Regulus Therapeutics Inc.
Q1 2015 Earnings Call Transcript

Published: 9 May 2015

[Operator:]

Welcome to the Regulus Therapeutics First Quarter 2015 Financial Results Conference Call. My name is Tonya and I will be your coordinator for today. I would now like to turn the call over to the company. Please proceed.

[Amy Conrad:]

Thanks Tonya. 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 March 31, 2015. Joining me on today's call our Kleanthis Xanthopoulos, PhD, President and Chief Executive Officer; Paul Grint, M.D., Chief Medical Officer; Neil Gibson, PhD, 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 turn the call over to Kleanthis.

[Kleanthis Xanthopoulos:]

Thank you, Amy and welcome everyone. Today, we're excited to discuss our continuing execution on our Clinical Map Initiative goals. We're off to a great start in 2015 and our recent accomplishments have positioned us for a data rich period across multiple programs in our microRNA therapeutics portfolio. On the scientific front, we've continued to solidify our leadership position in the field. We strengthened the profile of our lead asset, RG-101 which is a wholly-owned GalNAc conjugated anti-miR targeting microRNA-122 for the treatment of HCV with significant and sustained viral responses seen at the second dose level and extended follow-up results for some patients up to approximately five months. And just a few weeks ago, AstraZeneca selected RG-125, a novel insulin sensitizer for the treatment of NASH in patients with type II diabetes, as a microRNA candidate for clinical development. This represents our third candidate for clinical development to arise from our novel technologies in less than two years. We believe that demonstrates the productivity of our platform. In addition, this achievement was a key goal under our Clinical Map Initiative for 2015 and we're excited to meet this goal ahead of expectations. In addition to all this progress, we continue to advance our Alport syndrome program, enrolling patients in our natural history of disease study called ATHENA and we're about to initiate our first in human study with this compound. In order to continually feed our clinical pipeline with new therapeutically active safe anti-miRs, we continue to pursue several attractive microRNA targets in areas of high unmet medical need. Later on the call, Paul and Neil will provide more detail on our recent clinical and research efforts. Turning now to the business front, during the first quarter and recent period, we continued to show our dominance in this space with payments earned from our strategic partners and collaborators for our microRNA expertise. Importantly, we continue to maintain a disciplined financial strategy as we executed against all of our goals. Later on the call, David will provide the numbers for the quarter, including our cost guidance through year's end. Now, I would like to focus some time on our RG-101 program. Just a few weeks ago, we presented noticeable data at the International Liver Congress meeting, better known as EASL, in Vienna, Austria through multiple posters and, importantly, an oral late-breaking presentation. There are several key takeaways from the meeting that support the opportunity we have with RG-101 to fill gaps in the current HCV treatment landscape. First and foremost, we believe that the data generated today with RG-101 have been very well received by leading key opinion leaders and clinicians in the space. In a summary session on the final day of EASL on April 30, RG-101 was highlighted as one of the key assets in development to watch which we believe to be important scientific validation for the program. In coming out of the meeting, we feel even more confident for the significant role RG-101 can play in the ever-changing HCV treatment landscape. First and foremost at EASL, we learned that the field has yet to shorten the duration of treatment to less than eight weeks. There was much anticipation over certain four- and six-weeks datasets from oral combination regimens with viral responses that deliver results which fell significantly short of our expectations. We believe that RG-101 can do well here and provide us with an opportunity in the frontline setting, meaning we think we can shorten the duration of treatment, increase compliance and possibly improve upon high SVR rates. In addition, based on multiple abstracts presented at the meeting, we now know that the real world failure rate of oral agents is rising and it's approximately 15%. This represents a significant difference from the data generated from well-controlled clinical trials in the past and underlines the opportunity we have with RG-101 to be potentially successful also as a second line setting, meaning patients who had failed their oral regimens from compliance or emergency resistance that leads to increased failure rates. Our Phase II studies in which we plan to evaluate RG-101 in combination with several oral DAAs over four weeks may provide an elegant solution to these issues that the field cannot solve with the currently approved agents. Under our Clinical Map Initiative, we look forward to initiating these studies with interim data readouts by year's end. To conclude my remarks on RG-101, I want to remind everyone why I'm so excited about the company and our future trajectory. Over the last decade, there has been an exceptional large amount of scientific research happening to advance the entire field of RNAi therapeutics which is sometimes referred to as the RNA Decade. Specifically, in the last five years, there has been explosion in the number of actual RNA therapeutic drugs in clinical development which include antisense RNAi, microRNA and recently messenger RNA, with many programs now heading towards the market. Let's also not forget that the first systemic oligonucleotide, KYNAMRO, was approved just a few years ago in 2012. At Regulus, we believe we're the domain dominant microRNA company and we believe that we continue to build upon what we've seen in the RNA Decade. Furthermore, we believe that part of the next wave of innovative RNAi therapeutics will come from targeting microRNAs. To that end, we're currently working on multiple undisclosed targets in areas with high unmet medical need where we believe we can engineer anti-miRs with a high therapeutic index and the right delivery approach. There are over 800 functional microRNAs that have been identified in the human genome and over two-thirds of all human genes are believed to be regulated by microRNAs. Our approach to treating disease by modulating entire biological pathways with our anti-miR drugs continues to provide us with many opportunities to apply our proven technology platform to develop a new and major class of therapeutics based on microRNAs. We're extremely excited about the future of our company. We look forward to reporting continued progress throughout the year. Let me now turn the call to Paul and Neil to provide additional remarks.

