Dicerna Pharmaceuticals, Inc.
Q3 2015 Earnings Call Transcript

Published: 11 Nov 2015

[Operator:]

Good day, ladies and gentlemen, and welcome to Dicerna Pharmaceuticals Third Quarter 2015 Earnings Conference Call. At this time, all participants are in a listen-only mode. Later, we will have a question-and-answer session later on, and the instructions will follow at that time. [Operator Instructions] As a reminder, this conference call may be recorded. I will now like to introduce you host for today's conference, Peter Vozzo. Please go ahead.

[Peter Vozzo:]

Thanks, Charlotte. Good afternoon, and welcome to Dicerna's conference call to discuss 2015 third quarter financial and operational results. For anyone who has not had the chance to review our results, we issued a press release after the close of market today, outlining today's announcement, which is available under the Investor tab on our website at www.dicerna.com. You can also listen to this conference call via webcast on our website. It will be archived there for 30 days beginning approximately two hours after this call is completed. I'd like to remind listeners that we'll be making forward-looking statements on today's call. Therefore, I'd like to remind you 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 Factors section of our Form 10-Q filed with the SEC today. In addition, any forward-looking statements represent 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 near future, we specifically disclaim any obligation to do so, even if our views change. Now, I'll turn over the call to Dr. Douglas Fambrough, Dicerna's Chief Executive Officer.

[Douglas Fambrough:]

