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Epizyme Inc (NASDAQ:EPZM)

EPZ-5676 DOT1L Inhibitor Findings in Phase 1 Dose Escalation Study Conference Call

November 14, 2013 8:30 AM ET

Executives

Stephanie Ascher – Investor Relations

Robert J. Gould – Chief Executive Officer

Eric E. Hedrick – Chief Medical Officer

Jason P. Rhodes – President and Chief Financial Officer

Robert A. Copeland – Executive Vice President and Chief Scientific Officer

Analysts

Jonathan M. Eckard – Citigroup Global Markets Inc.

Raymond R. Chang – Cowen & Co. LLC

Gregory R. Wade – Wedbush Securities, Inc.

Charmaine Chan – RBC Capital Markets

Howard Liang – Leerink Swann LLC

Operator

Good morning and welcome to Epizyme's conference call to discuss initial results for the ongoing Phase 1 trial of EPZ-5676. 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 Epizyme's request. I would now like to turn the call over to the Epizyme team. Please proceed.

Stephanie Ascher

Good morning Stephanie Ascher with Stern Investor Relations. And welcome to Epizyme’s call this morning to discuss initial finding from the Dose Escalation stage of the Phase 1 Trial of EPZ-5676, or DOT1L Inhibitor. Please note that there are supplementary slides which you can find in the investors center section of the website, where you can also listen to a live webcast or replay of today’s call.

Before we begin, I would like to remind that today’s discussion will include statements about the company’s future expectations, plans and prospects that constitute forward-looking statements for purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including those discussed in the risk factor section of our 10-Q filed with the SEC on August 23, 2013.

In addition, any forward-looking statements represents our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change.

Now, I’ll turn the call over to Epizyme’s CEO, Robert Gould.

Robert J. Gould

Thanks Stephanie. We are very pleased to provide an update this morning on the EPZ-5676 clinical program and to discuss our future plans. Before we begin, let me thank everyone and draw all of your well wishes over the past several weeks. My cardiac surgery in October was successful and I am actively reengaging here at Epizyme, while I continue my recovery.

We are highly encouraged by the results of your sharing with you today and look forward to initiating the planned MLL-rearranged only expansion stage in December. 5676 is a first-in-class, small molecule inhibitor of DOT1L histone methyltransferase. It was discovered internally by Epizyme scientists using our product platform. Epizyme along with our partner Celgene is developing 5676 for the treatment of the acute leukemias with alterations within the MLL gene.

As a result of this specific identifiable genetic alternations, DOT1L is miss regulated and causes inappropriate methylation, resulting in the increased expression of genes that cause leukemia. We have published extensive pre-clinical data on the anti-leukemic effects of DOT1L inhibition in cancers with genetic alterations within the MLL gene referred to as MLL rearranged or MLL-r and MLL-PTD. Highlights of our pre-clinical data are provided for your reference at the end of this presentation.

We are completing the dose escalation stage of on going Phase 1 study of 5676 with 16 patients enrolled in the first 4 cohorts and are very encouraged by the initial findings which I will summarize.

Eric Hedrick, CMO will then describe these results in greater detail. As a first-in-class therapeutic candidate in a novel target class, evaluating safety and tolerability were central goals for the dose escalation stage of this study. To-date, there have been no dose-limiting toxicities observed and a maximum tolerated dose has not been encountered. This favorable safety and tolerability profile is a meaningful result for the DOT1L program and the entire HMTome target class.

It is also important as it allows us to continue to both escalate the dose and modify the administration schedule in the planned MLL-rearranged expansion stage. Determining the pharmacokinetic and pharmacodynamic relationship between dose exposure and methyl mark inhibition was also an important goal for this stage. In the dose escalation study to date exposure was proportional to dose as expected.

We also saw clear dose-in-time dependent methyl mark inhibition. For the primary objectives of the dose escalation stage were to evaluate safety, PK and PD we have enrolled eight patients with acute leukemia with MLL-rearrangements in cohorts 2 through 4. We observed treatment effects in four of these MLL-rearranged patients and do not see treatment effects in any non MLL-rearranged patients.

