ARIAD Pharmaceuticals' CEO Hosts ARIAD ESMO Investor Conference Call (Transcript)

Oct. 1.12 | About: ARIAD Pharmaceuticals, (ARIA)

ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA)

ARIAD ESMO Investor Call

October 1, 2012 8:00 am ET

Executives

Maria E. Cantor – Senior Vice President, Corporate Affairs

Harvey J. Berger – Chairman and Chief Executive Officer

Scott N. Gettinger – Associate Professor of Medicine, Yale School of Medicine

Frank G. Haluska – Chief Medical Officer and Senior Vice President, Clinical R&D

Timothy P. Clackson – President of Research and Development and Chief Scientific Officer

Analysts

Michael J. Yee – RBC Capital Markets

Matthew Harrison - UBS Securities LLC

Cory Kasimov – JPMorgan

Jim Birchenough – BMO Capital Markets

Joel D. Sendek – Stifel, Nicolaus & Co., Inc.

Phil Nadeau – Cowen & Co. LLC

Ying Huang – Barclays Capital, Inc.

Howard Liang – Leerink Swann LLC

Mike King – Dawson James Securities, Inc

Ryan S. Martins – Lazard Capital Markets LLC

Ling Wang – Summer Street Research Partners

Y. Katherine Xu – William Blair & Co. LLC

Echo Yinghui He - Maxim Group Securities

Operator

Thank you for holding for ARIAD Pharmaceuticals Investor Conference Call to review the Company’s clinical data, presented at the ESMO meeting. At this time, all participants are in listen-only mode. Following the formal report, ARIAD management will open the lines for a question-and-answer period. Please be advised that this call is being recorded at the Company’s request, and it will be archived on the Company’s website for three weeks from today.

At this time, I’d like to introduce Ms. Maria Cantor, ARIAD’s Senior Vice President Corporate Communications and Investor Relations. Please go ahead ma’am.

Maria E. Cantor

Good morning and welcome to ARIAD’s investor call and webcast. This morning we will review the clinical data presented Saturday at the 2012 Congress of the European Society for Medical Oncology from an ongoing Phase 1/2 study of our investigational tyrosine-kinase inhibitor, AP26113 in patients with advanced non-small cell lung cancer. You can access the presentation slides that we will review this morning by going to the investor page of ARIAD’s website www.ariad.com and clicking on the link to this morning’s webcast.

Joining me for this call are Dr. Harvey Berger, our Chairman and Chief Executive Officer; Dr. Tim Clackson, our President of Research and Development and Chief Scientific Officer; and Dr. Frank Haluska, our Senior Vice President for Clinical Research and Chief Medical Officer. Also joining us today is Scott Gettinger, Associate Professor of Medicine at Yale School of Medicine and an investigator in the Phase 1/2 study.

Before we get started, I’d like to state that during this call, we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements are subject to factors, risks and uncertainties such as those detailed in our filings with the U.S. Securities and Exchange Commission that may cause actual results to differ materially from the results expressed or implied by such statements.

Now, I’d like to turn the call over to Dr. Berger for opening remarks.

Harvey J. Berger

Thank you very much Maria, and good morning everyone. We’re very pleased to have the opportunity to update you on the clinical data’s that were presented this weekend from our ongoing Phase 1/2 trial of 113 in patients with advanced non-small cell lung cancer. We believe this study provides compelling clinical evidence of the anti-tumor activity of 113 at multiple dose levels in patients with ALK+ lung cancer, as well as initial clinical evidence of anti-tumor activity in patients with EGFR+ lung cancer.

During Saturday’s oral presentation at the ESMO meeting, Dr. Scott Gettinger detailed the findings to date from the Phase 1 dose escalation portion of the ongoing Phase 1/2 trial. We are very fortunate today to have Dr. Gettinger with us this morning to review the data and answer your questions about 113, about lung cancer, and about various new investigational treatment options for lung cancer.

As Maria noted earlier, the slide that Dr. Gettinger is about to present are available on the investor page of ARIAD’s website. Let me now hand the call over to him, to present the data and his perspectives on the key findings. Dr. Gettinger?

Scott N. Gettinger

Thank you Harvey. And it's my pressure today to talk to you about this Phase 1/2 Study of AP26113 and to share with you some of the findings today.

As you may know, the most exciting development in lung cancer over the last decade has been the identification of key driver molecular events in some of our patients with lung cancer, that are targetable with some of these newer oral tyrosine-kinase inhibitors. The first one that we heard about back in 2004 is the EGFR mutation, which lends itself to treatment with Tarceva, a small molecule inhibitor of the EGFR.

And back in 2003, 2004 we saw some dramatic responses in a trial evaluating an agent called gefitinib, and when we went back, we looked at that tissue from some of the patients we found this EGFR mutation. We then heard about an ALK rearrangement in a patient with lung cancer in 2007, and within a few short years crizotinib, small molecule inhibitor of ALK was developed and approved in the United States and Europe for treatment, based upon very high response rate similar to what we see with Tarceva, and patients with EGFR mutant disease.

Recently, we've heard about the ROS1 translocation and patients who have tumors driven by this molecular event into response as well to crizotinib as patients who have ALK rearranged lung cancer. So the problem with these wonderful drugs is that inevitably patients develop resistance, usually that happens within ten to twelve months. We’ve learned a bit about mechanisms of resistance in patients who have EGFR mutant lung cancer that has become resistant to either erlotinib or gefitinib medications now used to treat these patients. We’ve found that roughly 50% of them will be found to harbor a second EGFR mutation, known as the T790M mutation. And if the tumor harbors this, the effects of Tarceva are limited in these patients or gefitinib.

For patients with ALK rearranged lung cancer who develop resistance to crizotinib, we see similar mutations in ALK although at a lower frequency. And for patients with ROS1 translocations, we’re just beginning to treat them with crizotinib and by doing that repeat biopsies on our patients which I think most academic oncologists are dedicated to, we’re going to learn about mechanisms of resistance in that population as well.

So AP26113 is a potent ALK, and ROS1 inhibitor, ten fold more potent inhibitor of ALK fusions than crizotinib. Unlike crizotinib, AP26113 also inhibit the gatekeeper ALK mutation, the L1196M, which is similar to the T790M mutation in EGFR mutant patients with acquired resistance, so either a erlotinib or gefitinib, AP26113 also inhibits R0S1 fusions, a concentration similar to ALK.

And here on this slide, you can see some of the IC50s, we show that a relatively low concentration of this drug is needed to inhibit cell lines that are driven by these molecular events.