Thank you, Peter. Good afternoon, and thanks to all of you who have dialed into the call today. Joining me to present on the call are Bob D. Brown, our Chief Scientific Officer and Jim Dentzer, our Chief Financial Officer. We are pleased to be able to provide you with this third quarter update. As a reminder, Dicerna is using our proprietary RNA interference or RNAi gene silencing technology to develop investigational treatments for rare inherited diseases involving the liver and for solid tumors. We are pursuing gene targets that have historically been difficult to inhibit, using conventional pharmaceutical approaches, but are accessible by RNAi, and where the biological connection between those targets and the underlying disease state is well understood. We believe this strategy maximizes the probability of success of our development programs. In addition for our key programs, we are pursuing indications where Dicerna can maintain full or significant development and commercialization rights. Dicerna continues to make progress on the clinical objectives for our development programs for our first two product candidates. First, DCR-PH1 are programmed for Primary Hyperoxaluria Type 1 or PH1, which is a rare and severe genetic liver metabolic disorder. Notably, we recently filed an IND to begin clinical testing of DCR-PH1. And second, DCR-MYC, our oncology program targeting the MYC oncogene, which continues dose escalation in two clinical trials. In addition, during the third quarter we announced significant additional progress with our DsiRNA-EX Conjugate platform, which forms the basis of our earlier stage liver-targeted programs. To discuss our progress in more detail, I will begin by providing an update on the DCR-PH1 and DCR-MYC programs, after that, our CSO, Bob Brown will describe advances with our DsiRNA-EX Conjugate technology and its application to earlier stage programs. Finally, Jim will give an update on Dicerna’s financials. I would now like to turn you attention to our DCR-PH1 program for the treatment of Primary Hyperoxaluria Type 1 or PH1. PH1 is a severe rare genetic disease where a single gene error in liver metabolism causes patients to have high levels of oxalate in their urine, resulting in progressive and severe damage to the kidneys and other organs. Existing disease management practices for PH1 may slow, but do not stop disease progression. And most patients eventually experience complete kidney failure with a median age of kidney failure being in the early 20s. There are no FDA approved therapies or effective treatments for most patients with PH1, aside from combined liver/kidney transplant. Our drug candidate for PH1, DCR-PH1, is a lipid nanoparticle encapsulated, DsiRNA-EX molecule targeting the HAO1 gene, which codes for an enzyme called glycolate oxidase that plays essential role in the metabolism of oxalate in PH1 patients. DCR-PH1 has been granted Orphan Drug Designation by the US Food and Drug Administration and by the European Medicines Agency. Two aspects of PH1 make it a particularly attractive program for Dicerna. First, PH1 is a natural application of Dicerna’s technology based on the clear genetic basis of the disease and the fact that the metabolism defect in the disease seems to occur exclusively in the liver. Second, PH1 presents clear and easily assayed biomarkers, specifically urinary and plasma oxalate and glycolate levels, which provide direct read out of the efficacy of our targeted therapies for this disease. Dicerna’s PH1 product candidate has demonstrated impressive efficacy and validated animal model of PH1, which is a strain of mice that had been genetically engineered to carry the same metabolic defect found in PH1 patients. These mice have elevated levels of urinary oxalate roughly three times the normal background levels, which is similar to that commonly observed in PH1 patients. When administering DCR-PH1 product candidate in these mice, to knockdown the targeted HAO1 gene transcript and the enzyme embedded in codes glycolate oxidase, we saw sustained reductions in urinary oxalate levels to background or near background levels. We believe that similar results if observed in patients with PH1 would have a significantly beneficial impact on disease progression. The DCR-PH1 product candidate is also effective in silencing the HAO1 gene in cynomolgus monkeys. In normal cynomolgus monkeys we have seen that a single dose of DCR-PH1 lead to an average of 84% gene knockdown with up to 93% knockdown observed four days after dosing. 29 days after a single dose in monkeys, we saw an average of 68% gene target knockdown with up to 80% knockdown observed. We have observed that DCR-PH1 administration in monkeys resulted in significant increases in urinary glycolate levels as expected based on the mechanism of action of DCR-PH1. While there is no PH1 disease models monkeys, this observation of urinary glycolate elevation in normal monkeys after DCR-PH1 administration supports the notion that DCR-PH1 may inhibit the metabolic pathway responsible for oxalate formation in PH1 patients and thereby may provide clinical benefit to PHI patients. During the third quarter, DCR-PH1 passed a significant development milestone in that we filed and IND with the US FDA to begin clinical testing of DCR-PH1. That IND has been accepted and we are working to initiate dosing as soon as possible. In addition, we are also pursuing clinical development in Europe. Patients with PHI within a country often seek care from a small number of specialist physicians within their country. Dicerna has been active and working with the specialists for significant time in formulating the DCR-PH1 development strategy and there is great enthusiasm for the product. Initial proof-of-concept data for DCR-PH1 should be available in 2016. In addition, as previously disclosed, we will be initiating an observational study of PH1 patients. This study will enroll patients with genetically confirmed diagnosis of PHI. The primary objectives of the study are to characterize the base line variability and factors that influence changes in urine and blood, oxalate and glycolate levels and renal function over time among others. We believe this information will provide key data to inform our upcoming clinical trials and will facilitate the clinical development of DCR-PH1. I will now turn to our second product candidate DCR-MYC, which is our which is our DsiRNA-based therapeutic, targeting the MYC oncogene, formulated in Dicerna's proprietary tumor-centric EnCore lipid nanoparticle formulation. DCR-MYC is currently being tested in two ongoing clinical trials. First, a Phase I all-comers dose escalation trial with an expansion cohort focused on pancreatic neuroendocrine tumors. And second, a Phase 1b/2 in patients with hepatocellular carcinoma. Dicerna selected MYC as a high-priority target to silence with our DsiRNA technology, because it is frequently amplified or otherwise up-regulated in a wide variety of tumor types, suggesting a critical role in driving and maintaining tumor growth. The key role for MYC in tumor biology is also supported by a vast body of laboratory research and a wide variety of systems going back decades. But because MYC is an intracellular protein which lacks a good small molecule binding site, it has been a challenging target for small molecule and biologic therapy and has remained an elusive target for drug developers. We believe our Dicer substrate RNAi platform has the potential to overcome this limitation by targeting the MYC mRNA transcript. In pre-clinical studies, DCR-MYC has demonstrated significant and specific MYC gene knockdown in multiple tumor-bearing mouse models. DCR-MYC entered Phase I clinical testing in April of 2014 in patients with solid tumors, multiple myeloma or lymphoma. The endpoints for this Phase I so-called all-comers trial include safety and tolerability, and will evaluate the maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects and antitumor activity of DCR-MYC. We are evaluating anticipate-tumor activity by resist, using conventional imaging techniques, such as CT and MRI. In addition, we have incorporated FDG-PET imaging in the study, as FDG uptake by tumors may serve as a useful biomarker of MYC activity. Reductions in MYC activity are predicted to cause a decrease in tumor metabolic rate, which can be visualized by imaging glucose uptake using the FDG-PET imaging technology. FDG-PET is also a marker of early detection of response across several tumor types. DCR-MYC continues to advance through dose escalation in the Phase I all-comers trial. At this point we have demonstrated safety with a dose of 1 milligram per kilogram which is to say that the maximum tolerated dose is at or above this dose level. This level of tolerability compares favorably to other lipid nanoparticle formulated RNAi products tested in humans and meets our tolerability expectations for the product. At 1 milligram per kilogram, we observed anti-tumor efficacy in animal models of hepatocellular carcinoma. Historically, similar dose levels result in higher exposure in humans compared to animal models due to extended pharmacokinetics. Taken together, these considerations give us optimism for continued development of DCR-MYC. During the second quarter at the ASCO conference in June, we presented data from low dose cohorts of this Phase I trial. To recap, as of early May, 2015, 26 patients have been treated with DCR-MYC with 18 patients evaluable for response. Anti-tumor activity was seen in two out of three patients with advanced treatment refractory pancreatic neuroendocrine tumors or PNET. Specifically, evidence of a complete metabolic response based on imaging with FDG-PET was seen in one patient and a partial tumor response based on resist criteria in another patient. Both patients had failed standard and experimental therapies for PNET prior to starting with the study. Based on the results observed, we announced the expansion of the all-comers Phase I study to include a cohort of patients with PNET. The expansion cohort will enroll up to 20 patients with low to intermediate grade PNET who have demonstrated disease progression after treatment with standard therapies. These preliminary Phase I safety and efficacy results are encouraging and we believe support further study of DCR-MYC for use as a new treatment option for patients with cancer. Once we have achieved the maximum tolerated dose in the Phase I all-comer study, we will also be enrolling a cohort, which includes pre and post treatment biopsies from tumors, in which we will seek to identify the direct products of RNAi cleavage of the MYC transcript. While we have already demonstrated resist responses and reduced FDG uptake in patients, we hope to clearly establish proof of concept by demonstrating of RNAi activity against the MYC transcript in fresh tumor biopsies. We will provide a more detailed update on the DCR MYC all-comers trial before year end. Contingent upon achieving proof of concept with DCR-MYC, we will launch our second oncology program targeting beta-catenin into IND-enabling studies. In December 2014, we initiated a second clinical study of DCR-MYC, and a Phase 1b/2 study in patients with advanced hepatocellular carcinoma or HCC, who have either failed or are intolerant to sorafenib, or who don't have access to other therapies for HCC. The first patient in this study was dosed in January 2015. We selected HCC as an initial focus indication for DCR-MYC, both due to the observation that the MYC gene is frequently amplified in HCC patients and due to the commercial and competitive profile of the HCC market. HCC is one of the most prevalent cancers worldwide. Patients with advanced HCC have limited treatment options and there are no approved therapies for those who have failed standard of care treatment with sorafenib. We have sites for the HCC clinical trial both in the US and in Asia due to the high prevalence of this disease in the Asian population. We are pleased with the progress and enrollment rate of the study so far, and are continuing with dose escalation. I'd now like to turn the call over to Bob Brown, our Chief Scientific Officer, for an update on our DsiRNA-EX Conjugate technology progress.

