Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) Q4 2017 Results Conference Call February 14, 2018 8:00 AM ET
Kendra Adams - Senior Director, IR and Public Relations
Dr. David Schenkein - CEO
Dr. Chris Bowden - CMO
Andrew Hirsch - CFO
Dr. Scott Biller - Chief Scientific Officer
Steve Hoerter - Chief Commercial Officer
Eric Schmidt - Cowen
Kennen MacKay - RBC Capital Markets
Yatin Suneja - SunTrust
Anupam Rama - JP Morgan
John Newman - Canaccord
Terence Flynn - Goldman Sachs
Alethia Young - Credit Suisse
Good morning and welcome to Agios' Fourth Quarter 2017 Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at Agios' request.
I would now like to turn the call over to Kendra Adams, Senior Director, Investor and Public Relations.
Thank you, Candice. Good morning everyone and welcome to Agios' fourth quarter 2017 conference call. You could access slides for today’s call by going to the Investors section of our website, agios.com.
With me on the call today are Dr. David Schenkein, our Chief Executive Officer, who will review key business updates and milestone for 2018; Dr. Chris Bowden, our Chief Medical Officer, who will provide an update on our clinical development activities; Andrew Hirsch, our Chief Financial Officer, who will summarize Agios fourth and full year 2017 financial results; and Dr. Scott Biller, our Chief Scientific Officer and Steve Hoerter our Chief Commercial Officer will also be available for Q&A.
Before we get started, I’d like to remind everyone that statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent Form 10-Q filed with the SEC and any other filings that we may make with the SEC.
In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements.
And with that, I'll turn the call over to David.
Dr. David Schenkein
Thanks, Kendra, and good morning everybody and thanks for joining us today. When our labs open in January of 2009, we set out to build a strong research and development organization capable of creating and delivering important medicines against novel metabolic targets. As we reflect from a tremendous progress from this past year, we believe we're well on our way to achieving this vision. Most notably IDHIFA, the first product discovered and developed at Agios was approved in August.
At the end of the year, we also submitted a new drug application for our second precision medicine in AML, ivosidenib. It's rare for a single organization to discover a new medicine and then successfully bring that drug to clinical trials, FDA approval and ultimately to the market. We've proud to have accomplished this once already and we're focused on repeating on this success in 2018, which could result in two internally discovered AML therapies approved within 12 months.
In January, we laid out key 2018 milestones that build on our 2017 accomplishments across our clinical and preclinical portfolio. Starting with our cancer portfolio, we need to secure FDA approval of ivosidenib for relapsed refractory AML within IDH1 mutation in the third quarter of 2018. These patients have few available treatment options are in need of new therapies. We're also planning to submit a marketing authorization application to the European medicines agency for ivosidenib in relapsed refractory AML in the fourth quarter, assuming a regulatory packaged based on the Phase 1 trial is acceptable.
We have important work ongoing to advance ivosidenib into the front line AML and solid tumor setting, which Chris will update you on shortly. Our latest clinical cancer program AG-270 is a first-in-class MAT2A inhibitor on track to initiate a Phase 1 dose escalation trial this quarter. This is the newest program from research to enter the clinic and utilize as elegant science to target cancers with the most frequent metabolic gene deletion.
Moving to pyruvate kinase deficiency, we continue our work to develop the first disease modifying treatment with two pivotal trials for AG-348 ACTIVATE-T and ACTIVATE beginning this quarter and next. Finally, we unveiled for the first time in January the depth of our research pipeline which is poised to deliver multiple investigational new drug applications over the next 24 months. The most advanced research program is an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase or DHODH for the treatment of hematologic malignancies. We expect to submit an R&D for this program in the fourth quarter.
2018 will be suddenly a transformational year for Agios with the potential approval and commercialization of our first wholly-owned product, an ambitious set of goals to advance our clinical and pre clinical portfolios and the continued growth of our organization to support this important work. We plan to host an Investor Day in the second quarter to review the commercial and clinical strategies supporting these goals in addition to highlighting our robust research portfolio. This is an exciting time for us, but also for the patients who are waiting for better treatment options.
I will now turn it over to Chris to discuss our clinical activities.