These treatment effects included blast count reductions, differentiation effects and the resolution of the leukemia related symptoms. The safety PK/PD and treatment effects observed are consistent with the genetically defined therapeutic mechanism of action in our preclinical data. And we are highly encouraged as we move ahead to the next stage of this clinical program.

I will now turn the call over to Eric, who will provide a more in-depth review of the dose escalation study results.

Eric E. Hedrick

Thanks, Robert. I will provide more detail on the initial findings in the dose escalation stage of the study. We completed four dose cohorts with doses of 12 mg/m2/day, 24 mg/m2/day, 36 mg/m2/day and 54 mg/m2/day respectively. 16 patients were dosed within these cohorts and a fifth dose cohort at 80 mg/m2/day is currently enrolling patients. All cohorts to date have evaluated a 21 day on, seven day off treatment schedule.

The majority of the patients had a diagnosis of acute myeloid leukemia. Other diagnosis included acute lymphoblastic leukemia and chronic myelomonocytic leukemia. As Robert mentioned the re-arrangement of MLL was present in nine patients, eight with acute leukemia and one patient with chronic myelomonocytic leukemia and transformation. This is a heavily pre-treated patient population and includes six patients who are in relapse after allogeneic stem transplantation.

Overall 5676 have been extremely well tolerated and there have been very few events of adverse events of concern. Specifically there have been no dose limiting toxicities, no toxicities requiring either treatment interruption or dose reduction and no evidence to date of the dose toxicity relationship. There has been only one discontinuation of 5676 due to an adverse event. And in this case a patient with intracranial bleeding in the setting of severe thrombocytopenia related to progressive leukemia was considered unrelated 5676.

There has been only one great three event believed to be possibly related to the 5676, neutropenia in a patient that remains on study treatment as the assigned dose in the fourth dose cohort. Note that leukocytosis has occurred in two cases, but this is considered treatment related and not an adverse event. As we will be discussing greater detail in a minute, we have also seen treatment effect in four of the eight MLL-rearranged acute leukemia patients, while no such observations have been made in patients without MLL-rearrangement.

This selective treatment effect is consistent with the genetically defined therapeutic hypothesis. The pharmacokinetic profile of 5676 for the fourth dose cohort, this study demonstrates steady state exposure levels of 5676 have been dose proportional, ranging from approximately 150 nanograms per mil in cohort 1 to 550 nanograms per mil in cohort 4. Variability has been modest, 2 to 2.5 fold with the exception of a single high exposure outlier in the third dose cohort.

The pharmacodynamic effects of the 5676 on DOT1L target inhibition, as we’re measuring by methyl mark inhibition of the DOT1L target H3K79 in peripheral blood mononuclear cells, has been highly informative. First, at doses greater than or equal to 36 milligrams per meter squared, methyl mark reduction has been consistently observed.

Secondly, and perhaps more importantly, the kinetics of methyl mark inhibition demonstrate declining levels of methyl mark over time throughout the 21-day treatment course with the recovery of methyl mark approaching baseline levels after the 7-day off drug period. This suggests that a continuous, uninterrupted schedule of 5676 maybe required to maximize target inhibition. Fortunately, the highly favorable safety profile seen to date supports this schedule of administration. This will allow us to evaluating an uninterrupted schedule of 5676 in the MLL rearrangement only expansion stage of the study and to potentially continue dose escalation, if indicated.

With the current 21-day treatment schedule we do observe treatment effects of 5676 in patients with MLL rearrangement. As we’ve noted previously, a patient with MLL rearranged acute lymphoblastic leukemia in the second dose cohort exhibited evidence of 5676 treatment effect manifested as a significant reduction in circulating blast and resolution of leukemia-related fever. In the most recent dose cohorts of the study, we’re seeing three additional patients with MLL rearranged acute myeloid leukemia with treatment effects suggestive of a differentiation mechanism of activity. Some patients have also had resolution of certain leukemia-related symptoms such as fevers and cachexia. In one case, resolution of leukemia cutis, which is a cutaneous manifestation of leukemia, was noted.

