Regulus Therapeutics Inc (RGLS) 2014 Q3 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the Regulus Therapeutics' Third Quarter 2014 Financial Results Conference Call. My name is Dim and I'll be your coordinator for today. I would now like to turn the call over to the Company. Please proceed.

Good afternoon, everyone. This is Amy Conrad, Senior Director, Investor Relations and Corporate Communications at Regulus Therapeutics and I'd like to welcome you to our financial results call for the quarter ended September 30, 2014.

Joining me on today's call are Kleanthis G. Xanthopoulos PhD, President and Chief Executive Officer; Paul Grint, M.D., Chief Medical Officer; Neil Gibson, Ph. D., Chief Scientific Officer; and Dan Chevallard, Vice President, Finance and Accounting.

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.

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

Welcome, everyone, and thank you for joining us this afternoon. This past quarter and recent period has been very exciting for us. We made major advancements on both the scientific and business fronts, which have significantly strengthened our leadership positioning in the field of microRNA therapeutics.

Two weeks ago, we reported our first human proof-of-concept results with the microRNA therapeutic, RG-101, our wholly-owned GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of hepatitis C. We reported that at the lowest dose tested in HCV patients so far, RG-101 has monotherapy demonstrated an impressive durable effect on the HCV virus.

In the first cohort of 16 patients with varied genotypes in treatment history, two placebos and 14 actives were included. All 14 patients on active had a virological response and in these patients there was a mean viral load reduction of 4.1 logs at day 29. At day 29, six out of the 14 patients had HCV RNA levels below the limit of quantification. Moreover, from these six patients, three patients that have reached 57 days remain undetectable.

On the heels of this interim RG-101 result, we were able to strengthen our balance sheet with a public offering of common stock with the net proceeds to the Company being about $76.1 million to rapidly advance RG-101 and further support the growth of our pipeline. And we have also increased our year-end guidance to end 2014. We've now greater than $150 million in cash.

To rapidly advance RG-101, we have updated our Clinical Map Initiative goals to reflect our current thinking. We believe that RG-101 may be a potentially disruptive agent to the current treatment landscape and are currently having discussions with key opinion leaders in this space as we are planning for dialog with regulatory authorities in order to refine our potential plans.

To that end, we're investigating the possibility to pursue a potential dual track for RG-101 focused on a first-line combination strategy with existing DAAs to optimize clinical outcomes and potentially shorten the duration of overall therapy and a second fast-to-market combination strategy in patients failing direct antiviral agents.

In the second quarter of next year, we expect to initiate a Phase II combination study of RG-101 with a potential to begin even earlier depending on the speed of our dialogs with regulatory authorities and input from key opinion leaders.

Later on the call, Paul will provide more insight into our anticipated development plans. In addition to ongoing work for RG-101, we're also advancing RG-012, an anti-miR targeting microRNA-21, to treat renal dysfunction in Alport syndrome patients in the rest of the portfolio.

Under the Clinical Map Initiative, we expect to initiate a Phase 1 study of RG-012 in healthy volunteers. We are also advancing multiple other programs towards the clinic and expect to nominate a third candidate for clinical development in the first half of 2015. With all of this exciting recent progress, our confidence in our approach to treating diseases with microRNA therapeutics remains at an all-time high. The rich biology of microRNAs and their critical role in pathophysiology continue to provide us with tremendous opportunities to apply our established technology platform to develop a new and major class of therapeutics based on microRNAs.

Let me now turn the call over to Neil to provide additional remarks on the topic.

Thank you, Kleanthis, and good afternoon, everyone. As Kleanthis mentioned, we're extremely pleased with our recent scientific progress, particularly demonstration of our human proof-of-concept results with RG-101.

Following our call two weeks ago, I want to spend a few minutes to discuss the biology behind targeting microRNA-122 and the benefits of a host factor therapy in HCV. miR-122 is the most prevalent microRNA in hepatocytes and is a critical host factor for hepatitis C. miR-122 interacts with the HCV virus by binding to the two closely spaced seed sequences in the IRES region of the HCV virus that facilitate HCV's replication and function.

The IRES' [identical are controlled] for all HCV genotypes. Published data has shown that mutations in these two miR-122 binding sites prevent viral replication and function, potentially making the development of escaped mutants unlikely. In addition to the function of miR-122 in a disease state, the normal biological function of miR-122 has been studied in mice and non-human primates through both genetic and pharmacological approaches.

