have something unique here where we understand what we’re facing with the primary efficacy analysis and the p-value 0.054. But we’ve got these built in – we’ve got a built in larger study, but we don’t have the data mine and we can just go to larger cohorts – so cohort 2, cohort 3 or overall population to just gain more power to see – to gain a picture on the benefit. But then we have all the pre-specified analysis that we are doing in each one of the cohorts. And so, it’s a combination of both that lend to the – what is our belief on a clear evidence of a basis of approval. And there our list of pre-specified analysis, how many of them are there? There are like a 10 or 11, so like cohort 1 – and then there’s some post hoc analysis that we added as well. And so, you’re just trying to add them all up and show support. And again, as we said, the reason why trials like this are set up, all these pre-specified analyses because regardless of whether the p-value was 0.054 or 0.03, it’s a supportive analysis that are the most important thing to make a decision as to whether its approval will be based on one trial. I don’t think there’s anybody we’ve spoken to from a regulatory standpoint, from an academic standpoint that doesn’t see a clear benefit of this drug. The only question is, is it enough to get approval based on one study. And that’s why all of these analyses – understanding we have to get through the first hurdle because we didn’t achieve the threshold, that’s the utilization of these pre-specified analyses.
Alex, anything from you?
Yeah, that’s a good description, Bill. I think your question has to do with two things. So one is, how do you talk about cohort one and that’s where the central D-Dimer evaluation is important as well as others that Bill mentioned that we have done, some are pre-specified, some are supportive post hoc analysis, all of that will be presented. And then just [indiscernible] ultimately one of the conclusions that everyone takes away from this study is that there was an issue of power and it’s an enrich study, both cohort 1 and the overall. And so, it just happens that the overall study has much more power. And when we look at the overall results, no one can dismiss that when the power in the overall enrich study is in place, you see a very clear result. So, ultimately, as Bill said, the answer, which is we are presenting a comprehensive picture in all of these analysis a part of the evaluation. I’m sure FDA will do additional ones to confirm from their perspective and we welcome that and we will replicate as we collaborate through the review.
Yeah. In another sense, we’re trying to build – from a strategic standpoint, we’re just trying to say, 0.054, missed on one event, here are the additional supportive pre-specified and post hoc analysis that strengthened that cohort of patients, so that you allow for formal testing. And once you do, the evidence becomes pretty clear in the overall study population including all of the pre-specified analysis, the post hoc analysis, just really well powered and significant. And that’s the question, can you get through the cohort 1 to allow for the additional testing? If not, we’ll say great, they’re exploratory analysis, go ahead, you look great doing that on study. And if you ask, and it’s our belief that you will come to the conclusion that given that p-value, given precedence, one study approval is enough. And that’s really how simple I think it’s going to go with the FDA, understanding there’s a lot of complexity in some of the – maybe some of the analyses that are done. But some levels are pretty straightforward and we will see.
All right, thank you.
Thank you. [Operator Instructions] I’m not showing any further questions. I’d like to turn the call back over to Portola for any further remarks.
Yes. I just have one. I just want to thank everybody for their interest. We’ll continue to update on our progress. We look forward to seeing some at ESC. Certainly, we will let you know. And we expect to have some positive news next week. And if we gain approval and then we will have a conference call to go over the specifics. So I’d love to be at the Citi Annual Biotech Conference in September as well. But we’ll be talking to you before that. Take care, everyone.
Ladies and gentlemen, thank you for participating in today’s conference. This does conclude today’s program. You may all disconnect. Everyone, have a great day.
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