AP26113 is also a potent inhibitor of mutant EGFR, including both most common types of EGFR mutations, the Exon 19 deletion mutations and the L858R Exon 21 mutations. AP26113 also inhibits the T790M gatekeeper mutation, which we again see in roughly 50% of our patients with acquired resistance to the other approved drugs.

Importantly, AP26113 does not inhibit native EGFR, so we would not expect some metastasis that we see with erlotinib and gefitinib namely the limiting rash that our patients have to suffer.

Here you can see the IC50s where it show that we would expect a slightly higher dose of AP26113 would be needed to inhibit EGFR mutant lung cancer, and we’ll talk about this little bit later when we go over pharmacokinetics.

So the study objectives included to determine the safety profile including identification of a maximum tolerated dose as well as dose-limiting toxicities. We also examined the pharmacokinetic profile and really want to see if there is some sense of activity in patients with tumors driven by ALK rearrangements or mutant EGFR. And exploratory analysis are also being done to understand mechanisms of sensitivity and resistance to AP26113.

This diagram shows the study design; typical Phase I dose escalation part 3x3 design where we started at 30 (inaudible), a third cohort is for patients with EGFR mutant lung cancer with acquired resistance and finally a fourth cohort for other cancers that AP26113 targets. For example ROS-rearranged lung cancer.

So this shows you the key inclusion criteria, patients with any tumors that are refractory to current treatments, standard treatments were eligible except for those with leukemia, but we really were concentrating on patients with lung cancer, patients just to have relatively good performance status, zero to two, patients cannot have had active brain metastasis, however we do allow patients who have asymptomatic untreated brain metastasis to go on trial and I am going to show you a picture a little bit later about one of these patients.

Patients who need to have adequate kidney, liver and bone marrow function and a normal QT interval because this drug would theoretically increase the QTC interval. Tumor tissue is necessary for analysis, this tumor tissue can be from a initial diagnosis except for cohorts 2 and 3, where we will require tissue to be obtained after the development of resistance to either erlotinib, gefitinib, or crizotinib, and this will help us understand which patients might benefit most from AP26113.

Here we can see the patient characteristics, the majority of patients were Caucasian, they have had multiple prior therapies. Here on the bottom you can see that 76% of patients had to see that list three prior regiments for advanced disease, so this is a very refractory population where there is not really many options if any. Most patients had ALK rearranged or EGFR mutant disease lung cancer.

So this shows the dose escalation phase and as I mentioned we’ve been able to successfully escalate up to 240 milligrams daily, which is where we saw our first dose-limiting toxicity within an Grade 3 elevation ALT, which subsequently came down after holding the drug and this patient was redosed at a slightly lower dose and is doing fine as of now.

This is where our patients currently stand. So of our 15 patients with ALK rearranged lung cancer; only three have discontinued therapy. One of these discontinuation were because of a documented disease progression. There were two other patients who have come off adverse events. One of the adverse events was not related to study therapy, the other adverse event was likely related to study therapy, it was consisted of leg cramping that the patient felt was not acceptable, so the patient came off trial.

In our patients with EGFR mutant lung cancer, there were 12 patients, 8 have discontinued therapy, 5 because of documented disease progression, 1 because of clinical progression of disease, although imaging did not show progression disease, one for an adverse event which was not related to study therapy, and there was one sudden death on the trial that had been shortly after starting AP26113 and is unclear why that happened. We are looking into this, patient certainly had many other comorbidities, other medical problems that could have contributed to this and right now we are not sure what to make of this. But all in all patients have tolerated this drug quite well.

And this is shown here, an adverse events where we see a little bit of nausea and fatigue, a little bit of diarrhea, but if you look at the Grade 3 plus toxicities, there were very, very few. What you don't see in this list of adverse events is rash, which is what limits us with erlotinib and gefitinib and as we expected we didn’t see this. We also didn't see the visual disturbances that are characteristic of crizotinib, and that interfere with patient’s daily living.

So this is pharmacokinetic curves, and what we can see here is that at lower doses we do think that we can effect in addition on ALK, but we would – it seems like we need the higher doses 120, 180 and above to hit EGFR mutant lung cancer, and this drug (audio gap). So this is really the money slide in a sense, and this is where our patients – how our patients have down. So going through this of our 11 patients with ALK rearranged lung cancer treated at several different dose levels, in the patients who have resistance – acquired resistance to crizotinib, there were nine of these folks and six of them had responses. Now the remaining three, two of those patients never made it to imaging because they came off for adverse events, one unrelated to study therapy and the other one, the patient with the leg cramps and the third patient who did not make a partial response, did not make this because of asymptomatic brain lesion that had grown and cause some neurological symptoms.

However when this lesion was taken out, it was not lung cancer, it was actually melanoma and if it wasn’t for that the patient would have reached the PR, because the patient had significant regression in his known areas of lung cancer.

Turning to our patients with EGFR mutant lung cancer there were nine patients who had resistance to erlotinib or gefitinib and of those nine patients, one patient had a partial response, I mean this was at a dose level of I believe, 120.

Of our patients with EGFR-TKI naïve disease, patients who had not seen erlotinib or gefitinib. There were no responses. However of these two patients one of them had a very unusual EGFR mutation known an exon-20 insertion mutation and so what it’s forth these patients generally don’t respond to erlotinib or gefitinib.

The second patient did not have progression on imaging, but had clinical progression. It was taken off trial. So of the five patients who did not have ALK rearrangements or EGFR mutation none of these patients responded.

So putting this into context we saw the response in our ALK-rearranged patients at 60 milligram dose and above, response we’re seeing in patients was naïve as well as resistant disease to crizotinib. And responses were observed in all patients who actually got to imaging, and one of those responses is the patient with a brain lesion, so he is certainly regressed, but all patients who had some degree of progression.

The responses seem to be prolonged, it still needs some more follow-up in our patients who had ALK-rearranged disease, who was crizotinib naïve, patient is doing well at nine months after starting and another patient who has crizotinib resistant disease, she is at six months and she is doing well and the other patients have had less follow-up.

In our EGFR patients who’s responses were observed at the – one response was observed at the 120 milligram dose and remember this is a dose that were beginning to think that we might have activity based upon preclinical modeling. There were six patients treated with 120 milligram dose or higher. And of these patients, one has a PR, two have stable disease and three patients had disease progression. So there is clearly – we’re beginning to see some activity in the patients with EGFR mutant lung cancer with higher doses.

