Regulus Therapeutics Inc (RGLS) 2014 Q4 法說會逐字稿

Good afternoon, ladies and gentlemen. And welcome to the Regulus Therapeutics Fourth Quarter and Year-End 2014 Financial Results Conference Call. My name is Patrick, and I will be your coordinator for today.

I would now like to turn the call over to the Company. Please proceed.

Thank you Patrick, and good afternoon everyone. This is Amy Conrad, Senior Director, Investor Relations and Corporate Communications at Regulus Therapeutics. And I would like to welcome you to our financial results call for the fourth quarter and year ended December 31, 2014.

Joining me on today's call are Kleanthis Xanthopoulos, Ph. D., President and Chief Executive Officer; Paul Grint M.D. , Chief Medical Officer; Neil Gibson, Ph. D., Chief Scientific Officer; and David Szekeres, Chief Business Officer and General Counsel.

Before we begin, I would like to remind you that this call will contain forward-looking statements concerning Regulus' future expectations, plans, prospects, corporate strategy and performance which constitute forward-looking statements for the purposes of the Safe Harbor provisions 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 our filings with the SEC.

In addition, any forward-looking statements represent our views only as of the date of this webcast and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements.

With that I would like to now turn the call over to Kleanthis.

Welcome everyone and thank you for joining us this afternoon. The past year and recent period have been filled with many significant scientific and business accomplishments. We executed key goals for 2014 under our Clinical Map Initiative to advance our therapeutic pipeline and all of our 2015 Corporate goals remain on track. To this end, we've demonstrated the therapeutic benefit of inhibiting a microRNA in patients and expect to translate these learnings across our growing portfolio. We have earned upfront and milestone payments from our strategic partners for our microRNA expertise and we have maintained a disciplined financial strategy and healthy balance sheet to grow the Company into a domain-dominant biotechnology organization.

In a minute, Paul and Neil will go through the pipeline progress in more detail, but I did want to highlight a couple of key points as it relates to our lead asset RG-101, our wholly-owned GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of hepatitis C.

An important milestone was achieved with RG-101 in the fourth quarter last year, namely, the demonstration of our first human proof-of-concept results in HCV patients. Two weeks ago, we reported additional results from the same study that showed increased efficacy and potency at the higher dose for 4 mg/kg, a mean viral load reduction of 4.8 logs at day 29 and a greater number of patients going non-detectable at day 57.

I would like to provide some commentary on where we see RG-101 fit into the ever-changing HCV landscape. RG-101's profile as a single agent is very encouraging. All patients responded to RG-101 on both doses. We believe RG-101 is pan-genotypic, potent and the response to-date is insensitive to prior history of fibrotic liver status. These properties make RG-101 a perfect candidate to combine with any oral DAAs or direct-acting antivirals, to shorten the treatment period, which is a desired goal of this space, but also to increase compliance with its SubCu administration controlled by the physician. We believe that an oral DAA with the same profile, once combined with RG-101, may open the HCV treatment channels to general practitioners with a simple script and uniform effectiveness.

This thinking serve as the basis for our dual-track Phase II strategy for RG-101. In the coming studies, we plan to investigate one or two SubCu injections of RG-101, which fits the current PK and PD profile with one DAA for short periods of time, either four or six weeks, for all genotypes liver fibrosis status and prior treatment history. We also plan to continue to test RG-101 as monotherapy with single or multiple administrations, which we believe may be useful in [under-served] patient population. For example, it's currently estimated that 8.3% of the global HCV population are characterized as genotype 4. RG-101 has shown favorable efficacy in this population with four out of five HCV treated patients going below the limit of quantification after a single dose.

In addition to the ongoing work for RG-101, we've also made good progress with RG-012, an anti-miR targeting microRNA-21 to treat renal dysfunction in Alport syndrome patients in the rest of our emerging portfolio. Under the Clinical Map Initiative, we expect to initiate a Phase I study of [RG-012] in healthy volunteers in the first half of 2015, and to initiate a Phase II proof-of-concept study for RG-012 shortly thereafter.