[Paul Grint:]

Thank you, Kleanthis and good afternoon everyone. We're off to a great start this year and I'm pleased to discuss with you the many advancements made in our clinical portfolio during the last quarter and recent periods. Let's start with a look at the results presented in our RG-101 program. Just two weeks ago, at the EASL meeting, we were pleased to tell the complete development story of RG-101 with positive preclinical results through our first in human clinical trial results. The data presented highlighted RG-101's potent, durable and pan-genotypic affects in a diverse HCV population. This is the first time we presented data on the microRNA therapeutic at a major medical meeting. This was a meaningful accomplishment for the company as the meeting represents an important forum to educate and inform clinicians and key opinion leaders who treat hepatitis C patients. The slides and posters presented at the meeting can be found on the Investor Relations page of our website. As a reminder, patients received a single subcutaneous injection of RG-101 at day one and were followed for a period of eight weeks. In total, 32 patients were randomized, of which 14 received 2 milligrams per kilogram and 14 received 4 milligrams per kilogram of RG-101. Patients whose viral loads had not increased by more than a log from the nadir were included in the extended follow-up study. The data presented at EASL was an interim look at 20 weeks which included 22 patients who met the criteria for the longer-term follow-up study. In our late-breaking presentation, extended follow-up results evaluating a single subcutaneous administration of either 2 milligrams per kilogram or 4 milligrams per kilogram of RG-101 as a monotherapy in the hepatitis C patients with varied genotypes, liver fibrosis status and treatment history showed that 10 out of the 22 patients had HCV RNA levels below the limit of quantification at 12 weeks and 70% of those patients or seven out of 10, remained below the limit of quantification at 20 weeks. These extended follow-up results add to the growing data set we'd previously reported on RG-101. In the eight-week study, at the end of treatment day 57, 15 out of the 28 treated patients with either a single dose of 2 milligrams or 4 milligrams per kilogram of RG-101 had HCV RNA levels below the limit of quantification. The viral load reductions included in the extended follow-up results do not appear to be influenced by the IL-28 genotype, liver fibrosis status at baseline or prior treatment history. In addition, we're performing the sequencing and immunophenotyping work and we expect to report the findings later in the year. We're also profiling serum samples from the patients to identify a potential microRNA biomarker that could help in predicting response to RG-101. Under our Clinical Map Initiative, we expect to initiate Phase II studies evaluating RG-101 in combination with multiple oral agents over four weeks. We're calling the combination approach our sandwich design, meaning one subcutaneous administration of RG-101 given on day one, four weeks of oral agent and then one more subcutaneous administration of RG-101 given on day 29. We plan to investigate multiple oral agents in three separate arms with each oral agent to represent a key class of the oral DAAs. The goal in Phase II is to potentially shorten the course of therapy, improve patient compliance with our subcutaneous dosing regimen and possibly improve upon the high viral cure rate. We believe the data from these studies, if favorable, could significantly change the HCV landscape, especially considering the recent learnings at EASL. In addition to the sandwich approach, we also plan to continue to test RG-101 as monotherapy which we believe may be useful in underserved patient populations. For example, it is currently estimated that 8.3% of the global HCV population is characterized by genotype 4. RG-101 has shown favorable efficacy in this population with three out of five or 60%, of genotype 4 HCV patients still below the limit of quantification at 20 weeks in our study. In summary, we're very pleased to have strengthened the overall profile of RG-101 and we look forward to initiating our Phase II studies with interim data readouts by the end of this year. Now, let's switch gears 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 approved therapy. The disease is driven by genetic mutations in type IV collagen found near proteins. The impact of the mutations in the collagen gene results in disruption to the structure of the glomerular basement membrane in the kidney, 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. A recent highlight of this program was the orphan medicinal drug product designation by the European Commission which adds to the orphan drug status received in the United States last year. We're very pleased with this incremental update as it demonstrates the willingness of not only the U.S. regulatory agencies but the European agencies as well to help advance new therapies for diseases that have no approved treatments. In addition, our efforts during the first quarter and recent period on the RG-012 program have been focused on enrolling patients into the ATHENA or natural history study. The goal of this study is 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. Currently, we have 13 clinical sites across the globe that are actively recruiting patients. Data from the ATHENA 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 the Phase I study which we expect to commence in the near-term and the Phase II proof of concept study in Alport syndrome patients thereafter. Lastly, we recently advanced our clinical portfolio with the selection of our third candidate for clinical development, RG-125, a novel insulin sensitizer for the treatment of NASH in patients with type II diabetes or pre-diabetes. This candidate was selected by AstraZeneca through our strategic alliance to discover, develop and commercialize microRNA therapeutics and we were pleased to have earned the milestone payments for this work. Currently, we end AstraZeneca are working on IND enabling activities for the program and AstraZeneca expects to initiate a Phase I study in humans by the end of this year. To summarize, our recent progress has positioned us for an exciting period focused on the growth of our clinical portfolio. Let me now turn the call over to Neil for a review of our preclinical and discovery efforts.

[Neil Gibson:]