The published data show that miR-122 is a key regulator of metabolic function in the liver, although it is not essential for hepatocyte development. In the miR-122 knockout mouse, hepatocyte doses develops early in life promoting inclination, which progresses to fibrosis and eventually leads to hepatocellular carcinoma or HCC after approximately 12 to 15 months. However, contrary to the phenotypes in the knockout mouse, pharmacological inhibition of miR-122 in mice with anti-miRs for up to 50 weeks led to sustained reduction in cholesterol with no adverse findings absorbed after histopathological evaluation in liver.

In addition, inhibition of miR-122 treatment in a high-fed fat mouse model resulted in significant improvement in liver steatosis, a result that indicates a beneficial rather been detrimental effect. Furthermore, (inaudible) colleagues have recently shown that short-term inhibition of miR-122 for up to six months in a mouse liver did not increase the risk of HCC relative to control animals. This finding highlights the potential difference between short-term pharmacological suppression of miR-122 compared to germline knockout or elimination of miR-122.

These findings support our approach of short-term pharmacological inhibition of miR-122 with RG-101 as opposed to chronic long-term suppression of miR-122. We believe that the current HCV treatment landscape highlights the need for combination therapies that not only target the virus, but also target endogenous host factor such as miR-122.

Let me now turn the call over to Paul, who can take us through the attractive opportunity we have with RG-101 and the important upcoming clinical timelines in our portfolio. Paul?

Neil, thanks, and good afternoon, everyone. So, on today's call, I'll provide a summary of the recently-reported interim data on RG-101 and the different options we are considering to Phase II development. I'll also touch on RG-012 and our upcoming catalysts over the next several quarters.

RG-101 is our wholly-owned GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of hepatitis C. RG-101 is an extremely unique molecule that combines the most advanced chemistry 2.5 from Isis Pharmaceuticals, the GalNAc-conjugate from Alnylam Pharmaceuticals and Regulus' unique and proprietary chemistry, including the novel linker to facilitate the release of the parent oligonucleotide after hepatocyte uptake.

RG-101 is currently being evaluated in an ongoing four-part clinical study being conducted in Netherlands. Up to 100 healthy volunteer subjects and HCV patients with multiple HCV genotypes and treatment history are planned to be enrolled. In Part I, healthy volunteer subjects received a single subcutaneous dose of RG-101 at five doses up to 8 milligrams per kilogram or placebo.

The RG-101 was well tolerated and no significant adverse events were observed. We continue to dose healthy volunteers in Part II of this ongoing study in which healthy volunteer subjects receive a monthly single subcutaneous dose of RG-101 or placebo for four months. Results from this portion of the study are planned to be submitted for publication in the first half of 2015.

In Part III of the ongoing study, we combined RG-101 with simeprevir or OLYSIO, an approved oral DAA, in healthy volunteers. No drug-drug interaction effect was observed. These data provide pharmacokinetic evidence to RG-101 maybe combined with oral agents and we plan to investigate further combinations in an upcoming Phase II study.

Lastly, HCV patients received either single subcutaneous dose of RG-101 at 2 milligrams per kilogram, the first cohort, or 4 milligrams per kilogram, the second dose cohort or placebo in Part IV of the ongoing study to assess the safety and viral load reductions. As Kleanthis mentioned earlier on the call, we recently reported favorable interim results from the 2 milligram per kilogram dose cohort, which demonstrated human proof-of-concept.

We enrolled 16 patients in that cohort; ten GT1 patients, five GT3 patients and one GT4 patient. 14 patients received a single subcutaneous dose of 2 milligrams per kilogram of RG-101 and two received placebo. After the 14 patients, who received RG-101, eight patients were treatment naive and six patients had experienced viral relapse after prior interferon containing regimen.

We reported that the single subcutaneous dose of RG-101 demonstrated a virologic response in all RG-101 treated patients and we saw a mean viral load reduction of 4.1 logs at day 29 with a range of minus 5.8 to minus 2.3. Also importantly, six out of the 14 patients had HCV RNA levels below the limit of quantification and three patients, who have reached a 57, continued to have these HCV RNA levels below limit of quantification.

We continue to follow these patients enrolled in Part IV of our study for up to six months after dosing to investigate the possibility of these patients achieving a viral cure after a single administration of RG-101. Today, we are also pleased to announce the 4 milligram per kilogram dose cohort is now fully enrolled and we expect to report results from this portion of the study in the first quarter 2015.