We also expect to nominate a third candidate for clinical development this year. All told, our leading position in this space has allowed us to harness the rich biology of microRNAs, and to achieve best-in-class clinical results. As we mentioned before, there are about 800 microRNAs that have been identified in the human genome, and over two-thirds of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire network of genes, and as such, these molecules are considered mass regulators of the genome.

Our approach to treating disease by modulating entire biological pathways with our anti-miR drugs, continue to provide us with many opportunities to apply our proven technology platform, to develop a new and major class of therapeutics, based on microRNAs. This is the reason why we are very excited about the future of our Company.

Let me now turn the call over to Paul and Neil to provide additional remarks. Paul?

Thank you Kleanthis and good afternoon everyone. As Kleanthis mentioned, we're extremely pleased with our progress during 2014, and so far this year, particularly with the demonstration of our proof-of-concept results with RG-101 and the maturation of our clinical portfolio.

Following our call a week ago, I want to also spend a few minutes discussing where RG-101 may fit in the all-oral DAA HCV landscape, and the potential benefits of our monotherapy approach going forward. Chronic hepatitis C infection represents a huge unmet medical need, and we believe that the landscape is at another tipping point. Three non-interferon containing oral regimens have been approved in the United States. These regimens will treat genotype 1 and 2 patients. There are approximately 185 million people chronically infected with hepatitis C virus, and these currently improved agents may not cure the entire population, particularly with the continuous and rapid emergence of resistant mutations. It's also important to highlight the global distribution of genotypes. 46.2% of genotype 1s, 30.1% of genotype 3s, 9.1% of genotype 2s, 8.3% of genotype 4s, and 5.4% of genotype 6s, and genotype 5s comprise the remainder of less than 1%.

RG-101 can help address this global health care program in combination with other agents, or potentially alone in certain genotype distributions, such as GT3s or GT4s, where RG-101 has seen robust activity compared to the currently approved oral agent.

As a reminder, we reported that the potency of RG-101 was improved at the 4 milligram per kilogram dose level, and the significant response was same for the majority of the patients. In a similar manner to the 2 milligram per kilogram dose group, at 4 milligrams per kilogram, all patients responded, and importantly, at day 57, 9 out of the 14 treated patients were below the limit of quantification. If a patient remains below limit of quantification at six months, they will be followed for up to an additional year to investigate the potential for viral cures.

In the 4 milligram per kilogram cohort, a mean viral load reduction of 4.8 logs was demonstrated at day 29 with a range of minus 5.8 to minus 3.0. We believe that the viral load reductions do not appear to be influenced by the IL-28 genotype, liver fibrosis status, or prior treatment history. And at day 57, 15 out of the 28 treated patients with either a single dose of 2 or 4 milligrams per kilogram RG-101 had HCV RNA levels below the limit of quantification. Of these 15 patients, 12 were target not detected. We believe these results are impressive and further underscore our dual-track strategy to investigate RG-101 in combination with oral DAAs, and further as a monotherapy with one or multiple doses in our upcoming Phase II studies.

In addition, RG-101 continues to be well tolerated with no serious adverse events reported or discontinuations among the treated HCV patients. We are rapidly advancing RG-101 right now and look forward to initiating Phase II studies in multiple countries. Our objectives for the Phase II trial designs will be to highlight the simplicity of the regimens. We plan to investigate one or two administrations of RG-101 combined with an oral agents or agent with the potential to provide high viral cure rates in shorter periods of time. Also investigating RG-101 further as a monotherapy with once a month dosing will allow us to learn more about the asset alone, and may provide the possibility for viral cures in certain patient population.

We filed our pre-IND briefing book with the US FDA and are working towards filing a clinical trial application to conduct the next studies with RG-101 in multiple locations, in addition to our current work in The Netherlands. The next studies are expected to initiate in the second quarter of 2015 with interim data read-outs in the fourth quarter of 2015. In addition, we are profiling serum samples from the recently completed study to identify a potential microRNA biomarker that could aid in predicting response to RG-101.

So, to wrap up on RG-101, we are pleased to announce today that we will be presenting several posters at the upcoming European Association of the Study of Liver Diseases or EASL, 50th International Liver Congress Meeting being held in Vienna, April 22 to 26.