Thank you, Paul and good afternoon everyone. As Paul just mentioned, we were excited to have AstraZeneca select RG-125 for clinical development. This represents our third candidate for clinical development and demonstrates the productivity of our platform. RG-125 is a GalNAc-conjugated anti-miR targeting microRNA-103/107 for the treatment of NASH in patients with type II diabetes or pre-diabetes. The role of miR-103/107 in insulin resistance was first recognized by Markus Stoffel's group which found elevated hepatic expression of miR-103/107 in mouse models of insulin resistance. They went on to show that miR-103/107 levels in human liver biopsies positively correlated with insulin resistance in patients with NAFLD or NASH. In addition, over-expression of miR-103/107 by adenovirus or transgene leads to hyperglycemia and impaired glucose tolerance. As it relates to the compound itself, RG-125 has shown dose responsive reduction fasting insulin and glucose, improvement in HOMA IR and clamp studies that measure tissue insulin sensitivity. We plan to share these data sets at scientific meetings later this year. Currently, we're working with AstraZeneca to submit an investigational new drug application and AstraZeneca aims to initiate a Phase I study in humans by the end of 2015. Once an IND is accepted, AstraZeneca will assume development of the program and we're then eligible for milestone payments and royalties based on achievements of certain goals. We're excited about this program and look forward to seeing it advance into clinical development. Turning to RG-101, I'd like to discuss a few additional details of what we presented at the EASL meeting. In addition to the clinical data that Paul discussed earlier, we were pleased to tell the complete story of the compound. We presented three poster presentations highlighting the pharmacokinetics and pharmacodynamics of RG-101 in healthy volunteers, the preclinical pharmacokinetics and pharmacodynamics and toxicology of RG-101 and the efficacy of RG-101 in the preclinical model of HCV. The EASL presentations allowed us to highlight the wide therapeutic index we believe we have with RG-101. Following subcutaneous administration, rapid absorption and clearance of RG-101 was observed in plasma with rapid uptake and efficient conversion of RG-101 to the unconjugated oligonucleotide in the liver. RG-101 also showed reduced concentrations in kidney relative to what would be expected from administration of the naked oligonucleotide itself. The no observed adverse effect levels or NOAELs of 450 milligrams per kilograms and 45 milligrams per kilogram in mouse and monkey respectively were declared for RG-101. Taken together, the pharmacokinetic, pharmacodynamic and toxicological profile of RG-101 suggests that conjugation of oligonucleotides to GalNAc produce significant advantages that are likely to translate to more effective and safer clinical outcomes. This is an extremely important finding that highlights the progress we've made as a field in the RNA Decade and highlights the opportunity we have now to advance additional microRNA therapeutics into clinical development. To that end, over the last quarter and recent period, we continued to pursue several additional microRNA targets in oncology and orphan diseases within our internal research programs. We also are pursuing a number of other