So it’s hard to really understand how this drug benefits our patients by looking at a bunch of numbers. So showing some pictures can help, this is a patient of mine, who had ALK-rearranged lung cancer, has been on crizotnib for quite some time and then started developing progression of disease on imaging and also started to having increasing cough, shortness of breaths, fatigue, a little bit anorexia. We started her on trial and within two to three weeks those symptoms largely resolved. So this drug had an incredibly meaningful impact clinically on the patients, and not surprising she had radiographic response.

In the top series of pictures, you will see an axillary lymph node that has essentially gone away and there were actually several of these lymph nodes that regressed. And we did biopsying these lesions couple of months before starting trial therapy and this was indeed ALK-rearranged lung cancer.

The bottom picture is a picture of lymphangitic carcinomatosis, this is a way cancer can grow in the wrong and insidious way, grows like a pneumonia, not necessary like a mass getting bigger, but like a pneumonia spreading out. This was also biopsied and ALK-rearranged lung cancer. You can see that this area of haziness that is shown in the arrow has improved dramatically. What is not shown is the other areas in the lung where you see regression like this as well. So this patient had a meaningful radiographic and clinical response, and this patient is now on six months.

This is the second patient, who is fed a higher dose, 180 milligrams crizotinib resistant ALK-rearranged lung cancer. This is the patient with the asymptomatic brain lesion, who initially was – this was presumed to represent lung cancer, patient was allowed on trial because this was an asymptomatic lesion. You can see this dramatic response in the lung, but unfortunately during treatment the patient develops some neurological symptoms and was found to have some bleeding into that one lesion in the brain taking this patient to the OR, we learned that that lesion was not lung cancer, it was actually melanoma, and the patient did have a history of melanoma couple of years before starting. This patient has continued on therapy and is doing quite well. And if we weren’t incredibly conservative calling this patient a, patient with progression disease, you can think of her of a disease responding to therapy in all areas of known disease.

This is another patient with ALK-rearranged lung cancer, crizotinib resistant getting treated a 180 milligram. This patient had a dramatic response in the liver making criteria for response, but what was incredibly interesting about this patient is, the patient had two asymptomatic brain metastasis before starting therapy, and both of these have regressed. Here is shown just one lesion in multiple different ways, but you can see almost resolution of this brain lesion. So we now know that crizotinib has activity in the brain and I must say that, one problem that we’ve had with patients who have ALK-rearranged lung cancer is brain metastasis and often patients fail crizotinib because of progressive brain metastasis. So it is great to know that AP26113 has activity in the brain.

So to summarize, I want to also mention one other patient who has EGFR mutant lung cancer, who has acquired resistant to Tarceva, whose tumor was found to harbor the T790M, the second resistant EGFR mutation, and although she has met stable disease which was shown in one of the prior slides, she has clinically benefited. There is no question in my mind, she came on to trial with significant chest pain from disease on the edge of her lung eating into her chest wall, and she was on narcotics for this. And within a month of starting therapy, she came off narcotics. Now the scan shows stable disease, but clinically she certainly had a response.

So to summarize the data so far, the most common AEs that we’ve seen have been nausea and fatigue, which were generally low grade and we have not seen the rash that limits us with erlotinib, and gefitinib or the visual disturbances that we see with crizotinib. There has been one DLT identified to date at 248 milligram dose level, and this was an increased liver test, and this actually resolved with holding the drug for a short period of time and this patient is doing well with a lower dose. This cohort has been expanded and then we're going to make a decision about further dose expansion after we review the data on these patients soon.

We have not reached an MTD yet. We do, it appears that we are able to get enough drug into patients to reach the levels that preclinical models would suggest, would inhibit EGFR. So when we get to that 120 milligram, 180 milligram and 240 milligram, we’re hoping that we’re going to see some activity in EGFR mutant patients, where we wouldn’t expect so much at the lower dose. So you have seen very promising activity in our ALK rearranged patients. Again remember that, every patient that made it to assessment had regression of their disease. And we also know that AP26113 is active in ALK positive brain metastasis.

So one other thing, we heard about at this meeting about another drug the LDK, the Novartis drug, which is also has activity. I think to distinguish both of these drugs so far with the doses that we have escalated up and remember we’re seeing response at 60 milligrams. This drug has been incredibly well tolerated. And if you go, when you look at the graph of adverse events and you hear about the LDK, it seems that this has – it's better tolerated. But again, we need more follow up in higher dose that really make that assessment. But I feel privileged to be able to offer this drugs to my patients who have developed resistance to crizotinib, erlotinib or gefitinib, not only because it has activity – clear activity in tumors, but also it's tolerated overall better than some of our other alternatives. So that in itself is meaningful to me.

So I think that is– of course, of course we always have to thank our patients and the patient's families, they are really helping us understand things, they let us to repeat biopsies, they are wonderful people. Obviously we need to thank the clinical sides and we’re embedded to ARIAD and the investors to help develop this drug further.

I think that is the last slide and I'd like now to turn the call back to Dr. Berger.

Harvey J. Berger

Thanks very much Scott. I really appreciate your detailed update. So I think we really want to turn now to the Q&A and open the call up to questions that are on the line regarding the data and your summary of the results from ESMO. So if I can ask the operator to open the line and take the questions in the order that they are queued up.

Question-and-Answer Session

Operator

Thank you ladies and gentlemen. (Operator Instructions) Your first question is from the line of Michael Yee from RBC Capital Markets. Please proceed.

Michael J. Yee – RBC Capital Markets

Hey thanks, thanks guys, a question for Dr. Gettinger. Do you plan to go to higher doses for the EGFR? And what is your expectation there given what you've seen so far? You basically have suggested you already have therapeutic doses. So what do you think will happen in your prediction is? And then more importantly, we've seen a response here but what is clinically meaningful to you? I guess. And then a question for Dr. Berger, can I ask you to speculate then what is your regulatory path for EGFR? Thanks

Harvey J. Berger

Scott, why don't you take the first half first? Frank also might want to comment on the plans.

Scott N. Gettinger

All right, so because this is a Phase 1 dose finding study, I think regardless of activity I think you see it through, so you dose escalate as it is instructed in the protocol to the highest dose level. And then you can start thinking about different doses, as to what dose you would use for this or that. If you look at the preclinical models and preclinical models are not human beings and you can’t really correlate exactly one with the other, but it does appear that the higher dose levels are necessary to inhibit EGFR mutant lung cancer. Whether that means it’s going to be the responses that we hope to see when it be at 120 milligram, 180 milligram, 240 milligram or higher. It’s hard for me to tell you and I just, I think we need time and doing the study in the correct way will help us understand that. We really understand, I think EGFR mutant disease when we go to the Phase II portion, where we will treat several patients who with EGFR mutant lung cancer and acquired resistance, and then we’ll be able to look at some things.