Finding supportive of a differentiation effect include treatment related leukocytosis and evidence of cellar differentiation and maturation in the bone marrow, in one case with a reduction of blast percentage in the marrow. Further supportive of maturation of leukemic cells is the fact that we, through collaboration with Dr. Scott Armstrong at Memorial Sloan-Kettering Cancer Center have demonstrated the MLL translocation in mature, circulating neutrophils using a FISH analysis.

We note that these findings are preliminary and have been transient in nature with the possible exception of a patient in cohort 4, who remains on study treatment. However, given that the terminal effect of 5676 in MLL rearrangement leukemia cell lines in vitro appears to be related to differentiating effects on blast, we find these observations in patients to be very encouraging and consistent with the mechanistic hypothesis.

The fully characterized clinical effect of 5676 in MLL rearranged leukemia patients will require a longer follow-up and treatment of additional MLL rearrangement leukemia patients with the uninterrupted treatment schedule 5676 in the expansion stage of the study.

Based on these encouraging findings to date, we are moving ahead with our planned expansion with proof of concept clinical programs of 5676. As we’ve discussed, the current Phase 1 study in DOT1L transition to an MLL rearrangement only expansion stage this December, which will afford the opportunity to evaluate an uninterrupted administration schedule of 5676 in larger cohorts of MLL rearranged acute leukemia patients. We expect this stage to initiated the current dose of 80 mg/m2/day and again administer the drug on a continuous uninterrupted schedule. The continuous enrollment design will also allow for dose escalation wanted and the selections of Phase 2 dose will depend on the safety, PD and activity profiles of this treatment schedule.

Given the data from the dose escalation stage of the study and the treatment effects observed we expect expansion stage of the study to provide an initial assessment of clinical efficacy for 5676.

We also believe that the data from the current dose escalation study in adults supports the initiation of this study of 5676 in pediatric patients in early 2014. This study will be restricted to patients with the MLL-rearranged acute leukemia and will be similar in design to the adult study with the dose escalation phase and in expansion stage that we would expect to provide an initial assessment clinical efficacy.

Lastly, we plan to incorporate patients with the MLL-PTD abnormality into clinical trials in early 2014. These patients will be eligible during the MLL rearrangement only stage of the current study and we expect to initiate a dedicated MLL-PTD expansion cohort in 2014.

We are really pleased with the progress of the 5676 program and our entire portfolio, including EPZ-6438 or EZH2 inhibitor, which is currently in a Phase 1 dose escalation study. The 6438 study continues to enroll patients no dose-limiting toxicities have been observed to date. Across both of our clinical programs we expect to have four or more proof-of-concept studies ongoing in 2014.

I will now turn the call back to Robert.

Robert J. Gould

Thanks Eric. The 5676 Phase 1 study is proceeding as planned. As 5676 is a first-in-class inhibitor in a novel target class demonstrating a highly favorable safety and tolerability profile is a significant milestone and a necessary precondition for moving ahead. The treatment effects that we have observed in acute leukemia patients with MLL-r during the dose escalation stage are consist with a therapeutic mechanism of actions for this program and are clearly encouraging.

2013 has been an enormously important year for Epizyme as we translate the science of epigenetics into innovative, personalized therapeutics for patients with genetically defined cancers. 2014 will be another important year for Epizyme, the entire field and most importantly for patients as we advance our clinical programs in multiple proof-of-concept study.

Thanks everyone for your time and attention this morning. We’ll now take questions.

Question-and-Answer Session

Operator

Thank you. (Operator Instructions) Our first question comes from Jonathan Eckard with Citi. Your line is open. Please proceed.

Jonathan M. Eckard – Citigroup Global Markets Inc.

Good morning. Welcome back, Robert, and thanks for taking the questions. I was just wondering, if – a couple here. Could you just let us know if there was any common mechanism of progression or form of progression in the patients in the trial? And then my second question is regarding the rebound, I guess based on earlier data it seem like the 5676 actually had a pretty high residence time on the histone, and I was wondering if that rebound or the magnitude of that rebound was surprising and how that could be impacting the clinical results today. Thank you.