microRNA targets with our strategic alliance partners. These include microRNA-19 for oncology indications with AstraZeneca, microRNA-221 and microRNA-21 for hepatocellular carcinoma and microRNA-21 for renal fibrosis with Sanofi. A key to success in these programs is optimizing delivery, in other words ensuring that you can deliver the oligonucleotide to the right target cell or tissue. At Regulus, we continue to advance our delivery efforts. We've shown impressive clinical results when using the GalNAc carbohydrate which binds to the asialoglycoprotein receptor in the hepatocytes within the RG-101 program. And our third candidate, RG-125, also uses the same delivery approach. Because of the success demonstrated here, we plan to investigate additional receptors to allow for enriched delivery to certain cell types or tissues. If we're successful, we may be up to unlock additional value within our preclinical portfolio. With that, I'll turn the call over to David for a review of our financials. David?

[David Szekeres:]

Thanks, Neil and good afternoon everyone. In addition to our recent scientific achievements, we're pleased with the progress made on the financial front during the first quarter. We exceeded our cash guidance in 2014, finishing the year with approximately $160 million in cash, cash equivalents and short-term investments and finished the first quarter 2015 with $148.8 million in cash, cash equivalents and short-term investments. Turning now to our first quarter operating results, we recognized revenue of approximately $4.2 million in the first quarter 2015 compared to $1.6 million in the same period in 2014. Revenue for the first quarter 2015 was highlighted by the achievement of a $2.5 million preclinical milestone upon AstraZeneca's selection of RG-125 as a clinical candidate. Other revenue during these periods primarily reflect the amortization of upfront payments received from our strategic alliances and collaborations which we recognize over our estimated period of performance in addition to payments for other research services. Our R&D expenses were $13.4 million in the first quarter 2015 compared to $9.6 million for the same period in 2014. This increase was primarily driven by additional clinical study costs for RG-101, IND-enabling costs for RG-125 and an increase in personnel and research costs to support the continued growth of our pipeline. We expect our R&D expenses to continue to increase for the remainder of 2015 compared to 2014 as we continue clinical studies and initiate additional preclinical and clinical programs. Our G&A expenses were $3.6 million in the first quarter 2015 compared to $2.7 million for the same period in 2014. This change was primarily driven by an increase in salaries and related employee costs, including stock-based compensation. Our net loss for the first quarter 2015 was $14.5 million, resulting in a basic and diluted net loss of $0.29 per share compared to a first quarter 2014 net loss of $12.7 million, resulting in a basic and diluted net loss of $0.30 per share. Our net loss in the first quarter 2015 included approximately $1.8 million in non-cash charges associated with our amended and restated convertible promissory note compared to approximately $2.1 million in the same period in 2014. To reiterate our previous guidance, 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.