We also have tissue at the time of resistance to erlotinib, gefitinib in these patients and that might help us understand things as well. And the second question, what was the second question?

Michael J. Yee – RBC Capital Markets

Clinical meaningfulness, I guess?

Harvey J. Berger

So Mike, your question is about the regulatory path forward for the EGFR subset of patients. I think this is dependent on several factors, first of all, it’s dependent on our ultimate choice of dose, at least in so far the timing of that pathway is concerned. We do want to achieve the maximum tolerated dose and we’ll get an idea of what we have in front of us, when we know what that is. The next step of course would be to enter the dose expansion cohort that’s already built into the protocol. I think the patients who are likely to enter into that portion of the study are going to be better characterized from the standpoint of their genetics and will allow us to get a tighter estimate of what the response rate might look like in the EGFR patient population.

And then of course the actual registration pathway itself, it’s not yet defined, but following on what has been the path followed by additional targeted agents in lung cancer. And given that patients with resistant EGFR based disease especially those patients with T790M have no additional options. I think it’s very likely with the registration path where will be an uncontrolled Phase II study that’s clearly what crizotinib pursue, that’s what the Novartis agent is pursuing as well, and I think the FDA is likely to be permissive in allowing that to be a registration pathways.

So we haven’t finalized those paths yet. There is still under the development and of course as I say, the contingent on what happens in the dose expansion cohort, but that’s the most likely path forward.

Michael J. Yee – RBC Capital Markets

Scott, could you comment on what you would kind of consider clinically meaningful in EGFR-positive lung cancer, that’s resistant to Tarceva?

Scott N. Gettinger

So there are many ways to think about this. You can think about it by imaging, or you can think about it by symptoms. I can say from my patient who is clearly, clinically benefiting because her pain is much better, and there is certainly enthusiasm there. I think patients who have EGFR-mutant lung cancer who develop resistant to Tarceva, gefitinib, they tend to progress relatively slowly, but they may march along. And I think if a drug could stop that progression that you know in itself would be clinically meaningful. If you didn’t get regression, and you just got stable disease, I believe that would be meaningful in our patients. And we’ll see what happens we’ve already seen a documented response, but I think stable disease is also meaningful I mean you can tell if my has patient stable disease, but clinically she is much better.

Harvey J. Berger

Let’s go on to the next question.

Operator

Next question is from the line of Matthew Harrison from UBS, please proceed Matthew.

Matthew Harrison – UBS Securities LLC

Hi. Thanks for taking my question. There are two things I wanted to talk about. The first is, could you help us understand the tolerability advantages of 113, specific looking on the rash and how important data in a clinical setting. And then, the second thing that I think might be helpful to understand also is, this trial seems to enroll patients that had progress on erlotinib or another EGFR inhibitor. And then they have had a couple around with in hearts, or some other treatment. Can you talk about how different those patients are, than patients that may have progressed just from erlotinib and then gotten new drugs such as (inaudible).

Harvey J. Berger

Scott go ahead.

Scott N. Gettinger

So the first question about the rash and how important that is, and how meaningful if it that AP113 does not really seem to cost that. So I treat a lot of patients with EGFR-mutant lung cancer, I treat them with Tarceva, I treat them with other clinical trials, including a trial of afatinib and cetuximab. And the most disconcerting thing for me is the rash, and I think it's also the same thing with the patient. We love to tell our patients and everyone else in the field that erlotinib, gefitinib is so much better tolerated than Tarceva, but the vast majority of patients, 80% plus would get rash. And that's cosmetic in some patients, but in other patients it itches, it hurts, they can – your scalp can get inflamed and you can loose your hair, your fingers can fissure, you can get what’s called paronychia, little inflammation infection in your nail beds, and patients they live through it.

Now often we have to reduce the dose of erlotinib and gefitinib substantially in our patients. And then there are other patients who won’t let us because they say, well it’s working, I am not going to risk it. And they live miserable lives because of the rash. So it’s – if this pans out and 113 does have good activity in EGFR mutant disease and does not cause rash. This will be very meaningful for our patients. Me putting a patient on to another trial of another EGFR inhibitor (audio gap)

Operator

Ladies and gentlemen please bear with us we have a technical issue with the audio at the moment. This will be resumed in approximately one minute’s time. Thank you. Ladies and gentlemen please bear with us, the conference will shortly begin. We are still (inaudible) to join, thank you. Dr. Gettinger.

Scott N. Gettinger

Yeah, hello this is (inaudible).

Maria E. Cantor

That’s correct.

Operator

All right Maria, we’re back.

Maria E. Cantor

Okay, I think we should proceed in responding to the questions. It sounds like our audio is back. We want to apologize to everyone dialed into the call. So I think we should continue at this time. Dr. Gettinger I believe you’re finishing your response regarding the rash and the clinical experience that you’ve seen with your patients.

Harvey J. Berger

We can’t hear you.

Scott N. Gettinger

Can you hear me now?

Harvey J. Berger

Yes.

Scott N. Gettinger

So just to summarize, the rash is incredibly meaningful clinically and having a drug that can inhibit EGFR mutant lung cancer without causing a significant rash is really a step forward. The other thing that we didn’t discuss was diarrhea. That’s another thing that limits us with both erlotinib and gefitinib. And we really haven’t had much in the way of proms with diarrhea in this study. So in both regards 113 is tolerated better than erlotinib or gefitinib.

I think the second question was with the patient population of the EGFR mutant cohort. And these patients indeed do have several other therapies that they have received prior to getting going on trial and we all believe that the more therapies you get, the more resistant the tumor might become. I mean, it’s we don’t fully understand this with EGFR mutant disease, one thing we do know is that, in the first line setting the first, when you first receive Tarceva, whether you get it at the beginning of your diagnosis or after cycle or two chemotherapy or a couple different regiments, it still has similar activity. But in the refractory population we don’t know. So if you’ve developed resistance to Tarceva and then you go on to get platinum and combination of chemotherapy, another chemotherapy and some of these patients had other trial therapy, some of these patients had afatinib and cetuximab. So how is that going to affect the response rates, if anything it’s going to make the chance of response a little bit less. So in a patient population who just failed erlotinib and then went on statistically might see a difference.

Scott N. Gettinger

Great. Thank you. Next call.