Dr. Chris Bowden
Thanks David. I’ll start by reviewing our recent progress in AML, where we’re executing a broad clinical strategy that will enable us to help a large number of patients. At the American Society of Hematology Annual Meeting in December, we presented data demonstrating the important role of IDH inhibition in AML, both as a single agent in relapsed/refractory setting and for the first time in combination with standard care in newly diagnose patients.
Data from the two frontline combination trial demonstrated that ivosidenib and enasidenib respectively can be combined with full dose standard induction chemotherapy or azacitidine. Both Phase 1 data sets also showed encouraging signs of early efficacy. These results support our Phase 3 frontline development plan for ivosidenib that encompasses two trials. The first Phase 3 study AGILE is ongoing for patients with IDH1 mutant AML who are not eligible for intensive chemotherapy.
We’re also preparing for a new intergroup-sponsored trail combining both IDH inhibitors with standard induction chemotherapy, which is expected to initiate in the fourth quarter. Based on the evolving AML treatment and the regulatory landscape, the primary end point that is new trial is event free survival. We’re evaluating the potential to change the current end point, the AGILE trial from overall survival to event free survival as well.
We plan to present updated data for all of our Phase 1 AML trial this year. The single agent ivosidenib relapsed/refectory AML trial and Phase 1 combination trial of ivosidenib or enasidenib with azacitidine have been submitted for presentation at ASCO. We plan to submit the Phase 1 combination data with standard induction chemotherapy for presentation at ASH.
The AML landscape is changing rapidly with several new therapies approved in 2017, exciting clinical data presented at ASH and most recently updated NCCN Guidelines that recognize the important role of targeted treatments. The new guidelines now recommend testing all AML patients for the IDH1 or IDH2 mutation.
Enasidenib receive a Category 2A recommendation as a single agent for the treatment of relapsed/refractory disease in patients with IDH2 mutated AML in addition to newly diagnosed patients 60 or older with IDH2 mutated AML who are not candidates or declined intensive remission induction therapy. We are proud to be a part of this therapeutic shift with U.S. approval of enasidenib and IDH2 mutated relapsed/refractory AML.
Beyond AML, we are working to demonstrate ivosidenib's potential in cholangiocarcinoma and continuing to evaluate the role of IDH1 inhibition in lower grade glioma. Our ClarIDHy Phase 3 trial evaluating ivosidenib in previously treated IDH1 mutant cholangiocarcinoma is ongoing and we expect to achieve full patient enrollment next year. For glioma, we are evaluating ivosidenib in AG-881 effects in brain tumor tissue in a perioperative window trial that will initiate this quarter.
We have also submitted the AG-881 Phase 1 solid tumor data for presentation at ASCO. AG-270, our MAT2A inhibitor is our most recent clinical stage molecule with a Phase 1 dose escalation trial expected to begin this quarter for patients with solid tumors and lymphoma. Consistent with our patient selection strategy, only patients whose tumors have the deletion of the CDKN2A tumor suppressor gene or MTAP gene will be enrolled in this trial.
Now turning to rare diseases, we have two upcoming pivotal trials for AG-348 in pyruvate kinase deficiency. ACTIVATE-T expected to begin this quarter will enroll approximately 20 adults who are regularly transfused and ACTIVATE plan to begin in the second quarter will enroll approximately 80 patients who do not receive regular transfusions. To complement our clinical plan, we are also launching a global patient registry known as PEAK this quarter. This registry will enable us to follow adult and pediatric patients for at least two years to study of the long-term clinical implications of their disease.
Our preclinical work has demonstrated PKR activation has potential utility in other hemolytic anemias such as thalassemia and sickle cell disease. We have broadened AG-348 clinical development to include a Phase 2 proof-of-concept trial in thalassemia, which we expect to initiate in the fourth quarter of this year. 2018 will be a year of execution across the clinical organization, as we initiate multiple pivotal trials and expand the indication and investigation of medicines in our earlier portfolio.
I will now hand it over to Andrew to end with our financials.
Thanks Chris. I will start by reviewing our 2017 operating performance then I'll cover our cash position and runway guidance.