[Bob D. Brown:]

Thanks, Doug. Dicerna’s DsiRNA-EX Conjugates are our proprietary form of RNAi-duplexes that mediate gene silencing in the liver and that can be administered by subcutaneous injection. Our DsiRNA-EX Conjugates are designed to target the liver using the carbohydrate GalNAc or formerly known as N-acetylgalactosamine. The GalNAc carbohydrate moieties are natural form a simple sugar and are chemically conjugated to specific positions on our DsiRNA-EX RNA duplexes. These proprietary GalNAc RNAi Conjugates do not involve lipids or lipid nanoparticle. DsiRNA-EX is an enhanced version of our RNAi Dicer Substrate technology that we have reported previously, where one of the two RNA strands has been extended. These extensions are unique to Dicerna and year wise proprietary RNA structures designed to stabilize our DsiRNA-EX Conjugates and to allow additional space on the RNAi duplexes for added functions, such as liver targeting via GalNAc. Using this approach we've created a differentiated and independent approach subcutaneous delivery of RNAi inducing molecules to the liver. During the second quarter, we announced further advancements in potency of our DsiRNA-EX Conjugates. Specifically we've achieved potencies such that a single dose of DsiRNA-EX Conjugates significantly below 1 milligram per kilogram can reduce liver gene expression by 50% in mice and a single dose of 5 milligrams per kilogram can yield greater than or equal to 95% reduction in gene expression. We've achieved this level of potency with multiple DsiRNA-EX Conjugates, against multiple therapeutic gene targets and we previously shown that our DsiRNA-EX Conjugates retain their activity in monkeys, with a long duration of action, which again we have observed with multiple DsiRNA-EX Conjugates. We believe this level of preclinical RNAi potency will translate into simple, clinical regimens based on infrequent single side subcutaneous injections for effective liver gene knockdown in patients. As we've improved the potency of our DsiRNA-EX Conjugates molecules, we've also been streamlining our process for screening and optimizing therapeutic leads. This is allowed us to apply our technology to wide variety of liver associated disease gene targets. We are advancing lead candidates targeting both novel disease genes and established disease genes, given us emerging library of disease gene, silencing DsiRNA-EX Conjugates that can be advanced since the development by Dicerna or potentially in collaboration with partners. At this junction our library encompasses more than 10 liver disease gene targets in various stages of optimization. And this shows the broader applicability of the DsiRNA-EX Conjugates technology. We are driving towards to the first clinical candidate selection, based on DsiRNA-EX Conjugates technology and we expect to begin clinical development in 2017. Now I will turn over the call to our Chief Financial Officer, Jim Dentzer, for an update on our financial progress.