Operator

The next question is from the line of Cory Kasimov from JPMorgan. Please proceed.

Cory Kasimov – JPMorgan

All right. Great. Thanks for taking my questions. First I had a follow-up question on dosing, but in the ALK+ disease. So you have responses now at doses ranging from 60 milligram to 240 milligrams. Wondering how you’re thinking about dosing for this patient population in subsequent stages of development. And then my second question is for Dr. Gettinger, just interested in your additional perspective on how you think 113 compares with some of the other next generation ALK inhibitors in development. I guess that I am looking for some more detail in the safety comparison you alluded to in your prepared comments, as well as two potential differences in activity? Thanks.

Unidentified Company Representative

So let me take the first one Cory and let me also apologize to everybody for the technical difficulties that call provider had. So with respect to the dosing, you’re right that we have responses across a wide range of doses in the ALK+ patients. As we’ve said before and I think discussed with many, our goal is first and foremost to define the maximum tolerated dose in the dose limiting toxicity. Once we have that, I think we’ll be in a position to make a decision as to what dose to use ideally not only for the ALK patients but the EGFR patients.

If the safety and tolerability profile is good across the whole spectrum our clear preference of use 1 dose for all patients as the starting point. We believe we can achieve that, but obvious it will contingent upon having the remaining dose escalation data from this study. So, ideally one dose for all patients with 113. Let me turn the other question to Scott, the tolerability profile of 113 versus say the one or two other ALK inhibitors that are in development?

Scott N. Gettinger

So we did hear I guess two days ago now that about the other drugs that are targeting ALK and all the drug seem to have activity. LDK in particular there is many more patients with ALK rearranged lung cancer who have been treated compared to this, so it’s very hard for me to compare, just because we don’t have enough patients and plus we are still dose escalating whereas they got two doses of at least in the LDK trail of 750.

So what I can say is that there is two ways to evaluate tolerability, one is by looking at a table that is put up at a presentation on a paper that lists the percentage of grade, three, four, grade one, two toxicities. I think it’s very hard to truly understand the tolerability that way. And, although and that’s all you have, the other way is to treat patients. So I have not treated patients with the LDK drug, but I’ve had several patients who have been treated on that drug, at other centers.

And my experience from my patients and as well as the table that was put up at the presentation is that this drug has significant GI gastrointestinal toxicities and that was the experience in my patients as well as you can see listed, and requiring several dose reductions. So even those patients who were at the 750 milligram dose, lot of them have to be dose reduced, the once who were responding. And we heard the presenters say that that dose was felt to be required, that they were at no plans for them to go to a lower dose based upon tolerability because they felt that they needed that dose to affect in addition on ALK rearranged lung cancer.

So right, now, I think it’s too early to understand. What I can say is that my feeling from going through those tables and from knowing some patients on those trials that 113 has tolerated very well, majority of my patients have really not had much in the way of symptoms. I mean it’s kind of extraordinary with a drug. So that's just my anecdotal experience and I think we'll need more time to compare toxicities based upon tables and we just don't have enough follow up yet.

Cory Kasimov – JPMorgan

All right, thanks that's helpful. Harvey, can I just ask one quick follow up on the dosing question for ALK positive disease.

Harvey J. Berger

Of course Cory…

Cory Kasimov – JPMorgan

In those three patients who technically did not respond. What doses were they at?

Harvey J. Berger

We can answer that.

Cory Kasimov – JPMorgan

ALK or the EGFR?

Scott N. Gettinger

The ALK, I think it was 6 of 9 crizotinib resistant patients responded, 3 did not.

Harvey J. Berger

Hold on that – okay so you're trying to – Tim will answer this. You are referring to the three patients who were not considered PRs who had ALK+ disease right?

Cory Kasimov – JPMorgan

Correct.

Harvey J. Berger

Okay, Tim will answer.

Timothy P. Clackson

Thanks Harvey. Two were 120 and one was a 240.

Cory Kasimov – JPMorgan

All right great. Great, thank you very much.

Scott N. Gettinger

But remember that those patients, none of them progressed radiographically. They came off, because of adverse events and this – two of them came up because of adverse events and this third patient, depending on how you look at it, I might have called it a PR, but we were being very conservative because that small asymptomatic brain lesion which grew was initially thought to be non-small cell lung cancer, but it wasn't and if we knew that in retrospect the patient would have had a PR. So we've seen responses in all patients who had imaging assessments.

Harvey J. Berger

Right. So Cory, I missed, I thought you're asking about the three patients who failed to have progresses disease with EGFR mutant disease? So if are you asking about the ALK progresses?

Cory Kasimov – JPMorgan

Yes.

Harvey J. Berger

Those are at below doses and as Scott described and they were linked to adverse events than anything else.

Cory Kasimov – JPMorgan

Right, right, okay thank you.

Unidentified Company Representative

The numbers were actually 120 and two at 180.

Scott N. Gettinger

One of which was the melanoma patient.

Harvey J. Berger

That's correct.

Scott N. Gettinger

All right next question. Jim?

Operator

Thank you. The next question comes from the line of Jim Birchenough from BMO Capital. Please go ahead.

Jim Birchenough – BMO Capital Markets

Hi guys can you hear me?

Harvey J. Berger

Sure.

Jim Birchenough – BMO Capital Markets

Yes thanks for hosting the call. So few questions I guess, first for Dr. Gettinger. There is some suggesting that T790M may be present at base line in EGF mutant patients and it's a slower growing disease. You may unmask it with the Tarceva, so is there any work combining 113 with Tarceva, first question. Second question, do we know about the resistance pattern or we re-biopsying patients that failed 113, so we can understand what resistance mutations maybe driving that failure. And then the third thing and importantly Harvey, I want to understand the implications of this sudden death and specifically have you done any her channel assays with 113, any QT study and I guess from Dr. Gettinger’s perspective how worried should we be about that and what might have contributed beyond the drug to this one sudden death. Thanks.

Harvey J. Berger

Let’s see. Scott, why don’t you take the first question, your thoughts about combining with Tarceva.

Scott N. Gettinger

So first, so yes, with very sensitive techniques we have found a higher degree, higher frequency of T790M mutations in patients with known EGFR mutant lung cancer. There was a trial, the Eurotech trial, which they went back and they looked and they found a substantial number of patients have this. Now remember what we think is happening is that in a patient who has EGFR mutant lung cancer, it is very likely that there is a clone that has a T790M rather than just spontaneously developing that. And that clone is overshadowed by the majority of the tumor, which doesn’t have that secondary mutation. And then with time that clone grows up, so you give Tarceva, you shrink everything else out, and then you would expect that maybe the T790M clone would grow. And that might be quick, but more likely it’s going to be long, as most of the patients respond, we’ll respond for at least for 10 months, 8, 10 months. I mean the mean progression free survival is 10 to 12 months.