Eric E. Hedrick

Hi, Jon. Thanks for the question. This is Eric. Yes, in regard to the type of progression of disease, we cannot seen one particular pattern. They have all been fairly typical for the way that acute leukemic patients would progress either progression based on rising blast counts in the blood and or marrow, but we’ve not seen any one particular unusual pattern in the progressive disease cases. And maybe I’ll let Bob comment on the kinetics of the methyl mark.

Robert J. Gould

Thanks Eric and thanks for the question. Actually the rebound data that we are seeing is quite consistent with the preclinical data and the long residence time that we’ve associated with 5676. That rebound is measured seven days after the cessation of dosing. We don’t have any intermediate time points between stopping the dose and that seven day point. And if you look at the data even after seven days without drug the methyl mark has not returned to baseline.

And so that is completely consistent with our preclinical data, and that rebound based on the preclinical data will be a function of the dose as well as the duration of the exposure to the drug that we see and so moving to an uninterrupted schedule and higher doses we think will be most beneficial to patients.

Eric E. Hedrick

Yes, this is Eric I guess. If anything I would add is one of the I think important things for learning from the study so far is that 5676 has differentiated in qualities and if think of differentiation agents in leukemia, the kinetics of the response require that you treat for prolonged periods, and I think we are happy to see particularly safety wise that we are going to be able to do that, so I think that’s probably one of the more important things we learned from the study so far.

Jonathan M. Eckard – Citigroup Global Markets Inc.

That's great. I'm sure there is other questions, so I will get back into queue.

Operator

Thank you. And our next question is from Simos Simeonidis with Cowen & Co. Your line is open. Please proceed.

Raymond R. Chang – Cowen & Co. LLC

Good morning, it’s Ray Chang actually in for Simos this morning. Thanks for taking the question. I just wanted to ask why – if you could comment on why you think the other four MLL-r patients didn’t respond. Was their response perhaps in terms of methylation that did not translate to a clinical response? And if this is the case, just wanted to get your thoughts on what the hypothesis may be.

Eric E. Hedrick

Yes, hi, Ray. Thanks for your questions. You know maybe I’ll start out just kind of reminding people that this is a dose escalation study and the point here is really to understand safety and tolerability primarily and the fact that we’re seeing treatment affects is encouraging, but I think we’d be too preliminary to draw any conclusions about rate of response. I guess the thing I would also say is that we’re now at dose levels where we’re hitting the target consistently. We understand those schedule and that’s likely to be optimal and I think that really encourage value and as we go into this expansion phase we’re only treating MML-r disease at or get inhibited dose adding up the scheduled really to get a better sense of clinical efficacy.

Raymond R. Chang – Cowen & Co. LLC

Okay, great. Thanks. I’ll get back in the queue.

Eric E. Hedrick

Thanks.

Operator

Thank you. And our next question is from Greg Wade with Wedbush. Your line is open.

Gregory R. Wade – Wedbush Securities, Inc.

Hi. Good morning and thanks for taking my questions. Robert, welcome back, and Eric, congratulations on a little success that occurred yesterday. It is something you worked on as well. I wonder if you might expand on some of the work that’s being done to identify characteristics of the responder population and perhaps the nonresponder population. I know you have sort of addressed this previously. But is there any commonality in the history of what patients have received perhaps in prior treatment that might predict response or absence of response? And what basic science are you doing on samples to better characterize this? Thanks.

Eric E. Hedrick

Thanks, Greg. And maybe I will start kind of toward the end of that question. In that we’re looking at a variety of factors that can potentially correlate response including the particular fusion partner. We are going to be able to assay for changes in gene expression profile ultimately. So I think we are looking at a variety of things that in time, once we have a better appreciation of the efficacy we can start to tease out responder versus nonresponder.