We recognize $43 million of revenue for 2017, which includes $41 million of collaboration revenue and $1.9 million of royalty revenue from net sales of IDHIFA. We are encouraged with the quarter-to-quarter growth of IDHIFA sales, and by the trend and the key performance metrics we disclosed earlier this year. The year-over-year decrease in revenue was the result of a $25 million milestone payment received in 2016, upon the initiation of the IDHIFA Phase 3 identified trial.
On the operating expense side, during 2017, we incurred $293 million in research and development expenses. This represents an increase of $73 million from 2016 and was largely driven by increased investments in ivosidenib program including NDA preparation cost and clinical trial activity in both frontline AML and cholangiocarcinoma.
R&D expense also increased on year-over-year basis as a result of IND enabling activities for our MAT2A inhibitor AG-270. 2017 general and administrative expenses were $71 million, an increase of $20 million from 2016, driven by increase in investment in our infrastructure and commercial capabilities with the launch of IDHIFA and expected launch of ivosidenib in 2018.
Turning to our cash balance, Agios is in the strong financial position, as a result of our yearend cash balance of $568 million and the net proceeds from our January fall on offering of $560 million. We now have just over $1 billion of capital, which provides us the ability to fund the business through at least the end of 2020. This financial strength will allow us to focus on the execution of important value driving activities over this time frame, including our planned ivosidenib launch later this year.
Clinical trials required to secure labels for ivosidenib in frontline AML and cholangiocarcinoma. Further evaluation of the role of our IDH mutant inhibitors in low-grade glioma, two pivotal trials of AG-348 for PK deficiency, exploration of the role of PK activation in thalassemia and other hemolytic anemias, clinical development of AG-270, IND-enabling activities and early clinical development of our DHODH inhibitor all while maintaining investment in our productive discovery research engine, which we expect to deliver multiple INDs in this time frame.
We're pleased with our ability to appropriately invest across the business and thank all of our investors for their support.
With that, operator, please open the lines for questions.
[Operator Instructions] And our first question comes from Eric Schmidt with Cowen. Your line is open.
Maybe just a couple of quick regulatory questions, I think you mentioned an ivosidenib approval in Q3. Do you have priority review or expect -- I guess you're expecting prior review? What's the status of the acceptance?
Dr. David Schenkein
Thanks Eric. David here. So, we haven't announced that yet and when we do receive it, which we expect to receive this month and we will announce that. This is based -- the timing that we put out with Q3 was based on what we saw with IDHIFA. And so, we’re assuming the same but until we have that, when we will have that we will let you know.
And then over to IDHIFA, are there plans on behalf of your partner Celgene to submit for EMA approval at some point?
Dr. David Schenkein
So as you know Eric, we announced that as you heard on the call this morning and we've previously announced that we plan to submit for ivo by the end of this year. So, we haven't announced anything, but I think it’s a fair assumption that we expect them to be filing this year as well.
Thank you. Next question comes from Kennen MacKay of RBC Capital Markets. Your line is open.
Chris, one, maybe on the shift from an end point of overall survival to PFS. Can you maybe walk us through the rational there? Is that just to save the time on the duration of the clinical trial and still having OS as a secondary, maybe just a bit more color there would be helpful?
Dr. Chris Bowden
So, last year was a pretty important year I think for AML overall in terms of several new approvals and certainly things that are going to change for the better for patients with AML. One important regulatory development was of event free survival being used as a provable end point for Mylotarg and for any of you, who were at the FDA's ASH presentation. They recognized event free survival as marker of clinical benefit. So that's of interest to us for any randomized trial in the AML space. And what it does is it offers the potential for a couple of things is that when you do a survival study, you always have the issue of secondary therapies more as event free survival really measures, truly measures the effect of the treatment that you are testing in that trial.
And the other thing that we can consider, we haven't made any decision yet would be you can actually offer crossover to, so someone is on that trial and they are randomized to their control one and there is the potential on it in an event free survival of trial for them to crossover to the active therapy. And when you have -- when you know your mutation status, when you come into the study, that can be a pretty important motivator for both patients as well as healthcare providers. So those are some of the things that we are considering as we put this into the mix of thinking about of event free survival for the AGILE study.