So you have to remember that when can’t understand that T790M is present. Now I would add it to Tarceva, I think the question would be is, would 113 be better than Tarceva in the first line. As I think that’s the more meaningful question because if you can target both the known activating mutations as well as the resistance mutation early on, it might delay the emergence of resistance to the compound. I mean there are other mechanisms of resistance and maybe those will come into play, but so that would be the – thing to think about.

In terms of other combinations, I can’t really talk to other combinations but from an academic point of view certainly combining a drug like 113 with other drug is very appealing because of the great tolerability. The side effect profile where as were limited so when we combine say afatinib and cetuximab, which works in some patients, but the toxicities, the rash they both claims the rash. So certainly it would be academically something interesting.

The last question about the repeat biopsies, yes we are certainly dedicated to doing biopsies on the developer resistance to 113, whether it's in patients who have ALK-rearranged lung cancer or EGFR mutant disease. And I think most if not all the investigators on the trial have repeat biopsy protocol where we do this, and we’re going to have tissue on the when patients acquire resistance to erlotinib or gefitinib. And then we are going to compare that obviously to biopsies that are collected at the time of acquired resistance to AP113. We might find that some differences might predict benefit or not. So we are all dedicated to doing that.

Unidentified Company Representative

Scott could you make a comment or response to a question about the sudden death in one patient, and then Tim will take the other questions.

Scott N. Gettinger

So we certainly didn't expect that death. It was a sudden death obviously. So the patient had only a few days of treatment and was found dead in a morning when he was seen the night before and he was doing okay. You have to remember that on Phase I trials of drugs that are first in human studies, we see this. And we are always alarmed by it, but it is not an uncommon finding that you most likely, and in most situations it’s not from the drug, it's because our patients are sick. You know they have lots of comorbidities, lots of other medical problems, and patients die. And if you see one patient with a sudden death on a clinical trial, it certainly make sure we’re aware, but it doesn't change my desire to develop this drug. Now if we saw more than one sudden death cases then that's a different story. But one death in and of itself does not detract from my enthusiasm about this drug, or increase my fear tremendously, because we haven't seen consistent problems in other patients, that might have in this patient you could have conceivably thought could led to the patient’s death.

So although you can exclude the contribution of 113 to this patient’s sudden death, there are certainly lots of other explanations in general why a patient with advanced lung cancer can die relatively suddenly from their cancer. So that's what I can say about that.

Jim Birchenough – BMO Capital Markets

Thanks Scott. Tim could you just answer briefly to the QTC question?

Timothy P. Clackson

In the non clinical studies and the functional that I have say that the compound has no inhibit activity greater than 10 micro milligrams, so there is no expectation you would have that kind of activity in Tarceva, typically excludes, patients of QTC prolongation from the trial, just see you can look at the signal the routine clinical (inaudible), there is no preclinical signal.

Jim Birchenough – BMO Capital Markets

Thanks guys, very helpful.

Harvey J. Berger

Next please.

Operator

Next question comes from the line off Joel Sendek from Stifel Nicolaus. Please go ahead.

Joel D. Sendek – Stifel, Nicolaus & Co., Inc.

Hi, thanks a lot. So a couple of follow-up questions. I wanted to just drill down on what you said earlier Harvey, that ideally you want one dose for 113, but I’m wondering is that might not be realistic anymore since, you have a response in EGFR 120, who knows what the reason for the death is 180, but it happened and I guess your dose escalating there, but it seems to me if you hear that dramatic responses you’re getting as well as 60 milligrams in ALK. In the ALK patients that if it doesn’t seem as if it’s we were heading that direction, can you help me with why it might still be feasible to continue to work here and end up at one dose? Thanks.

Harvey J. Berger

Nothing in the presentation is dated to-date changes are viewed as we can get to one dose for 113. I think in order to be sure that you’re inhibiting all of the mutations of 113 and many are known, many are not yet known and to maximize the depth of the inhibition and the duration of the inhibition overtime. You really want to go to a single dose. We think the depth at 180 is really almost not to remain to the issue whatsoever. And I don’t think just because we see responses at 60 milligram, 120 milligram, 180 milligram across the board that should change our view that we try to get to a single dose for both targets. We may conclude differently when we look at more data, but look what we know today, with the goal of maximizing duration, maximizing inhibition of mutations, we want to get to the highest dose we can. And also the tolerability profile even up to so far after including 240 milligrams, such that there is no reason not to go with a relatively high dose. We’ll see what the 240 cohort shows as we expand it and look at the following data and likely get to higher doses, then we’ll be in a position to look back and decide what doses to use?

Joel D. Sendek – Stifel, Nicolaus & Co., Inc.

Are you going to – beyond 240, is the next stuff 300?

Unidentified Company Representative

I mean more than likely yes. I think that’s reasonable something around 300 so to be 300, 320, something in that range, sure, but we’ll decide once we finish the 240 milligram cohort follow-up?

Joel D. Sendek – Stifel, Nicolaus & Co., Inc.

And then when will we get the next – sorry about the – just final question, when we will get the next dataset do you think?

Unidentified Company Representative

Next scientific meeting with the data are presented, probably the only thing that we’ll update on will be when we go into Phase II, which is likely to happen. I’m sure will happen before the next data update and it’s likely will disclose what dose we’re using at that point although not for sure. But certainly when we’re in Phase 2, we’ll make that publically know, but that’s it, until we have another scientific presentation.

Joel D. Sendek – Stifel, Nicolaus & Co., Inc.

Great. Thank a lot for the update.

Unidentified Company Representative

Thanks Joe.

Operator

Thank you. The next question comes from Phil Nadeau from Cohen and Company. Please proceed.

Phil Nadeau – Cowen & Co. LLC

Good morning. Thanks for taking my questions. Just a few brief ones, first, could you give us a bit more information on the duration of response in ALK patients. You touched on it, I am just wondering kind of what the ranges there? Second, have you looked at the T790M status in the EGFR mutant patients and what was that? And then third, on brain mets, your finding was really intriguing. I’m wondering how you kind of stay there in the future, given that brain met patients were excluded from the study. Do you try to do one that you look specifically on brain met patients. Thanks.