Currently, we are considering different designs for the Phase II. Our goals would be to evaluate the potential to shorten the duration of therapy and enhance compliance with our subcutaneous dosing. To satisfy these criteria, we are investigating the possibility to pursue a potential dual track for RG-101, focused on both the faster-market first-line combination strategy with existing DAAs to optimize clinical outcomes and potentially shorten the duration of overall therapy and the second-line combination strategy in patients failing DAAs.

We are considering options in both Europe and the United States and we're aggressively planning for our next study, which we expect to commence in the second-quarter 2015. There is a potential to begin earlier in 2015, but this depends on the speed of our dialogs with regulatory authorities and input from key opinion leaders.

Let's switch gears now to RG-012 and the upcoming Clinical Map Initiative timelines. RG-012 is an anti-miR targeting microRNA-21 for the treatment of Alport syndrome, a life threatening genetic kidney disease with no currently approved therapy. The disease is driven by genetic mutations in the type IV collagen family of proteins. The impact of the mutation in the collagen gene results in disruption to the structure of 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 have made steady progress in this program. We are pleased to initiate our ATHENA natural history study of disease to learn more about the actual progression of Alport syndrome by documenting the changes in certain renal biomarkers and glomerular filtration rate or GFR in Alport syndrome patients.

Data from the ATHENA study will provide the clinical basis for the design of a 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. We are currently enrolling patients in ATHENA and working towards filing an investigational new drug application.

RG-012 has received orphan drug designation from the US FDA and we follow the similar application with the European authorities. Under our Clinical Map Initiative, we expect to evaluate RG-012 in healthy volunteers in a Phase I study expected to commence in the first half of 2015 and the Phase II proof-of-concept study in Alport syndrome patients thereafter. Next week, we plan to report additional preclinical data on RG-012 at the American Society of Nephrology meeting being held November 11 through the 16 in Philadelphia.

Specifically, we will present preclinical combination data of RG-012 with an Angiotensin Converting Enzyme or ACE inhibitor. 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. The preclinical combination data will be important to demonstrate the utility of adding a microRNA therapy to this emerging standard of care.

To summarize, we are entering a very busy period, focused on the balancing our clinical portfolio with both RG-101 and RG-012 and the rest of our growing portfolio.

Let me now turn the call over to Dan to review our financials. Dan?

Thanks, Paul. During the third quarter of 2014, we maintained our strong financial position and ended the quarter with $94.1 million in cash, cash equivalents and short-term investments. We recognized revenue of approximately $1.1 million in the third quarter of 2014 compared to revenue of $6.1 million for the same period 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 our estimated period of performance.

Our research and development expenses were $10.2 million in the third quarter of 2014 compared to $7.1 million for the same period in 2013. This increase was primarily driven by costs associated with our Phase I clinical study of RG-101, initiation of our ATHENA natural history of disease study in Alport syndrome patients, IND-enabling costs for RG-012 and a continued advancement of other therapeutic programs.

We expect our research and development expenses to continue to increase as we initiate additional clinical studies and IND-enabling or other regulatory filing activities in the future. Our general and administrative expenses were $2.6 million in the third quarter of 2014 compared to $1.9 million for the same period 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 the third quarter of 2014 was $9.8 million compared to a net loss of $2.2 million for the same period in 2013. Our resulting basic and diluted net loss per share was $0.23 and $0.26 respectively for the third quarter of 2014 compared to a basic and diluted net loss per share of $0.05 and $0.07 respectively for the same period in 2013.

As Kleanthis mentioned earlier on the call, we are pleased to have closed our public offering of common stock earlier in the week and have increased our cash guidance to end 2014 with greater than $150 million in cash, cash equivalents and short-term investments.

With that, I'll turn it back over to Kleanthis to wrap up the call.

Thank you, Dan. We are very pleased with our progress over the last quarter and recent period and I'm excited about the opportunity we have to create a new and major class of drugs with our proven technology platform. We look forward to reporting additional progress (inaudible) Medical Meeting and at the Credit Suisse (inaudible) Healthcare Investor Conferences later in the year.

Operator, we are ready to take questions. Thank you.

(Operator Instructions) Eric Schmidt, Cowen.

Thanks for taking my questions. Just first on RG-101, I know you've committed to the Phase II combo study starting in the second quarter. I guess I'm just kind of curious as to how you choose or how you think about choosing the right combination for RG-101 at this stage and how that sort of filters into your decision on whether to take this into a first-line setting or for a factory setting or both?