And then one other question on AML, and in the updated NCCN Guideline that just came out earlier this six months, they recommended treatment with enasidenib just until progression which is little bit different than the label which advocated for at least six months of treatment, so that patients who are belated responders or experiencing clinical benefits though not necessarily experiencing response could again show some kind of benefits. Can you maybe talk a little bit about, how you're promoting to this in this deal? Does it really aiming for the certain minimum of six months to treatment in patients who aren't progressing on the drug or I guess just help us walk us through that?
Dr. David Schenkein
Hi, Kennen, David here. Maybe I'll just have Steve talk a little bit about, what we are doing on the sell side and then if necessary we can come back to Chris and talk about the NCCN Guidelines. Steve?
So you're writing your statement. What we promote to in the seal is consistent with the FDA label, so that would be having patients, recommending patients to be treated for a minimum of six months or until disease progression.
Dr. Chris Bowden
Kennen, it's Chris here. I think the -- when you look at the NCCN update and you look at the label and when we talk to investigators and docs who are using the drug, I think there's much more in common there which is the main thing is that they are going to continue treatment until sign of overt progression. Because they understand that the time to best response can be go out as our as almost six months, which is why that language ended up in the label for relapsed/refractory AML patients with an IDH2 mutation. So, I think it's pretty clear overall for people who are using the drug how to use it and I think overall with the NCCN Guideline, for us were really an indicator of the impact that IDHIFA is having already.
Got you. Thanks Chris and appreciate the color there. And you're right that language of response is taking up the sort of well in range of three to five months is in the guidelines. And just one final question on the guidelines and what was brought previously about the recommendation for patient who could be frontline but not a candidate for the induction therapy or patients who declined intensive therapy, which where something they got to talk about quite a bit at ASH. Could you may be just talk about, I guess the size of this market opportunity and particularly how that sort of relates to the size of relapsed/refractory market opportunity? Thank you very much. And one more piece of that, if I may actually, and I guess maybe the conditions of these patients versus patients who would be relapsed/refractory IHD2 mutant patients. Should we expect the more duration here? That’s it for me.
Dr. David Schenkein
Thanks, Kevin, David here. So, we talked about this before. It's hard to get it. I can't give you an exact number, but our estimate is that there may be as high as 25% of the diagnosed AML population are essentially not being offered therapy today because of either age or comorbid illnesses that would preclude them from getting standard induction or even hypomethylating agents in some cases. So, we think it’s a very sizable population for the eligibility for the clinical trials for both enasidenib and for ivosidenib, patients have to be not eligible for standard therapy. So we think it's in that population, obviously, we're only going to promote to the IDHIFA label and for the label that we hopefully will receive for ivosidenib. But we do think it is a sizable population out there where hopefully overtime we can demonstrate more and more benefits to those patients.
Thank you. And our next question comes from Yatin Suneja of SunTrust. Your line is open.
Just on the European filing for ivo. What needs to happen between now and then? And is there anything that European guys might be looking at differently when you compare with the FDA specifically with regard to the relapsed/refractory setting?
Dr. David Schenkein
Yatin, it's David here. As we said before that we will have discussions with the EU regulators about whether the package of data that sitting in front of the FDA now is sufficient for traditional approval. And assuming those conversations go well then we will be submitting at the end of this year. So I can't really comment on any details around what exactly they are looking for, but really we will be assessing whether or not package of data we currently have is adequate and I believe Celgene is doing the same thing for IDHIFA.
Got it and then I do have a few question on the MTAP program. Could you maybe tell us like some of the biomarkers that you might be looking in that study and then in the preclinical work that you've done like how those biomarker correlate with responses? And I do have one more question.
Dr. David Schenkein
Yes, so, I'll let Scott to talk about some of the biomarker work we’re doing.
Dr. Scott Biller
Yes, so just to take a step back, we're really excited about this program. It's another example of a Agios first where we've discovered a validated novel approach to drug in cancer using metabolism. And in this case, it covers about 15% of all tumors. So, in terms of patient selection, it turns out that the MTAP gene which is lost in these tumors is co-deleted with the tumor suppressor CDKN2A. So patients will be out on the trial, if they have CDKN2A loss and that's a tumor suppressor that's standard now in next generation sequencing panels. Once, the patients are on, they will -- it will be validated that these patients also have a loss of MTAP by IHC. So that's the main patient selection strategy that we're using. Obviously, we will be looking a lot of different biomarkers to see the correlation between a response and other genetic and epigenetic factors, but the main biomarker here is actually MTAP, is MTAP loss.