Let's switch gears now to RG-012, and the upcoming Clinical Map Initiative timeline. RG-012 is anti-miR targeting microRNA-21 for the treatment of Alport syndrome, a life threatening genetic kidney disease with no approved therapy. The disease is driven by genetic mutations in the Type 4 collagen family of proteins. The impact of the mutation of the collagen gene result in disruption to the structure of the glomerular basement membrane, increased expression of microRNA-21, increased fibrosis and progressive loss of renal function, which leads to end stage renal disease, requiring dialysis or kidney transplantation.

Since our last quarterly call, we made good progress in this program. We enhanced the preclinical profile of RG-012 with favorable data presented at the American Society of Nephrology Meeting in November last year. Specifically, we presented preclinical combination data of RG-012 with an angiotensin converting enzyme or ACE inhibitor, ramipril. ACE inhibitors are emerging as the standard of care in patients with Alport syndrome, used to treat proteinuria or abnormal amounts of protein in the urine, an indicator of chronic kidney disease. Together with the key opinion leaders, we believe that ACE inhibitors are not sufficient to treat the actual progression of Alport Syndrome. We were pleased to present the treatment with RG-012 was shown to protect kidney function better than ramipril alone and an additive therapeutic effect was observed in combination with ramipril. These preclinical combination data are important, as they demonstrate the utility of adding a microRNA therapy to an emerging standard of care, which may be key for future clinical studies in humans.

In addition to enhancing its preclinical profile, we continue to advance RG-012 during the quarter and recent periods. Enrollment is going well in our ATHENA Natural History Study of Disease to learn more about the actual progression of Alport syndrome by documenting the change in certain renal biomarkers and glomerular filtration rates or GFR in these patients. Data from these seamless study will provide the clinical basis for the design of the Phase II study to monitor the therapeutic effect of RG-012 on the decline in renal function and time to end stage renal disease in Alport Syndrome patients. Under our Clinical Map Initiative, we plan to evaluate RG-012 in healthy volunteers in a Phase I study expected to commence in the first half of 2015. And then a Phase II proof-of-concept study in Alport Syndrome patients thereafter.

To summarize, we believe that 2015 will be a data-rich year and we remain focused on building a meaningful clinical portfolio based on microRNA.

Let me turn the call over to Neil for a review of our preclinical and discovery efforts. Neil?

Thank you, Paul. Good afternoon everyone. In 2014 and thus far in 2015, we have continued to pursue several microRNA targets that are focused on oncology and orphan disease indications. In addition to those internal research efforts, we have advanced several programs with our strategic alliance partners. These include microRNA-103/107 for the treatment of metabolic disease and microRNA-19 for oncology indications with AstraZeneca. microRNA-221 and microRNA-21 for hepatocellular carcinoma and microRNA-21 for renal fibrosis with Sanofi.

Specifically, we were pleased to present new preclinical data at key scientific meetings, which contributes to our continued leadership in the field. As it relates to the 103/107 program, we presented favorable preclinical data at the Oligonucleotide Society Meeting in October last year. We and AstraZeneca presented data, further demonstrating the potential benefit of a microRNA therapeutic for the treatment of metabolic disorders. In diabetic mouse models, subcutaneous administration of a miR-103/107 anti-miR improved insulin sensitivity and glucose excursion and mediated improvements in glucose homeostasis in a diet-induced obesity model and in a hyperinsulinemic-euglycemic clamp setting. These observations were accompanied by significant changes in adipocyte size. Under our Clinical Map Initiative, we expect to nominate at least one additional microRNA candidate for clinical development in 2015, either independently or with a partner to continue to grow our therapeutic pipeline.

Let me close my remarks by touching on the progress made with our biomarkers platform. A little over a year ago, we established our Regulus microMarkers division, focused on identifying mircroRNAs as biomarkers in a variety of bodily fluids, such as serum, whole blood, urine, CSF for a variety of diseases. We've entered into a research collaboration with Biogen Idec and are working with another undisclosed large pharmaceutical partner and numerous academic research collaborations. We have now profiled greater than 3,000 clinical samples, which we believe is a very significant accomplishment.