Eric, Kleanthis is here. I'll make some comments and maybe my colleagues can -- cannot do that. Obviously -- first of all, scientifically, given how oligonucleotides are so different and are metabolized, completely different than small molecules, we don't anticipate any problems combining with any of the [head or] cycle-based direct-acting antivirals.

And as such, basically, we can pick and choose from all of the existing opportunities. It will depend on two things; one, the availability of the particular DAA in the site or the country that we're going to be doing the study; and two, on discussions regarding or potentially combining with certain pharmaceutical companies and these discussions are ongoing. There is a potential that we're going to try to test them with as many as possible and those are the things that we are now fine-tuning.

Okay, helpful. And then, maybe switching over to Alport syndrome and the ATHENA trial, is there anything you can learn from the natural history study that kind of informs you on the role of miR-21 in this disease or any connection between that microRNA and what's happening in patients? So, is it purely just to see how patients perform over time with kidney function?

Well, Eric, this is Paul Grint speaking. So, hopefully, it's both of those. So one of the key goals of the study in a prospective fashion is to follow these patients and look at endpoints of both measured and estimates GFR and obviously that's going to be important for us to see in a rate of decline and look at these methodologies and contemplate the use of those in Phase II.

Now, together with that, we're taking multiple blood and urine samples from these patients to look at some of the known and recognized biomarkers, but also to look at microRNA signatures as well. And so we hope that that maybe there is something that we can see that will educate us as well.

Okay, then thanks for that, Paul. Last question just again on the Alport side, I think it was you or Neil who mentioned ACE inhibitors are becoming a more standard of care there. Do you know in your animal models whether you have additive or synergistic activity with an ACE background?

Hi, Eric, it's Neil. That data will be presented at the ASN, (inaudible) the next, what -- what is it? Seven or eight days.

Yes.

Okay, thanks a lot.

End of next week.

Jim Birchenough, BMO Capital.

Hey, guys. Just following up on the earlier question, (Audio Difficulty).

Jim, you fell off. Operator, maybe we should take the next question and then when Jim gets back on line, we'll reconnect him.

Alan Carr, Needham & Company.

Hi, thanks for taking my questions. A quick one, can you clarify, you were talking about a dual track earlier, one was combination with DAA presumably naives, the second one also combo with DAA, but in patients who've failed it, just DAA (inaudible)?

That is correct, Alan.

Okay and thanks. And then, the other question, I missed the beginning of the call, but can you comment on, I guess, big picture about relationship with a big pharma here in, your overall strategy maybe a transition towards turning on more programs on your own. I'm wondering what kind of -- the GSK collaboration ended, wondering what you get back from that. Can you give me an update on that? Thanks.

Yes, let me start with the GSK. Basically all of the 122 related programs and activities are now fully owned by Regulus as all the activities around microRNA called 155 that was nominated as a collaboration target a couple of years ago. So, we have the total control over both of these programs right now.

Big picture, do you see yourself transitioning from away from these collaborations to independent development?

That's our goal for RG-101 at least for the Phase II that we are outlining right now. So we like to combine and we think RG-101 has a very strong basis and likes as a program to be combined with just about every direct antivirals. So, we're going to be doing these experiments in the Phase II that we just outlined independently with a collaboration at this stage at least.

How many of these programs do you think you can operate in the clinic in parallel?

Let me not comment, we're in the middle of all these discussions with KOLs and internally. That's part of the reason why we're updating our Clinical Map Initiative, because RG-101, as we've got data behind us, demands a lot of attention as it should. So, we are working through all of these details. Any more comments?

I think, from the hepatitis C standpoint, this hepatitis is new. I mean it's just over two weeks ago and clearly as Kleanthis has outlined, based on what we know about the molecule, we have the opportunity to combine this with a lot of different molecules. It's an interesting time of year. Within the last month, there's been a new combination approved in hep C. AASLD starts later this week. I'm sure there's going to be lots of new information there.

And so, clearly, our goal is to move aggressively into Phase II, but we're at a point in time where the landscape is changing quickly and where we're obviously working with key opinion leaders to take that into account as we design our programs.

I'm thinking actually beyond RG-101 and 012, how many programs do think -- you're not committing I guess to how many beyond those two that should be able to carry on in particular going forward?