As to what we’d able to say at this point is really limited. I mean this population in general is a typical AML Phase 1 population. It’s really highly pretreated and includes many patients who failed allo transplant, which obviously gives you a sense of how heavily these patients have been treated. And so I guess the other that’s important to keep in mind is really starting to understand this drug as a differentiating therapy. And remember that differentiation therapy is sort of cause-response over a different time course than cytotoxic therapies. So I mean that’s why we really think that once we get into the next stage of study we’re delivering the drug in an optimal way and we’re able to follow patients for longer that we are just going to get a better sense of the kind of questions you have.

Gregory R. Wade – Wedbush Securities, Inc.

And then just to quickly expand on that. Was there any similarities in the way the patients responded in terms of changes in methyl mark, the time course of that response, and then their subsequent clinical response? And then lastly, if this is a differentiation effect, is there a rational combination that you think would make sense based upon the changes that you are having on the tumor? Thanks.

Eric E. Hedrick

Yes, and so again, with limited numbers of patients it’s difficult to comment definitively on the pattern. What we can say is that all the patients who have had treatment effects have had methyl mark inhibition, so there is some correlation there. And again, we’ll just need to treat patients with an optimal schedule for longer to further understand whether there is a typical profile involved. All the patients who have had treatment effects have started to manifest those effects within the first treatment cycle. That is one other thing that we have seen. And then – I’m sorry – I forgot the second part of your…

Gregory R. Wade – Wedbush Securities, Inc.

Once you have differentiated the tumor, is there a rational combination that makes sense?

Eric E. Hedrick

Yes, so it’s interesting. So at ASH this year, we’ll be some preclinical data that looks 5676 in combination with most or all of the standard-of-care leukemia treatment agents and we tend to see synergistic activity. And again, what’s the mechanistic basis mechanistic basis of this, I’m not sure we entirely understand. But it would make sense that a differentiation effect, which is really addressing one of the fundamental properties of leukemia cells, right, differentiation blockade, would lend itself towards combination with other agents. And I think the other thing that’s encouraging even at this early point is that toxicity-wise, we don’t see any reason why we wouldn’t ultimately be able to combine this drug with other agents in the clinic.

Jason P. Rhodes

Greg, this is Jason Rhodes. Thanks for the question. So we see pre-clinically very clearly is that with sufficient dose and exposure over time that we really have profound tumor regression as a single agent. And the data that we’ve seen so far in the clinical study doesn’t give us any reason to think that that won’t translate.

Our observation really is that 21 days is not a sufficient period of exposure and of course, we are still dose escalating. So we’ll continue to increase dose as well. And so assuming that this is a differentiating effect that we’re seeing, that will take some extended time course we believe to see that kind of durable efficacy. We think of that longer-time course just to be very clear about it. It is not indefinite.

We know that we’re talking about with other differentiating periods of let’s say up to 60 days. And so again we don’t know anything today that will cause us to think that we will need significantly different time course. So given that the expansion stage will help us to assess this question of whether we can get to efficacy with a change in the administration schedule presuming that that’s the case, we do continue to plan to develop this drug as a single agent. That said the synergy that we see in combination we are presenting at the ASH; there are number of abstracts that published recently.

The ability to see increased efficacy in combination is attractive, at a subsequent stage of clinical development and we imagine that we’ll probably pursue that as well over time.

Robert A. Copeland

And this is Bob Copeland. I’d also just add to that to remind folks that in the preclinical setting in both cell culture and in venografts, the differentiation effects that we saw across a range of different MLL rearrangements were always terminal.

Operator

Okay, thank you. (Operator Instructions) Our next question is from Jonathan Eckard with Citi. Your line is open. Please proceed.

Jonathan M. Eckard – Citigroup Global Markets Inc.

Hello again. Just was wondering a couple more questions. Do you think you need to add the 28-day continuous infusion into the Phase 1 before starting the expansion cohorts for safety just for safety reasons?

And the other one is could you explain what were the criteria for progression in this Phase 1 trial? And based on the mechanism, as well as the results you’ve seen, would there be logic in potentially incorporating a modified response criteria that may allow for minor progressions in the early part of treatment in order to get to a point in the treatment course where the drug could kick in?