[Jim Dentzer:]

Thank you, Bob. As many of you have seen, we filed our 10-Q today. There is a great deal of detail contained in that document. I’d like to focus on the main financial metrics that we believe are important to use when evaluating the efficiency of our business. In the third quarter of 2015, Dicerna had a net loss of $16.9 million, compared to a net loss of $11.2 million for the same period in 2014. Research and development expenses were $12.1 million for the third quarter of 2015, compared to $7.5 million for the same period in 2014. The increase was due primarily to increased expenses related to the discovery and early development of future programs, increased expenses related to the preclinical and clinical start up activities for DCR-PH1, increased costs related to DCR-MYC manufacturing for clinical development and clinical trials and increased employee related expenses, including an increase in stock based compensation of $0.2 million. General and administrative expenses for the third quarter of 2015 totaled $4.9 million, as compared to $3.7 million for the same period in 2014. The increase was primarily from an increase in pay role expenses, which includes an increase in stock based compensation of $0.7 million, and an increase in professional fees, primarily from legal costs incurred related to the Alnylam complaint. As of September 30th, 2015, the company had $108.0 million in cash and cash equivalents and held to maturity investments, as compared to $98.6 million in cash and cash equivalents and held to maturity investments as of December 31st, 2014. In May 2015, Dicerna completed an offering of common stock resulting in net proceeds to the company of approximately $45.4 million. Based on its current cash position and operating plan, the company expects that it has sufficient cash to fund operations for at least the next 12 months. This estimate assumes no additional partnership funding and no new debt or equity financings. More detailed financial information and analysis maybe found in the company’s annual report and its quarterly report on Form 10-Q filed today with the SEC. With that I’ll turn the call back to the operator so that we can take questions.

[Operator:]

Thank you. [Operator Instructions] First question comes from the line of Michael Schmidt from Leerink Partners. Your line is now open.

[Jonathan Chang:]

Hi. Hi, this is Jonathan Chang, stepping in for Michael. Thanks for taking my questions.

[Douglas Fambrough:]

Hi, John.

[Jonathan Chang:]

My first question is what kind of data can we expect to see at the DCR-MYC year end updates from both the HCC and all-comers trials?

[Douglas Fambrough:]

Pankaj, would you like to take that. We have Pankaj Bhargava, our Chief Medical Officer on the line as well and he will answer that question.

[Pankaj Bhargava:]

Sure. Hi, Jonathan. So this – both studies in DCR-MYC are ongoing trials and as you can imagine we are going through our dose escalation phase. As Doug mentioned previously, we have achieved a dose of 1 milligram per kilogram in the all-comers trial and are escalating beyond that. We will have updated safety results, as well as results from efficacy seen in the patients treated so far from both the HCC, as well as the all-comers trial.

[Douglas Fambrough:]

For clarity Jonathan, the biopsy cohort initiates upon definition of maximum tolerated dose, which is not occurred yet. So there will not be biopsy data as part of that update.

[Jonathan Chang:]

I see, okay. Thank you. And then maybe just sticking with MYC program, could you talk about why you think DCR-MYC has shown such a favorable tolerability profile so far, compared to other ONT [ph] products historically?