Harvey J. Berger

Frank you want to take those quickly.

Frank G. Haluska

Sure, so the question about the duration of response. We haven’t characterized it in a great deal of detail because the follow up on those patients are early, and those patients who’ve responded at the higher doses have only been accessed for the first time, that is that eight weeks. But the longest duration is as Scott mentioned, nine months in an ALK naïve patient because that patient started earlier the study and six months in a patient who has been previously treated with crizotinib. I said ALK naive, I mean crizotinib naïve.

With regard to the T790 characterization, yes, we’re in a process of characterizing genetically the tumors, seven patients have T790 mutations by history. In many cases, we’ve not yet analyzed the biopsies that led to the patients being on the study. In particular the one patient who responded did not have a T790M that patient had a Exon 19 dilution and we are waiting for additional material on that patient.

And the final question was the extent to which characterize brain metastasis for the patients. This is a good question, I think that this is a heterogeneous group of patients with small asymptomatic metastases and those certainly have an adverse prognosis, but of more meaning will be patients who have clinically apparent in progressive disease. And I think that can only be studied in a dedicated clinical trial and I wouldn’t rule that out at all in the future. I think that we do have first indication of clinical activity here and I think that the potential for studying that patient population is a good one.

Unidentified Company Representative

Frank, could you comment I think the – comment was made that brain met patients were excluded. I think there was a change along the way. You might want to just clarify that.

Frank G. Haluska

What we wrote was active brain metastases are excluded, that is patients who have clinical symptoms who require typically steroids or anti-epileptic medicines or patients who require active treatments. So patients with small lesions that are asymptomatic or a patient whose treatment dovetails well with the trial are allowed. We’ve actually formally amended the trial to make sure those patients do come on study. So this patient in particular wasn’t keeping with the eligibility criteria and as the trial moves forward, I think we’ll get a little bit better opportunity to characterize some of those patients.

Harvey J. Berger

Let’s move on.

Operator

Next question comes from the line of Ying Huang from Barclays. Please proceed.

Ying Huang – Barclays Capital, Inc.

Thank you for taking my question. I have a few for Dr. Gettinger. Number one, for that case of one dose-limiting toxicity of liver enzyme elevation. Do you know exactly how high that was compared to the upper limit of normal levels? And then was that also accompanied by a bilirubin increase in that patient or not? And then two, we saw four cases of greater than grade three pneumonia, can you give us a little bit color on that? And then do you think that’s drug related or not? And then three for the one patient who report response. Did that patient receive any experimental therapy including afatinib

and (inaudible). Thank you?

Harvey J. Berger

Scott do you know the details of the elevation in ALC in the one DLT, was that your case?

Scott N. Gettinger

It was – I mean, I don’t know about the bilirubin, so I’ll let Frank answer that I can certainly try the other ones.

Frank G. Haluska

So I’ll start with that, the patient had Grade 3 elevation not Grade 4, off the top of my head, you do not know the value of the elevation, but it’s in the neighborhood of five times up a little bit normal. Of note the patient’s elevation resolved after eight days and at 180 milligrams, the patient is a PR patient. So it was of clinical minimal import for the patient, and your other question was about bilirubin elevation. The answer to that is no, the patient didn’t have an elevated bilirubin, it’s not trending towards those cases of severe liver disease function that I characterize that way.

Harvey J. Berger

And then (inaudible) Scott?

Scott N. Gettinger

Yeah, I understand your concern about that. So there were four cases of pneumonia and with small molecule tyrosine-kinase inhibitors, we do see pneumonitis and with erlotinib, gefitinib, crizotinib they all have associated pneumonitis. So, but I think with these cases, they didn’t appear to be the typical pneumonitis cases where you have imaging which shows peripheral ground glass opacities that develop in a certain way. They appeared at least the two that are my patients, they appeared more pneumonia like, infectious either viral or bacterial and these patients were treated with antibiotics because that was the presumption not from a pneumonitis. But I agree that we need to keep a very close eye on that, because this is something that we’ve seen with other drugs. And then in terms of the other question in the patient who responded, I don’t know if the patient had any other experimental therapy that the EGFR mutant lung cancer patients have…

Harvey J. Berger

Scott, we’ll answer that stuff.

Unidentified Company Representative

Yes, the patient that has two rounds of chemo, Bevacizumab, as well as obviously erlotinib had not been on the afatinib cetuximab trial.

Ying Huang – Barclays Capital, Inc.

Okay, if I may…

Harvey J. Berger

Let’s move on, if we can, given the time.

Ying Huang – Barclays Capital, Inc.

Thanks.

Operator

Next question is from the line of Howard Liang from Leerink Swann. Please proceed.

Howard Liang – Leerink Swann LLC

Thanks very much. You mentioned that patient with a PR with EGFR mutation had exon-19 deletion. Talk about the two patients with stable disease, what the active mutation originally, just wondering if you have seen any activity in patient with (inaudible) patient with require the high exposure.

Unidentified Company Representative

And Howard I’m going to let Tim take this.

Timothy P. Clackson

As the majority of the patients have been on the trial so far have the background of the exon-19 deletion like history remember role of it by history for the moment. And one of the patients that had stable disease had a history also in that background T790M.

Scott N. Gettinger

That patient was my patient who had exon-19 deletion and then on repeat biopsy T790M mutation identified and that patient is the one who is having a clinical response, but stable disease and I will also add that that patient had been on afatinib and cetuximab and had progressed with worsening pain on afatinib and cetuximab.

Harvey J. Berger

Next question.

Operator

Next question is from the line of Mike King from Dawson James. Please proceed.

Mike King – Dawson James Securities, Inc

Hi guys thanks for taking my question. I wanted to just see if I could ask about how (inaudible) next question a little bit differently and find out how much PK work was done in conjunction with the trial because what I am curious about is, do you know what kind of blood levels you had in these EGFR mutant patients and whether you have a sufficient concentration to block the receptor, and is that – do we know if that MTD is going to be the biologically optimal dose based on what we know so far.

Harvey J. Berger

I’ll let Tim take that. In brief, so all the t-kinase we have it’s valuable at the moment is in the presentation that went up to 180. So you can see the trough blood levels there high doses match and in some cases exceed the target the IC50s increase clinical studies for EGFR, that doesn’t mean that the optimal concentration that hit to get the effectively once. You need to be substantially above the IC50 we believe also we need take into account issue such as oncology, penetration to the tumor. So as it was mentioned earlier, our strong (inaudible) pull all the way to the MTD and find a way to get the maximum exposure of the drug to the patients. That’s the best way to deal with resistance and supposedly give a prolonged effect.