Based on the progress demonstrated with Biogen Idec, we earned our second milestone related to the identification of microRNA biomarkers for multiple sclerosis, or MS. The microMarkers division used its robust technology platform to successfully meet quality specifications for extracting and reproducibly profiling microRNAs from an initial set of whole blood samples from our recent Biogen Idec MS therapy trial.

Under our Clinical Map Initiative, Regulus microMarkers aims to identify a microRNA biomarker signature with a potential to differentiate relapse remitting MS patients from healthy volunteers and to compare with treatment response profiles. The microMarkers Group will also profile samples from healthy volunteers in HCV patients in our recently completed study of RG-101 to identify potential microRNA signatures, and profile urine and blood samples from Alport syndrome patients in ATHENA to potentially identify clinical useful microRNA signature. This is exciting technology and we look forward to reporting more progress on this front and from the rest of our preclinical discovery efforts this year.

With that, I'll turn the call over to David for a review of our financials. David?

Thanks, Neil and good afternoon, everyone. On the heels of the favorable results announced with RG-101 during the fourth quarter of 2014, we strengthened our balance sheet with public offering of common stock, with the net proceeds thus being about $76.1 million. At that time, we increased our year-end cash guidance in 2014 with greater than $150 million in cash. Today, we are pleased to report that we exceeded our cash guidance, ending 2014 with $159.7 million in cash, cash equivalents and short-term investments.

Turning now to our 2014 operating results, we recognized revenue of approximately $7.7 million in 2014 compared to $19.6 million in 2013. Consistent with prior periods, revenues primarily reflect the amortization of upfront payments received from our strategic alliances and collaborations which we recognized over an estimated period of performance.

Our research and development expenses were $41 million in 2014 compared to $29.9 million in 2013. This increase was primarily driven by cost associated with our completed clinical study of RG-101, the initiation of our ATHENA Natural History of Disease Study in Alport Syndrome patients, IND enabling cost for RG-012 and the continued advancement of other preclinical development programs.

We expect our research and development expenses to continue to increase as we initiate additional clinical studies in IND enabling or other regulatory filing activities in the future. Our general and administrative expenses were $11.5 million in 2014 compared to $7.4 million in 2013. This change was primarily driven by an increase in salaries and related employee costs and other operating expenses associated with general business activities.

Our net loss for 2014 was $56.7 million, resulting in a basic and diluted net loss per share of $1.29, compared to a 2013 net loss of $18.7 million, resulting in basic and diluted net loss per share of $0.49. Our net loss in 2014 included approximately $12 million in non-cash charges associated with our amended and restated convertible promissory notes, compared to approximately $1 million in 2013. This increase was primarily attributable to increases in the value of our common stock in 2014.

Looking forward in 2015, we expect to maintain our strong financial position and end the year with greater than $100 million in cash, cash equivalents and short-term investments. With that, I'll turn the call back over to Kleanthis for closing remarks.

Thank you, David. As you have already heard on this call today, we're very pleased with our execution and our overall progress during the last year and so far in 2015. We look forward to building upon our, now, proven technology platform to create a new and major class of drugs based on microRNAs. With that operator, we are ready to take your questions. Thank you.

(Operator Instructions) Eric Schmidt, Cowen & Company.

Maybe for Paul on RG-101, it wasn't clear to me in terms of the EASL update in April, whether that will actually feature longer-term follow up -- further follow-up from what we've already been led to believe on from the update earlier this month?

Yes, obviously, Eric. Thanks for the question. So we still intend to provide as much as we can with regard to the longer-term follow-up. Obviously it depends on how the patients are doing, but we do continue to follow them up at frequent intervals. So we should have a data set that covers the long-term follow-up number reported at the beginning of last week [here].

And has Regulus decided, at least internally, which direct-acting antivirals it thinks make the best combination here? I know you have some combination data already safety wise.

Yes, Eric. I will answer that, (inaudible) Paul just said. So on our estimations, there would be patients that would have reached seven or eight months post single injection by EASL. So, we certainly, as the data become available, we plan to include that at EASL, and that obviously would be very interesting.