And then in terms of your focus on the tumor types, would you be focusing on let say the more smaller orphan-type indication? Or would you do for bigger indication or bigger tumors like lung, bladder and some other where we have MTAP position?
Dr. Scott Biller
Yes, Yatin, it is too early to speculate on that, as we've talked about the Phase 1 dose escalation part of the trial will be a basket trial. So eligibility, as Scott has already mentioned will be dictated by their genetics and virtually any tumor will be included other than glioblastoma because they are treated by different docs. Once we get passed that and we established safety in pharmacodynamic and PK parameters then we will make decisions about which indication to move forward and that will largely be based on both clinical and preclinical data. And so, we haven't articulated yet and we will as we get closer.
And then just one final question, this one on the PKD program, I mean we saw you recently updated the incidence and prevalence estimate for the disease. Just trying to understand how comfortable you are with the new estimate, since like the prevalence is still pretty, I mean the range is pretty wide from the one in 20,000 to almost 1.5 or 1 million? So just maybe help us understanding or how you come up with the new numbers?
Dr. David Schenkein
Yes, thanks Yatin. I am going to ask Steve Hoerter to address that.
As for a rare genetic disease, often times, the literature references are pretty broad in terms of the range of the incidence or prevalence of diseases such in pyruvate kinase deficiency that certainly the case here where we see a very-very broad range in the literature, and in fact very few references in the literature to guide us in terms of what true prevalence of the disease is. So, we've been doing a lot of work around disease education, patient finding work, certainly talking to thought leaders in this field. And I would say all of that at aggregate has lead us to the estimates that we've provided, which is a refinement from the prior estimate, and we feel comfortable at the stage with that range of 3,000 to 8,0000.
Thank you. And our next question comes from Anupam Rama of JP Morgan.
Maybe you could walk us through how the sales infrastructure will change here over the next few months heading into the ivosidenib approval? And what sort of quarter-over-quarter, how we should be thinking about the expense side there?
So I’ll touch on the expense side and then maybe Steve you can talk about after how the infrastructure will unfold. So I think as we mentioned at JP Morgan your conference that, so sales force is largely going to be on board in the first quarter. So I think where you can look to is probably a slight increase in the first quarter, but the Q1 2018 kind a G&A or SG&A is probably likely going to be fully loaded and bake in most of that expense. There may be some additional expense later in the year, as we produce promotional material excreta, but largely will be at that run rate for Q1 2018.
So in terms of the infrastructure, so as Andrew mentioned, we've now hired the full sales organization to support the typical launch of ivo. That number is in the mid 30s in terms of the sales representatives and management and that team is in the process of being trained as we speak to get ready to go out and promote IDHIFA together with Celgene and then be ready for the ivo launch, later on this year.
Thank you. And our next question comes from John Newman of Canaccord. Your line is open.
Just a few questions, the first question is. You mentioned that you will now be looking at event free survival versus overall survival, as your primary end point. And I'm curious, does this imply that you will need to see a relatively larger benefit versus overall survival, and I'm wondering if you expect maybe the FDA to ask for the survival data after the initial approval, to confirm the effect? I am just kind of curious as to what they might be looking for here?
Dr. David Schenkein
Hi, John, its Chris here. Really interest topic, I do want to remind you all that the primary end point is overall survival. We're looking at and reviewing the potential to make that change to event free survival. In that space on some of the comments I made earlier, some of the things that happened last year. Now with regards to the magnitude of the treatment effect for event survival, yes, it has to be clinically compelling and that certainly part of that discussion that we want to have with regulators and investigators, as we think about -- contemplate this change.
And then, your other -- the last part of your question which is, do you have to provide survival data? If you -- if one were to make a change or when you do a trial with event free survival as a primary end point, the answer is yes. And you have to provide information around what type of treatment effect you might expect to see? What's you powered show? So survival remains a very important end point albeit even when it's a secondary endpoint in a randomized Phase 3 study in AML or any other oncology indication for the most part.