So, Alan, it's Neil. We have obviously multiple programs in the portfolio and we've always been looking at managing a steady state of up to four to six programs as we mature a portfolio.

Okay, thanks for taking the question.

Jim Birchenough, BMO Capital.

Yeah, hi guys, I think I got cut off earlier. Maybe I'll just focus on what yet to be learned from the RG-101 Phase 1 and what the timelines will be for key milestones like sustained viral responses that sort of thing. Could you maybe lay out the timelines for data from the Phase 1 we'll see going forward?

Yes Jim, it's Paul. So, I think the news we announced today was that we've obviously completed the enrollment of the 4 milligram per kilogram dose cohort. So, the original protocol was designed in essence for eight weeks to follow-up for these patients. And so as you can do the simple math from (inaudible) and as we've stated, we obviously intend to report at least that component of the study both for the 2 milligram per kilogram and the 4 milligram per kilogram HCV-treated patients in the early part of next year.

We've amended that protocol. So, we can continue to follow those patients up to six months. I mean clearly does those folks that have gone below the limit quantification early in the treatment, of course, we're very interested to see the durability of that response. And as we stated before, our goal is to at least from the hepatitis C standpoint to be able to present a more complete picture of that at the appropriate medical meeting in the first half of next year.

And maybe just a follow-up, just in terms of what we've learned so far with 4.1 log reduction in such a quick period of time, is there anything for modeling the kinetics of the decline in viral load that would suggest that you might have success at shortening course of therapy? When added to other DAAs, is there any way to model out what you think the additive effect might be or how you might be able to shorten the course of therapy by adding RG-101?

Yes, Jim, if you look at the individual patient response to RG-101, you will see that we have significant responses by (inaudible) continued to be sustainable, reach a maximum on an average of day 29 and as we just said before, they want to have reached the limit of quantification that continued to stay there; almost a month after that, at least to three most advanced patients. So, if you take day eight as an example and you see a response of three log and above and you add them a direct antiviral at some point between day one and day eight, with a rapid decline of viral kinetics following a good direct antiviral, you would expect to see most of these patients reaching below the level of quantification in that timeframe.

So, you extrapolate that to the course of therapy and there are reasonable expectations of why you may reach eight, six or potentially even four weeks, that will be sufficient.

Liana Moussatos, Wedbush Securities.

Thank you for taking my question. When do you expect to have human proof-of-concept results disclosed for Alport? And then are there any mutations or polymorphisms and miR-122 that could affect RG-101 binding?

I mean there is no reported changes in the miR-122 sequence in humans we have been able to find. So, we don't anticipate that there is any potential impact out of our mutation or polymorphism on miR-122 that would impact RG-101 binding through that microRNA.

And conversely, Liana, all genotypes and all clinical isolates that we've looked at have identical sequences, binding sequences for 122. So not only we don't see any variations on the microRNA, but we don't find any variations on that target on the virus.

It's Paul. So, if you want to see the question, our goal is to commence the Phase II proof-of-concept study in the fourth quarter next year. And so obviously based on what we see from the natural history study now with respect to the timing that we go to follow patients out, I think we are looking probably at about the 2017 timeframe to establish the clinical proof-of-concept.

Bill Tanner, FBR Capital Markets.

Paul, I had a couple for you. As it relates to the RVR four weeks, I guess when the data came out, there were some folks who were wondering about the competitiveness versus the DAA and obviously at 57 weeks, you had a better RVR and I think you talked about the route of administration and the mechanism of action for 101, but I am just curious if you think maybe the drug has caught up over this ensuing four weeks, the observation of 57 weeks and if not then, what would you view as a competitive RVR?

Good question. Obviously, not sure at this point. We're following the people out. Then, we'll have the answer to that in the early part of next year. I mean I might be trained and there is -- what simplistic thinking the way we like to think is in chronic diseases like this or (inaudible) infectious diseases, if you can combine therapeutics with different modes of action, generally you get a much better response in terms of virus stopping (inaudible) killing your bacteria that you want to get rid of.

So, I think the good news for us is that we've got a novel mechanism. It's targeting a host factor that you've heard. It's potentially pan-genotypic and the good news from at least limited information we have is the prior response to therapy, it doesn't seem too to affect the outcome. So we're in a very unique position here, I think to combine RG-101 with a number of different potential agents and time will tell with respect to the outcome of that and our ability to shorten treatment courses.