Robert J. Gould

Thanks. May I will tackle the last part first. So how to judge progression in the study really is a discretionary and the investigator makes a call as to whether the disease is stabilized or is improving in some way or has progressed and might think you made a good point which is, this drug doesn’t look like it’s directly cytotoxic. It looks like it works through other mechanisms with those kind of agents. Yes, you need to integrate in kind of the clinical assessment into the standardized response criteria. And if you wouldn’t mind repeating the first part of the question, that would be great.

Jonathan M. Eckard – Citigroup Global Markets Inc.

Well, the first part was, do you feel that you have to I mean, I know the drug has been safe to date, but is it needed to do a 28-day continuous infusion in this Phase 1 portion before starting the expansion cohorts?

Robert J. Gould

Now, we think that we can directly go into the continuous, uninterrupted treatment schedule. We’ve really seen no toxicities that are recoverable, where you need the seven day off period to recover and so we feel entirely comfortable migrating straight into that schedule.

Jonathan M. Eckard – Citigroup Global Markets Inc.

Okay. Thank you.

Operator

Thank you. And our last question is from Michael Yee from RBC Capital Markets. Your line is open.

Charmaine Chan – RBC Capital Markets

Hi, this is Charmaine on behalf of Michael. Thank you for taking our questions. First one has to do with the number of cycles that patients in cohort 2 and 3 have had completed to date. And since you are following them and they get treatment effects quite early, are you seeing any changes in these treatment effects?

And secondly, with the uninterrupted dosing going forward in the next expansion trial, can you help us understand how that might or might not impact the frequency and grades of neutropenia that you are seeing because you do have one patient with Grade 3 in cohort 4. Thank you.

Eric E. Hedrick

Sure. And so that’s Charmaine. The first question is really about the length of therapy in the cohorts thus far. So actually the longest treatment course on study so far has been four cycles and they think on slides that we accompanying the presentation today, you’ll see that in the third dose cohort of particularly the patients who had treatment effects who ultimately had progression disease have between two and three cycles of therapy. But I think it’s safe to say – and there were patients in the fourth dose cohort who are ongoing study treatment. And so I think that the bottom line is again because of what’s becoming clear about the mechanism of action of the drug versus the continuous treatment schedule over multiple cycles is what’s going to be required here.

Yes and that sort of relates to expectations for the next stage of the study and once we start administrating the drug in what we believe to be an optimal way will be able to really understand the clinical efficacy in a much more clear way.

Charmaine Chan – RBC Capital Markets

And the neutropenia and the uninterrupted administration?

Eric E. Hedrick

Yes. So neutropenia has not been an event that has been a recurrent event in the study. And so what to make of one patient that’s an isolate neutropenia we’re just not sure and that’s been one of the interesting encouraging findings today when you look across the adverse events. There is really nothing that stands out as a recurrent event that would make us think of an association. So I mean at this point of the study we’re really fortunately just dealing with kind of isolated occurrences and I don’t know if that predicts anything for the next stages of study.

Jason P. Rhodes

All right. And this is Jason. I’ll just eco something that Eric said. So this study was obviously dose escalation study designed to assess safety PK and PD and it was meant as a prelude to the expansion stage that we planned to initiate next month. So in terms of the study design, we’re very pleased with the results. We have a very clear understanding of the safety and tolerability profile which is highly favorable and we also understand PK to be dose proportional and regarding PD that it’s dose and time-dependent.

So we think we are in a very good position to actually ask the question about whether we can achieve durable efficacy in the expansion stage, recognizing that it was a dose escalation study, not a Phase 2 or an efficacy study. We were nonetheless very fortunate to see a number of leukemia patients with MLL-r and to then see treatment effects both in terms of blast count reductions and also leukemia related symptoms among a set of them that are consistent with the genetically defined therapeutic hypothesis.

So in regard to those two things, the result of the study really have exceeded our expectations and we are very excited and very interested as I think everyone in this call is, to begin the expansion cohort stage with this modified administration schedule and to be able to assess efficacy and also continued safety obviously coming to that study.