[Douglas Fambrough:]

Sure. The data that we showed at ASCO clearly demonstrated that we have seen only mild adverse effect with DCR-MYC. Most of the toxicity so far has been grade I and II. The drug has demonstrated very mild effect in terms of infusion reactions in the earlier cohorts, which were very easily managed with the use of steroids and we have not seen any further infusion reactions with this product. If you look at the class of lipid nanoparticles, the major dose limiting toxicities are usually either infusion reactions or dose limiting toxicities with liver function elevation et cetera. So we have continue to dose escalate, we have not seen any of those toxicities to limit us from dose escalation at this point, which we find very favorable to this product in terms of its development and the dose levels that we achieved. Also if you look at the other lipid nanoparticle programs, most of the drugs have declared an MTD in the range of 0.5 to 0.75 milligram per kilogram. So we are above the maximum doses declared in other programs, which again we find as a favorable safety profile for this drug.

[Jonathan Chang:]

Okay, great. Thanks, it’s very helpful. And then maybe just one last one, for the PH1 program, how do you see yourself positioned competitively compared to the Alnylam's PH1 program? And what gives you confidence that there is large enough opportunity in this ultra-orphan indication for both? Thanks.

[Douglas Fambrough:]

Thanks, Jonathan. We also have Ted Ashburn in the room, who is our SVP of Product Strategy and heads up the PH1 program, so Ted?

[Ted Ashburn:]

Sure. Thanks, Doug. Apologies for my scratchy voice today. But I think I'll take your questions in reverse order. And again, PH1 as Doug mentioned is a severe rare genetic disease. But we're fortunate that we do have a good sense of what the number of birth might be per year for the indication and the literature would suggest one case for about 150,000 births, which suggest when you do the math that there is a robust population out there, not in ultra-orphan population, but not one approaching the 200,000 limit for orphan drug. So we think that there is a robust number of patients there and I think competitively we have the IV formulation that has shown robust knockdown of the messenger RNA in several animals species and we will be entering the clinic in a very short amount of time and think that this is a – that drug is going to be very competitive with the program that’s coming out of Alnylam. We've had several discussions with KOLs about the preferences versus IV versus subcu. There is really no clear distinction there and in some cases they will pick one over the other based on their preferences and also on the patients preferences.

[Douglas Fambrough:]

Jonathan, this is Doug, I am going to expand a little bit on that answer. The most severe on that medical need and this patient population is for a group of patients who are already on dialysis and in many cases that dialysis is effectively daily, with perhaps a day off to give the patient a break each week. So there is extensive hospitalization and lines into the patients. In this context, an IV therapy fits very nicely into current standard of care. This is also a population where the ultimate treatment is a joint liver and kidney transplant and as you could imagine the cost of the treatment is tremendous, the dialysis and transplantation and subsequent follow up costs. The potential for an effective treatment to eliminate the need at least for a liver transplant provides a pharmacoeconomic rational for pricing that is unarguably a very substantial number. That kind of pharmacodynamic – pharmacoeconomic argument suggest that the number of patients on drug required to generate a nice ROI and this kind of product is really a fraction of the total known patients and the economic opportunity as a whole is I think a very powerful one for a product like DCR-PH1 when it shows efficacy. And in that context, putting those factors together, we feel this program is economically compelling and competitive with the other programs out there that are targeting the same population.

[Jonathan Chang:]

Great. Thanks very much.

[Operator:]

Thank you. Our next question will be coming from the line of Steven Willey from Stifel. Steve, your line is open.

[Steven Willey:]

Yes. Hi, good afternoon. Thanks for taking my questions. So maybe just to expand a little bit upon I guess what looks to be a little bit of a delay in the initiation of PH1 dosing. I think prior to previous guidance I think you are previously expecting to initiate dosing in – I think it was 4Q, and I think now it’s been characterized this first half. So is this – if you could maybe just provide some overview of what the rate limiting steps are there with respect to trial initiation?

[Douglas Fambrough:]

Steve, this is Doug. Thank you for the question. There is no specific thing that’s led to a delay substance. We are working with the agency to - have and agreed upon protocol. We have succeeded in doing that and have the IND accepted. We are going through the standard steps. We have tried to predict when events would occur as accurately as possible. But there is always some play in that. And the program is basically on track.