So in regard to your second question, we have zoomed in, in a couple of three different direct antivirals and we're now finalizing the details, but we haven't yet decided on a single one. Remember, given we're looking for something that would be equivalent to RG-101, in other words, will be pangenotypic and something that obviously will have a good activity, so we can simplify the regimen.

And maybe one more Kleanthis. Given what you've seen with RG-101, the proof of concept and also the diversity of potential commercial opportunities in HCV that you've alluded to, I guess that could also come with the diversity of price points and value adds. Does it make sense to develop a next-generation anti-miR 122, just to have a diversity of product offerings in the space?

Yes, it's hard to -- given the [pre-D] effects, it's hard to imagine how we can improve, but maybe Neil has -- he always has ideas (multiple speakers).

But just maybe an alternative, as opposed to even a next-generation, something that would allow you go after multiple facets of this marketplace with different price points?

Yes, potentially -- Neil, any comments?

I normally take the view that there is something that you need to fix, we would try and do that within the next generation program, but their movement is not obvious from any of the data we've generated that there's anything we need to fix.

Alethia Young, Deutsche Bank.

One, you said an interim data in the fourth quarter. Can you clarify if you mean like RVR or SVR, just kind of exactly what you meant by that?

Well, I think what we will present is as much data we've got, depending on the time points. I mean, we've sort of [had this] discussion before is obviously the relevant -- and this is going to be topline, the relevance of the current definitions of RVR, SVR, which obviously came really from the oral DAA, additional clinical trials, how relevant they are to obviously -- to the RG-101 situation here. But clearly what we can present is topline data with respect to HCV RNA at different time points following an administration course of RG-101.

Will you have combination data by then?

That's our intention. Yes.

And then when you were talking a little bit about with Eric's question on the three DAAs you've invented, do you have a preference for commercialized DAAs or ones that are in the pipeline still?

As I said, we haven't decided yet. We're looking at both cases again. We are looking for pan-genotypic simple agent and that will be the best, Alethia. But we're looking both at commercial and things in development.

And then just on geographies, like when you're talking about running trials, I'm sure there's some sort of strategic commercial kind of thoughts going into where you might go and trial things. Can you just explain that to us a little bit more how you're thinking about that and the opportunity there?

Yes, Just briefly, there are, I think, two or three key considerations as we think about the geography for running clinical trials. We've talked about and we'll keep talking about one of the exciting things about RG-101 is its pan-genotypic activity. So therefore, some of the genotypes that we would want to include in clinical trial means that we're going to have to go outside of the US. So clearly, we have the opportunity to go to a number of different countries in the world with our CTA filing. Also take into account experience in different countries in hepatitis C clinical trials and we are already undertaking feasibility studies looking across a number of different countries with regard to the availability of patients -- you have centers, patients, different genotypes. So we will -- as we refine the design of the studies, we'll go to the appropriate geographies if they are going to meet our needs.

And just one last one. Lots happened this year as far as like kind of de-risking kind of the biologic. I'm just curious, when you think about your next target that's coming up soon, like how do you think your position down like biomarkers and microRNA biology like where does that line up best when thinking about like next target?

I think it lines up in a number of different ways, Alethia. Obviously there is the ability to align the biomarkers effort with their clinical studies we do. So for instance, measuring biomarker -- microRNAs in urine will give us opportunities to see if there is a potential read-out that could correlate with efficacy in the RG-012 program, but also in oncology there's number of different studies that highlight that, both from a messenger RNA perspective, as well as a microRNA perspective. Diseases like hepatocellular carcinoma segment into six or seven different segments and looking at zero microRNAs that correlate with those microRNA patterns or microRNA signatures of each of the individual segments will allow us to enrich our clinical studies for patients that we want to study.

Jim Birchenough, BMO Capital.

Hi guys, congratulations on all the progress. On RG-101, I mean it's quite remarkable that at day 57 you've got so many patients that are still undetectable, but on the other side of it, there are patients that do have detectable virus reemerging. What do you understand about the mechanism in that re-emergence and how does that inform dosing, do you think really a second dose will be enough or is it really to be a combination that's key? I'm just trying to understand the rational progress to kind of identify patients that don't respond but acknowledging how impressive the responders are given a single injection?