[Kleanthis Xanthopoulos:]

Thank you David. As you've heard today, we're very pleased with our execution against our Clinical Map Initiative goals and our overall progress during the last quarter and recent period. We look forward to building upon our proven technology platform to create a new and major class of drugs based on microRNAs. With that, we're ready to take your questions. Operator?

[Operator:]

[Operator Instructions]. And our first question comes from Alan Carr of Needham & Company. Your line is open, Alan.

[Alan Carr:]

A couple of them. I wonder if you could talk a bit about the expectations for the Phase I Alport trial coming up. I know it's in healthy volunteers, but I'm wondering what you can learn with respect to efficacy there. And then also, around RG-125, I know you're going to be presenting some data later this year, but I'm wondering if you can go over the extent of preclinical data you have there to justify clinical development. And then I guess a third one here is this is three programs going into the clinic. What's your expectations for bandwidth in terms of number of clinical programs going forward? Thanks.

[Kleanthis Xanthopoulos:]

Alan, let me address the last question first and then I'll turn it over to Paul and Neil respectively to answer your questions one and two. So, in terms of bandwidth, we have modeled our growth and sustainability to run, at any given point, between six and eight programs. And clearly, three clinical programs are very, very achievable. Remember that 125, once we file the IND, will be developed fully by AstraZeneca with intellectual input from us but not more than that. As we plan our growth and look into the next three years of planning, we think we can have about four of our own clinical programs in that time period and that can be satisfied with the modest growth in FTEs that we plan over the next several years.

[Paul Grint:]

So in answer to your question about the Phase I for RG-012, this is a single ascending dose study in healthy volunteers. I mean the key goal of this obviously is to look at safety tolerance and the pharmacokinetics. And obviously, we can compare back the exposure there with regard to what we've seen in the preclinical setting to make some assessments and forecasts with regard to dose for the Phase II study. We've talked about this before. You know, we did in last year in the pre-IND we had with the FDA, we had also proposed to do some multiple ascending dose work in healthy volunteers. However, they encouraged us basically to get into patients as soon as possible. So, they agreed to the outline design of the Phase I single ascending dose but then said it's best to get into patients. So with respect to biomarkers, good question. Don't know. We'll obviously be taking a lot of serum and urine samples from the volunteers. We'll be looking at signatures and we'll see what we see there.

[Neil Gibson:]

For the 103/107 program, Alan, what we've shown in a number of different preclinical models, including the high fat fed dial mouse model as well as the db/db mouse model, that you can get a nice reduction in glucose and insulin or an improvement in HOMA IR which is really a measure of insulin resistance. And also in a clamp model, we've shown that we can actually highlight the fact that inhibition of 103/107 is an insulin-sensitization mechanism. Other work that we've done with earlier leads also showed the inhibition of 103/107 can reduce triglycerides, etc., all supportive of having a novel insulin sensitization mechanism that could also help with the complications of NASH in diabetic or pre-diabetic patients.

[Operator:]

Our next question comes from Alethia Young of Deutsche Bank. Alethia, your line is open.

[Alethia Young:]

One, I think it was interesting, some of the takeaways at EASL, so I was wanting to get your view on some of the interesting kind of broad hepatitis C takeaways and how, especially around duration, resistant mutant and how it ties into the potential for your regimen to kind of position itself in a differentiated way.