And one additional question on the AG-348 program in PKD. So I am just curious, I'm assuming you do have this built in, but I just wondered if you have a strategy built in for the study design here that will allow you to very carefully control the dosing. So for example, if you needed to make some dose reductions or if you needed to suspend dosing for a short period of time, I'm just curious if that's built in the clinical such that you can mitigate any safety concerns that may pop up?
Dr. Chris Bowden
John, yes, Chris again. Yes, we have a lot of guidance direction and oversight in both protocols in terms of dosing up and whether you have to take a pause or the event that an investigator would want to dose down, so that lots of guidance there and we will capture that data very compositely.
Thank you. Our next question comes from Terence Flynn of Goldman Sachs.
You guys are guiding to the first clinical data at ASCO from the Phase 1 trial of 881, solid tumors. Just wondering, if you can remind us to hear the profile of 881 relative to IDHIFA and ivosidenib based on some of the preclinical data PK? And also, are you actually hoping to see a higher level activity here than we saw with ivo and the solid tumor setting?
Dr. David Schenkein
Terence, David here. So let me remind you that 881 was designed as a backup molecules of ivosidenib, more brain-penetrant inhibitor, it turns out as an inhibitor of both the IDH1 and IDH2. And maybe Scott can comment a little bit on some of the preclinical data that we showed in 2017 on 881.
Dr. Scott Biller
Yes, so we have disclosures both that the triple meeting again at SNO on AG-881, characterizing of the preclinical data and all the aspects of the discovery of that molecule. So as David mentioned, the 881 was designed to be significantly more brain-penetrant than ivosidenib. But in preclinical models, we could show at the therapeutic exposure ivosidenib has very significant 2HG reduction. Of course that's our pharmacodynamic biomarker. So, we were able to measure that in brain tumor models where the tumor is actually in the brain behind the blood brain barrier. And we can see up to 85% reduction in 2HG with therapeutically relevant doses of ivosidenib.
With AG-881, we could see even more profound reductions in 2HG up to 98%. So, you've heard about this in perioperative study that's one of the main goals of the study where we're going to be comparing ivosidenib to AG-881 and in perioperative study dose before resection, so you can get brain samples and in humans get a very accurate sense of impact on 2HG as well as brain levels of the drug. So that's really the next step for the development of these molecules in low-grade glioma.
Thank you. And our next question comes from Alethia Young of Credit Suisse. Your line is now open.
One on the MTAP program. Have you guys decided how you'll communicate initial findings with the number of people? Or is it just kind of based on how the robust the data is? And on the second question, just talk a little bit about some of the rate limit expectations associated with launching ACTIVATE-T and ACTIVATE? And do you have any general thoughts around the enrollment cadence?
Dr. David Schenkein
Thanks Alethia. So, on the MTAP program, and then I'll have Chris talk about ACTIVATE. It will be no different than any of our other new clinical starts and that is when we have enough data that will make sense to bring to a medical meeting, we will bring it there. And since we just don’t know, how many coverts we’re going to need to achieve the right doses, I can't really predict when that will be. We'll obviously have a track record of doing that as quickly and as appropriate at the right venue. Maybe Chris can talk a little bit about activate.
Dr. Chris Bowden
Hi, Chris here. So, we’re on track to get both of these studies up and running and according to our guidance, so ACTIVATE-T and ACTIVATE in the first and second quarter of this year respectively. And then the main issue is to bring them in is to recruit them as rapidly as possible. So we're in that active operational Phase, now these are global studies and we've done a lot of patient finding work across the organization and really looking forward to getting all as all of the site up running as rapidly as possible, so that we can recruit these trials and get the data as quickly as possible.
Thank you and that concludes our question-and-answer-session for today. I would like to turn the conference back over to Dr. Schenkein for any closing remarks.
Dr. David Schenkein
Thanks. 2018 will be an important year for Agios as we work to bring a second precision medicine to the market and execute across our broad oncology and rare genetic disease portfolio. I'd just like take a second to thank all the tremendous employees at Agios for their dedication and passion to make a difference in patients' life and I also want to thank all the patients, the caregivers, and the positions who participated in our clinical trials. Thanks to all of you for joining us today, and we look forward to seeing many of you at our Investor Day. Have a good day.
Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program. You may all disconnect. Everyone have a great day.