Charmaine Chan – RBC Capital Markets LLC

All right. I agree, and the data is very interesting. The last point I would just make is given this promising early results, is there a correlation to whether you think 80 mgs is in the biologically effective range from preclinical studies, anything that would lead you to think that you’re sort of hitting in the right dosage range already? Thank you.

Eric E. Hedrick

Yes. So based on what we’ve seen so far, we know that 80 milligrams will be within the target inhibitory range. What we need to understand and this is highly suggested by the data so far that if we don’t interrupt the treatment, we will drive towards maximal target inhibition and that’s really what we need to understand first in the next stages of the study and then we have a design that will allow escalation if needed, but I think we’re at a really get starting point in that, we know that starting dose is going to be a target inhibitory dose and then we will be very interested in learning early how will the uninterrupted schedule relates to the extend of methyl mark inhibition and hopefully the treatment effects that we hope to continue to see.

Charmaine Chan – RBC Capital Markets LLC

Great, that’s very helpful. Thank you guys.

Eric E. Hedrick

Sure, thank you.

Operator

Thank you. And our last question is from Howard Liang with Leerink Swann. Your line is open.

Howard Liang – Leerink Swann LLC

Hi, thanks very much. I guess it's a very small number of patients, but do you feel that there is a dose response beyond what you described in the treatment effect column. Just is there anything that you see there is a dose response?

Eric E. Hedrick

Yeah, thanks Howard. As you felt the number is really too small to make that sort of conclusion. We do know that once we get above 36 milligrams per meter square, we are inhibiting target not square we are seeing these treatment effects and so the optimal effects will be on activity. I think we want to really understand until we start giving this drug and then optimize way without the drug holiday.

Jason P. Rhodes

Right. Howard, this is Jason. What we see and this is on Slide 11 in the presentation is that, the methyl mark at doses in both the third and fourth dose cohort are continuing to decline and so just as we are approaching what we think based no pre-clinical data is sort of a necessary inhibitory level to drive efficacy, we are pulling patients off drug and fundamentally that schedule is obscuring this treatment effects that we are seeing and that could over time translate into efficacy. And so we are obviously very interested in continuing to understand both the time dependency, but also the dose dependency and think we are well setup to explore that and understand it in the expansion stage.

Howard Liang – Leerink Swann LLC

I may have missed it, but what was the reason why this dosing regimen which drug holiday was chosen?

Jason P. Rhodes

Yes. I think this gets back to the fact that this is first-in-class drug against a completely novel group of targets. It is first HMT inhibitor ever to be tested in patients and there the right thing to do was design this conservatively from the start and allow for off drug period in the event that we saw toxicities that were required that what we know now is that we are not seeing those toxicities.

Howard Liang – Leerink Swann LLC

With the optimized regimen, can you talk about for this disease what you would like to see, whether it would be full-blown CRs, PRs, or bone marrow suppression?

Jason P. Rhodes

Yes and so we’re evaluating this drug as it would any potential leukemia agent and we will be using sort of the standardized response criteria that guide for how active and efficacious drug is. So we will be looking for this drug to actually induce responses post end-of-life criteria.

Howard Liang – Leerink Swann LLC

Okay, thank you very much.

Jason P. Rhodes

Yeah, thank you Howard, we appreciate it.

Operator

Thank you. And I am not showing any further questions at this time. Mr. Gould, please proceed with any further remarks.

Robert J. Gould

I just wanted to conclude by thanking everybody for their time and attention to this and hope you got a sense of our excitement and enthusiasm for 5676 as we move into the expansion cohort in our only patients with the 80 milligram per kilo dose, as well as the continuous infusion.

I think the pristine safety profile that we’ve seen today is the dose proportional pharmacokinetics and pharmacodynamics that we demonstrated with really the objectives that we targeted in the first Phase 1 study and we are highly encouraged by that. So thank you very much for your time and attention.

Operator

Ladies and gentlemen, thank you for participating in today’s conference. This does conclude the program and you may all disconnect. Everyone have a great day.

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