Jim, let me start first and I'll turn it over to Paul and Neil for any additional comments. It is a very, very interesting and very promising picture that is emerging after a single dose. We've seen with the latest data, 9 out of 14 going undetectable, target not detected for 12 out of the at least 15 and we're seeing, now, patients several months after the initial injection that continue to be undetectable. You're correct to say that two of the patients that were undetectable after 57 at the next measuring point, the [aerial] show -- we're actually showing virus coming back. We are sequencing all of this and by EASL, we'll have all the sequences. We have reasons to believe that those are not mutations, but rather that at day 57, as we have discussed before, we have less than 6% of the compound left in the liver, so those perhaps are our explanation as we stand here today, is that those are viruses that ultimately escape the pressure from the drug as the drug concentrations go down and this correlates perfectly with the timing of when we see that happening.

But equally important, we actually have patients that have not gone undetectable, but continuing a very slow decline over now three, potentially four months. So, those patients, of course, in addition to all patients that respond with very little help from DAA will go undetectable and that's why we're thinking a combination with DAA would be -- we expect to see some very, very remarkable results. But in certain populations we also see the potential for monotherapy for reasons that we think we'll begin to understand. For example, GT4s appear to be hypersensitive to RG-101 and that certainly makes further exploration as a single agent.

Could you maybe break out the GT4 results or are you saving that for EASL?

No, we can break it down. Paul, maybe you want to mention the -- out of the -- 9 of the 14.

So, there is one GT4 in the 2 mg/kg dose group. And that GT4 patient was treated with drug and was target not detected at day 57. In the 4 mg/kg dose group, there were five GT4 patients. One of those GT4 patients was a placebo. Of the other four patients, three of them were below limit of quantification at day 57 with the other patient just hovering above the limit of quantification, so within the 100 range of viral units per ml.

And to be clear, you haven't seen any resistant mutations?

No, we haven't got the sequencing data yet Jim, but we'll have that all and be talking about that at EASL.

And then maybe just a higher level question, when I think about the role of targeting a master switch, perhaps not surprising that in a multi-factorial disease like HCV virus, you have these results. Any thoughts on looking at HPV where there is a similar complexity of disease and have you done any work on potential role of a microRNA in that disease?

I think, we continue to look at that Jim, but in the context of HPV it's not the same story as HCV in the fact that HPV doesn't [go often] endogenous microRNA. So with some of those viruses that we've been looking at, they may include their own viral microRNAs that are an opportunity for us to potentially target.

Jim, in general terms, it looks like DNA viruses have chosen to incorporate into their genomes their own microRNAs. So we know that to be the case for CMV HBV, HSV, partially because of course DNA viruses have larger genomes than RNA viruses. And those microRNAs in a very delicate way control either integration or latency of the infection. So, clearly there are some interesting targets in HBV, HSV and CMV for microRNA, we simply don't have the bandwidth and given the success of the other programs at this point to do anything meaningful, but we are collaborating with academic institutions to look into that a little more as an exploratory program. RNA viruses do not, at large, encode their own microRNAs, as is the case for HCV. But, like HCV there's a couple of other viruses that are using endogenous microRNAs to their advantage.

Alan Carr, Needham & Company.

Going to the comment on -- I think your number three program, if you have any updates for us on -- You have a pool that you're working with. Have you narrowed that down, the number of candidates, programs that might become -- that they are going to be important to the clinic? And then also, it might be nice if you can give us an update on how things are going with the partnerships, and where our expectation should be for 2015 around them? And then, after number three, when should we expect number four and number five candidates? Is this an annual thing? I would like to hear your thoughts on that.