[Steven Willey:]

Okay. And then with respect to the – I think it was 10 liver disease targets you talked about being in various stages of optimization, pre-clinically, maybe could you just explain a little bit as to – if those are concentrated within a kind of specific – if there within any kind of specific therapeutic category, are they kind of the orphan disease or they metabolic targets, infectious targets, should we expect that they encompass kind of all of those things?

[Douglas Fambrough:]

So it’s the latter Steve, its all of those things. So at the research level, we have developed the DsiRNA-EX Conjugate platform into one that through the streamlining that Bob mentioned its pretty easy to just apply it to another sequence and that – we have wanted to explore the breadth of applicability and the ease of adaptation to additional genes. And so we have gone broadly amongst genes, in addition to driving for the highest potency amongst priority genes. But in doing so, we have tried to touch upon a variety of therapeutic areas. Our core interest for development by Dicerna remain in the rare genetic disease space. And there are already identified targets that I think people will follow this space very aware of and there are targets that I have not heard other companies discussed. We have both of those amongst that set. And we have tried to touch on other classes of disease targets that where a delivery to a parasites [ph] is highly relevant, that includes things like cardiovascular and liver fibrosis. It’s unlikely that we're going to have a major Dicerna funded independent initiative in an area like fibrosis. But this gives us the option in the future of potentially working with partners in those areas. And it allows us to begin to establish a data base in those areas to support those discussions. With a number like 10 it’s quite a few. We can solve those around in different places. I've been very pleased at the broad applicability of the technology or maybe I should say the modularity of it where we can take learning’s from one gene, apply them really without modification to another gene and find we're at an excellent starting point for optimization right off with that. I think that is going to be very powerful thing for us, 2016 and the coming years.

[Steven Willey:]

Okay. And then just to clarify, the initiation of dosing in the neuroendocrine tumors cohort to PNET cohort, that’s going to also coincide with the identification of and MTD in the dose escalation phase, correct?

[Douglas Fambrough:]

We're bringing the sites online and we may just go ahead and start. We're pleased with the dose that 1 milligram per kilogram now and going back to the data we released at ASCO, the metabolic response was observed that 0.1 milligram per kilogram and the partial response by resist was observed at 0.2 and as we have gone through more cohort than we originally anticipated which has expanded the timeline for dose escalation with DCR-MYC. I think that as the sites specifically 14 [ph] that come online we'll just initiate dosing at the most recently cleared level. I would not have an expectation that DCR-MYC will achieve a substantially higher dose than we have achieved currently. And I say that based on analogy to other lipid nanoparticle programs, as well as the preclinical toxicology package. I don’t know where maximum tolerated dose is, but I don’t think it is going to be far higher than what we have now. But we'll bring the PNET online soon, probably with or without definition of maximum tolerated dose.

[Steven Willey:]

Okay. That’s helpful. Thanks for taking the questions.

[Operator:]

Thank you. Our next question comes from the line of Eun Yang from Jefferies. Your line is now open.

[Eun Yang:]

Thanks very much. So for PH1, natural history study, observational study was supposed to begin by end of September. So can you give us update on when you expect to start with this study, now with the delay of Phase I trial to first half over next year?

[Pankaj Bhargava:]

Yes. Hi, this is Pankaj Bhargava, Chief Medical Officer. So we are currently in the process of initiating that study and getting sites online to enroll patients. So that study is very much in start up phase right now and we expect to have enrollment very soon.

[Eun Yang:]

Thanks. And then for MYC, so it sounds like you guys are going to start to PNET study without reaching maximum tolerated dose. So once you start enrolling, I think in the past you said that you would enroll about 20 patients. So you kind of give us a timeline of when you might give us some data from the study, will that be ASCO next year?

[Pankaj Bhargava:]

Sure. This is an open label study in patients with pancreatic neuroendocrine tumor and we have the - really the expert sites with PNET that have already conducted prior registration spends in this indication that will be enrolling on this trial. So we expect to disclose data as they become available. We – since we'll be starting enrolment early in '16 I am not sure if we'll have substantial data by the time of ASCO, but we'll certainly have data in the latter half of the year.

[Eun Yang:]

Okay. Thanks. And then lastly KRAS program, any update on – I mean, last update we had in March, any update on the development from partner KHK?

[Pankaj Bhargava:]

We don’t have any update on that. It continues to be the case that KHK is actively working on that program and has indicated to us that it remains a priority research project, but we have not been given any timeline update on path to clinical initiation, when we receive an update we will incorporate that in our communications.