Let me now also clarify, so that we're comparing apples-to-apples here. All the studies that I have done with direct antivirals, including the most successful ones, OLYSIO and Sovaldi, as monotherapy, they had between three and seven days. And that's for a very specific reason, the FDA demanded that, because with monotherapy again, you don't want to expose the virus with single agent because of potential resistance on set.

So, it's impossible to compare RG-101 single dose to a monotherapy, because their RVRs were not remarkable at all. The ones that you're referring to they were always done in combination with rival and interferon original.

Yes, didn't want to believe necessarily the RVR observations for 101 yet, because I guess the proof is in the pudding. It's more like when you have date for the combination or whatever and then maybe in a larger number of patients. Second question I had, maybe Paul, is I guess Kleanthis mentioned earlier about and maybe I probably know, expectation that there would be any kind of drug-drug interaction with other DAAs, what's the contemplation then as it relates to maybe differential efficacy of 101 with the DAAs? And the point being is that it's fine if there's not drug-drug interaction, but as one begins to look at combining it with other DAAs and studies need to be done, how are you guys thinking about whether you're going to see some kind of differential combination effect?

Well, that's exactly the discussions we're having now with some of the key opinion leaders to help guide us with regard to we have a lot of options of drugs out there, what will be a priority list of those options, whether the other variables that we might want to look at in the Phase II study, we've talked about such as shortening the duration of therapy. So those are all ongoing discussions right now.

Okay, all right, thanks very much.

(Operator Instructions) Christopher James, Brinson Patrick Securities.

Hi, good afternoon, thanks for taking my questions and congrats on a tremendous progress made. Just a quick question regarding the two paths, do you plan to position RG-101 across -- continue to position it across all genotypes or is there a path to specifically target [GTE3] patients? And do you anticipate 101 being investigated in cirrhotics and/or HIV co-infected patients in Phase II?

Chris, Kleanthis here. The success we saw with RG-101 on all genotypes in treatment history is actually creating some interesting challenges for us in choosing all of the above possibilities that you outlined. We're going to know a little more after all the conversations that we're having and of course going into AASLD, we have a lot of meetings planned with KOLs, but I can tell you that most likely from at least my point of view and take that as preliminary outline, the objective to combine it as the first line and with an endpoint to certain therapy, they are probably 4% naives, but the second line will be very interesting in looking at relapse. So, potentially difficult to treat patients such as co-infected or cirrhotics.

Right. I know you're using the 8-milligram dose in the first part of the Phase I study, is there a potential to use that to dose up to 8 milligrams per kig in any future studies?

Yes, let me just clarify for you. So, in the single dose part of the Phase 1 study, we did dose up to 8 milligrams per kilograms a single dose. We had the ability to dose higher, but frankly, we chose not to, because as we looked at some of the pharmacodynamic markers in both cholesterol and alkaline phosphatase and no healthy volunteers, we saw changes that were pretty much maximal between 2 and 4 milligrams per kilogram and it was that information that helped us select 2 milligrams per kilogram as the dose initial cohort in hepatitis C patients. So, we stopped because we felt that we covered the doses that was needed to have a biological effect. I think we have the ability to go higher, but at this point, clearly we believe based on the information we've seen that 2 and 4 milligram per kilogram dose in hepatitis C patients is in the right range based on pharmacokinetic data, but also based on the interim data that we showed as well. So, at this point in time, we don't have intentions to go higher, but we do have the ability to, if we needed to.

Yeah, that's exactly right. Just to clarify, because of an excellent safety and tolerability profile, we have the ability to go to 8 and 16 mix (inaudible) if we wanted to. Obviously, we're waiting 4 mig per kigs data to see what response we're seeing there if indeed that matches the pharmacodynamic profile that Paul just alluded to. And the flexibility that we have will of course be exercised depending on the patient population. If we have to go for higher doses in cirrhotics for example, the beauty is that we do have the safety and tolerability to go there. So, we will take one step at a time and will decide on the dose depending on the specific (inaudible) we're going to be treating.

Great, that's helpful and thanks again and congrats.

Thank you.

Thank you. And at this time, I'm showing no further questions. I would like to turn the call back over to Kleanthis for further remarks.

Thank you all again for joining us on the call. We are very excited as you can tell about the future of our Company and microRNA therapeutics in general and look forward to reporting more progress to you soon.

Thank you, ladies and gentlemen, that concludes today's conference. Thank you for your participation. You may now disconnect.