Well, let me start with the last one, and having Neil across the table from me, he's nodding vigorously that, we definitely have now a platform with a proven clinical effect, and we believe that we can deliver at least one development candidate a year, based on a Company that has about 65 people in R&D as we stand today. So you should expect to see once a year for us to move a program towards the clinic. In reference to your two previous questions on what is that we're looking for, I mentioned again and again that I think it is very important, given the very encouraging profile of RG-101 to find something that has the same profile. It has to be pan-genotypic, it has to be versatile, so that we can move into a single script. It doesn't necessarily have to be the most potent, because if you look at another data that we have, 28 HCV patients that were treated with RG-101, all of them, regardless of genotype, regardless of previous history, or fibrotic index status in their livers, they all responded. And to give you a sense, they all went from 1 million to 10 million international units per ml in the blood is below [800]. Any respectable DAA should be able to finish the job for the few that have not already responded. So, the more important thing is to be a pan-genotypic. And if you look at pan-genotypic NS5A inhibitors in [nukes] are appealing, obviously, but there are other classes that we think can also be combined. We will obviously disclose that in the next -- within the next quarter as we finalize our plans.

I would also -- before you get to bigger collaborations, wondering about -- you're going to nominate a third clinical candidate this year. Will you be having better sense of -- with now -- down the pool there of which ones that might be?

Yes, there is still a couple of programs that are potential programs for generating that candidate. And obviously, today we talked in brief about the 103/107 program, which is a partner program. So it's difficult to provide accurate guidance there, because we obviously have to have extensive discussions with our partner about the candidate nomination. But having said that, I think it was clear from the comments I made that when you have a mechanism that is potentially an insulin sensitization mechanism, that's a very encouraging molecule to have in your portfolio and the fact that we have in vivo efficacy in a number of different model systems is very encouraging. So usually the rate limiting steps for any clinical candidate nomination is showing robust consistent efficacy in multiple disease models. And for this program we clearly have that and we have similar efficacy developing in some of our other internal programs, Alan.

And that is -- Alan as we said before, we are building a very robust oncology franchise. So that's what Neil is referring to in terms of other programs that may also be competing for the nomination.

And in terms of collaborations, it's a very interesting question. So I think we addressed the kind of synergy and collaborations with RG-101. So, I'll spend the time to answer the other we have. On the rest of the programs, we have already established collaborations, as you know, with AstraZeneca and also with Sanofi. Sanofi maintains options to a couple of our programs. There is a lot of interest of companies to collaborate with us, and we're thinking that very carefully in terms of whether and how many programs we should partner, but for the moment we have not concluded anything specific, other than to say that we are like any other biotech, always in discussions with potential partners for selective therapeutic areas and selective microRNA targets.

Do we have any expectations around the deals with Sanofi or AstraZeneca by the end of 2015, anything will be publicly disclosed, I guess, over the course of the year, other than the candidate potentially being nominated for clinical development?

Right, you can consider that being at this point our choice and we're fortunate to be in that situation, Alan, And most of the discussions that we are having internally is how do we balance advancing our own programs and portfolios versus adding an additional partner. One of the things that we've been very fortunate is to have raised significant capital, so we can actually prosecute our own programs aggressively and we also stand to earn a lot of milestones from existing collaboration. So that's very important to continue. So, (multiple speakers) is there, and it's up to us to decide, and obviously, if we do you're going to hear [first].

Liana Moussatos, Wedbush Securities.

Going back to RG-101 combinations for the Phase II trial, are you thinking of only choosing one DAA or is there a possibility of having both a pipeline DAA, and approved DAA in separate arms, and what are the parameters for choosing one that's already approved versus one that's in the pipeline?

So I think, Liana, the answer to your question is yes, we have the potential to look at all of those. The obvious difference if one is approved, we can go and acquire that, buy and put in the study. If it's one in someone's pipeline, we're obviously going to have to collaborate with them with regard to getting access to that and have to create a design where that's in combination with RG-101.

And are you only considering single agent DAAs, like you would look at so (inaudible)?

No, we're considering either single agents or combinations. I think exactly, as Kleanthis said, as we look at the different populations we want to treat, we are sort of also going through the exercise of working out what would be the best combination or combinations to pair with 101, depending on the nature of the patients, the way they are going put in the clinical trials.

Thank you. This ends our Q&A session for today. I'll turn it back to Kleanthis for closing remarks.

Thank you again for joining us on the call this afternoon. We are very excited about the future of microRNA therapeutics and really looking forward to reporting more progress with you soon.

Ladies and gentlemen, thanks for participating in today's program. This concludes the program, you may all disconnect.