[Eun Yang:]

Thank you.

[Operator:]

Thank you. [Operator Instructions] Our next question comes fro the line of Ritu Baral from Cowen. Your line is now open.

[Ritu Baral:]

Hi, guys. Thanks for taking my questions. It’s Ritu. Its already answered, on the PH1 program for the PH1 are sites up like do you have patients screened, so you have IRB approvals and then given that you already broaden relationships with specialists that treat PH1, once you do get up and running how quickly do you anticipate enrollment of the trial? Thanks.

[Pankaj Bhargava:]

Sure. Yes, hi Ritu, this is Pankaj Bhargava. So we are – as Doug mentioned earlier, we have recently received a approval for IND from the FDA. We are currently in the process of the activities that you just mentioned in terms of IRB submissions and getting the sites up and running for the study. So we will – we are marching ahead as quickly as possible and several of the lessons that we learned through the initiation of the observational study, the fires [ph] observational study they are coming in very helpful as we initiate the Phase I trial. So we are marching ahead as quickly as possible and we will certainly announce our enrolment once we have it.

[Douglas Fambrough:]

Because this is a specialist driven indication, it really is the case that the investigators think about patients on a name basis. As per plan, the trial would involve in initial dose escalation phase and we given a number of sites that we're working with and the number of patients we need to enroll would not anticipate that we would have significant delays waiting for patients. So I think the study would proceed basically as – essentially as rapidly as it can proceed and is unlikely to face delays due to enrollment.

[Ritu Baral:]

Okay, great. Thanks. And I guess, what percentage of your sites would you say you have up and ready?

[Douglas Fambrough:]

Sorry, could you repeat that question please?

[Ritu Baral:]

Sorry, what percentage of your sites are up, like what or at least that up that you're seeing already?

[Douglas Fambrough:]

So we are in the process of getting these sites up, as you can imagine with the IRB contract and et cetera, there is a timeline for each of different site and as well as in Europe there are CT approvals, so the sites are in the process of coming up at this point.

[Ritu Baral:]

Okay. Great, thanks for taking the questions.

[Douglas Fambrough:]

Sure.

[Operator:]

Thank you. Our next question will be coming from the line of Eun Yang from Jefferies. Your line is now open.

[Eun Yang:]

Yes, thanks. Just one follow up question. So with DCR-MYC, it doesn’t sound like reaching MTD is that important at this point as you see enough activity in 1 milligram per k. So question to you is that, is it I know in cancer MTD is important to generate robust efficacy, but maximum efficacy, but do you think that with a DCR-MYC is it necessary to identify or reach MTD?

[Douglas Fambrough:]

We do see a dose response for MYC knockdown with increasing doses in animals, which would suggest that maximum efficacy or maximum MYC knockdown should be achieved at maximum tolerated dose. The decision to enroll the PNET cohort, as soon as the site comes online, as opposed to immediately after maximum tolerate dose, is driven by the observation and activity has been observed at a significantly lower dose and there maybe something about that tumor type, I am not going to speculate on this call, but there are interesting speculation –as to mechanism. The observation of activity at lower dose is there. We also strongly suspect that we are not very far from the maximum tolerate dose and the value of waiting to achieve the MTD versus initiating PNET dosing more important to get that dosing started. So I am not making a comment on lack of importance of MTD in general and we will do our expansion cohort and HCC trial at maximum tolerated dose and we will take our biopsies at maximum tolerated dose. We did not want to delay kicking off the PNET cohort so we felt at the current we achieved level particularly relative to where activity was observed during this escalation, justified initiating it as soon as sites come online.

[Eun Yang:]

Okay. So in the past you expected to reach MTD by year end, is that still your expectation?

[Douglas Fambrough:]

It could happen, the – as we have discussed in prior calls, the dose escalation process has extended a longer time than we expected when we initiated the trial. We of course don’t know what MTD is going to be, but we suspect that we are fairly close. It is possible we will have to find it by the end of the year.

[Eun Yang:]

Okay. Thank you.

[Operator:]

Thank you. And at this time I am not showing any further questions. I would now like to turn the call back to Douglas Fambrough for any closing remarks.

[Douglas Fambrough:]

I want to thank everyone for participating in our call today and for your questions. We look forward to keeping you all up to date on our progress. We’ll talk again next quarter. Have a great night.

[Operator:]

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