Mike King – Dawson James Securities, Inc

Tim given the half life, is it possible though just got to their ID dosing with 113 or is that out of the question?

Timothy P. Clackson

We want to go to be, I don’t think we want to go to DLT given the long half slides.

Mike King – Dawson James Securities, Inc

Okay, thank you for answering the question.

Harvey J. Berger

Can we have the next question please?

Operator

Thank you. It’s from line of Ryan Martins from Lazard Capital Markets. Thank you.

Ryan S. Martins – Lazard Capital Markets LLC

I’ll ask some of the question, so given that one DLT patient actually resolved and had a PR on a lower dose. I’m trying to understand what kind of flexibility you may have on your dosing even if you do see your DLT in the three expanded patients at 240 mg. And then just another one is on the mutations that are characterized historically, when are these characterized, are these characterized at the time of progression, or this is historically when the patients were first diagnosed?

Harvey J. Berger

Frank why don’t you take the first question about the protocol, and may be Tim will take the second.

Frank G. Haluska

Sure. So thanks Ryan. The flexibility that we have around the observations that we might make at 240 is still an open question. In that, not all DLTs are equivalent. This patient for instance had what was by protocol definition, dose-limiting toxicity that is a Grade 3 non-hematological toxicity, but the patient remained on study and went on to have a partial response with dose modification. So if we were to see a similar event, I think we’d undertake a discussion with the investigators as to what they thought the meaning of those observations were, if for instance, we saw something that was not reversible or more consequential for the patients that would have a different implication.

So the short answer is that there is some flexibility about our thinking and we can only wait and see what the data show us at 240.

Timothy P. Clackson

All right. And Ryan Phase III will affect looking at mutation, in this part of the trial, the Phase 1 trial, we only require the tissues available historically, and those are the basis that we have so far, were available we will look at tissue from more recent history including potentially trial entry.

Let me move to the Phase II portion for the resistance cohort we will then require an immediately prior tissues, and that will give us more information obviously and exactly what the patient had at entry, and with the investigators we’re going to try as much as possible to get closer samples as well.

Harvey J. Berger

All right, next question please.

Operator

Next question is from Ling Wang from Summer Street. Please proceed.

Ling Wang – Summer Street Research Partners

Thank you for taking my questions. I was wondering whether you can provide more details on the seven patients with T790 mutation, EGFR mutation, what are the doses we received the drug and how many of them had stable disease or disease progression? Thank you.

Harvey J. Berger

That’s a little bit difficult to run free for the patients in term. I think perhaps maybe I’ll just focus on the last part of your question. The two patients that has stable disease, as Scott mentioned one of them was hit and that patient had a history of T790M, the other patient did not. Of course we can’t know whether that mutation subsequently might have developed after the historical sample was taken.

Ling Wang – Summer Street Research Partners

Okay, you comment on the doses that this patients received?

Harvey J. Berger

One of the patients with stable disease, the one I just mentioned there was stops at 120 mg and the other was on 180 mg.

Ling Wang – Summer Street Research Partners

Thank you.

Harvey J. Berger

Next question please.

Operator

Next question is from the line of Katherine Xu from William Blair. Please proceed.

Y. Katherine Xu – William Blair & Co. LLC

Thank you. I am just wondering, Tim, more of the exon-20 insertion mutation that for that naïve patients. Did you see activity retro with 113?

Timothy P. Clackson

We still evaluate things that we just began to look at our confront years as Scott mentioned that was the next month from an extremely challenging activating mutation. So that’s why we didn’t have those preclinical data in the in close of it the presentation because they are not really ready yet. That was clearly the greatest we had at our activity but at this stage we just don’t can’t characterize that.

Y. Katherine Xu – William Blair & Co. LLC

Okay, and then for the three progression disease, could you comment on the mutation data you chose as well?

Timothy P. Clackson

Are you talking about with the EGFR?

Y. Katherine Xu – William Blair & Co. LLC

Yeah, the three PD.

Timothy P. Clackson

Yes, they had a mixture of typically extra 19 ways over that T790M mutation. I think it’s more relevant to think about the treatment history as opposed to their own mutational history. They will have all the patients very heavily in multiply pre-treated.

Y. Katherine Xu – William Blair & Co. LLC

Thank you.

Harvey J. Berger

Okay. Next question please.

Operator

This is from the line of Echo He from Maxim Group. Please proceed.

Echo Yinghui He - Maxim Group Securities

Hi, thanks for taking my questions. Just from the drug mechanism standpoint and what would you think the reason that you feel like EGFR would require higher dose than the ALK presentation, is that because the expression level of these two molecules or is it because the specific affinity of 113 to these two type of molecule. Sorry also the – have you ever seen any evidence of ALK-mutation that voluntary might be active against?

Scott N. Gettinger

So firstly, the drug intrinsically more active against ALK than EGFR in our preclinical studies. This is the consequence of its structure and fit into this two binding pocket, this hit both the IC50 to lower for ALK.

Second question is a very important question, in our preclinical studies that have been presented, we’ve actually done complete mutational streams to characterize resistance mutations to 113. And we know that there are certain concentration there are no such mutations that developed, in other words we can overcome them. And the kind of drug levels we are seeing in patients now are in that range. So there is a possibility that all potential ALK mutations that lead to crizotinib resistance will be overcome by one month free and that there maybe no mutations that can emerge at the doses we’re applying. Obviously we will test that in our future clinical works.

Echo Yinghui He - Maxim Group Securities

Okay, thank you so much. I understand.

Harvey J. Berger

Thank you. I believe that’s the last question. I would like to thank all of the participants, all of our analyst’s who post questions this morning for their active participation. I’d also like to personally on behalf of all of us thank all of our investigators from Yale, the Translational Genomics Research Institute, the University of Chicago, the University of California, San Diego, the MGH, University of Colorado, and the University of Pennsylvania; and importantly all of the patients who participated in the trial and for their commitment to helping advances program.

I particularly like to thank Dr. Scott Gettinger, who spent a good part of the morning today on the call and talking with investors very much appreciate his extra efforts trying to help all of us understand these results. So we look forward to moving to Phase II to updating everyone on the further development, clinical development of 113, and remind everyone of our investor and analyst day in a couple of weeks in New York and I think everybody should already have – of our investor group received invitations. So thank you very much and that will be the end of our call.

Operator

Thank you for your participation in today’s conference. This concludes the presentation. You may now disconnect and have a good day.

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