[Paul Grint:]

We've talked about this a bit. So I think there's obviously -- EASL was a large meeting. There was a lot of information there, you know, much of it good with regard to oral combinations in certain patient populations. But as Kleanthis highlighted in his initial remarks, I think the two things of interest for us is as the companies continue to push for shorter and shorter combination oral therapeutic regimens, four weeks seems to be definitely off the table, six weeks probably not possible. And it looks like it's going to be eight weeks and hence, as we've discussed, our strategic approach to combine with RG-101 to try and get to four weeks. With regard to, again, something that Kleanthis mentioned and the real-life experience that we're seeing with regard to the falling response rates now out there in the real world is not in the controlled Phase III studies in rates around 85%. What's an interesting question there is how much of that is compliance and how much of that might be due to resistant variants. Well, I think either of that is good news for us because, as we've said all the way along, I think RG-101 offers a big opportunity to enhance compliance because, as a treating physician, you can give or watch the injection being given to the patients. But also as a mechanism targeting wholesale factor, we believe that that should not affect our resistant variants, should not affect our ability to obviously block that virus replication. And that's something we obviously intend to study in the clinic moving forward. So I think as the therapies get used more and more in the real world, the opportunity for us in the treatment failure population for whatever reason I think becomes real and significant and there's definitely going to be a medical need. I think -- I don't know if you were at one of the presentations there, but now people are talking about using PEGylated interferons and ribavirin in combination to treat these patients who fail the current oral regimens. So interesting times.

[Alethia Young:]

And then as far as with your data sets, particularly there, what was kind of the feedback around the conference that you got from [Technical Difficulty] and different people in the field? And as we go forward outside of the conference, what has been the feedback?

[Paul Grint:]

So, the feedback from the medical community has been very positive on a couple of fronts. As Kleanthis highlighted, so the breakfast wrap up on Sunday morning, RG-101 was highlighted in a slide on its own as a standalone as an important drug to look at targeting new mechanisms. People, I think, were very pleasantly surprised by the durability of the effect. We do had to keep reminding everybody this is only a single administration and it wasn't our expectation or intention to think that a single administration would give durable responses out now to five months in patients. But overall, as I've talked to some of the people who attended the late-breaking oral session, they were really quite excited and we've had a number of people contact us since who are very interested to participate in future clinical studies.

[Alethia Young:]

Have you guys specified if you're looking at only kind of assets there on the market or are you still open to looking at pipeline assets as well in the future combination?

[Kleanthis Xanthopoulos:]

The disclosed initial thing which we're going to be running the trials under the CDA are with compounds on the market, specifically Harvoni, Olysio and Daclatasvir. However, we've been approached by many other entities with assets in clinical development and we're considering all the different alternatives here. But the stated intent in the short term, that I said will come with assets that are on the market.

[Operator:]

Eric Schmidt, Cowen and Company.

[Unidentified Analyst:]

This is Jeff on for Eric. Thanks for taking my questions and congrats on all the progress, especially with RG-101. I might've missed it, but did you mention that the monotherapy RG-101 study would also be initiated in 2015?

[Paul Grint:]

Yes. That is our intention, absolutely. I think what we said before is we're not looking at just one Phase II study. We're looking into a series of Phase II studies to help us better understand the utility of 101 both alone and in combination and in different genotypes.

[Kleanthis Xanthopoulos:]

Just to clarify, the monotherapy will have two injections or potentially three interspaced by 29 days.

[Unidentified Analyst:]

And for the Alport syndrome, can you just remind us sort of a little bit more on the background of the disease and what are current therapy out there for these patients?

[Neil Gibson:]

So Jeff, there is no approved therapy for Alport syndrome patients, so they ultimately do get treated predominantly with ACE inhibitors but those are basically used not in an approved therapy sense. So it does alleviate some of the symptoms. Now, the background was that we knew from the miR-21 knockout animals that when you introduce stress into the kidney, you could actually attenuate the degree of fibrosis that you would see that was normally associated with an increased expression of wild type miR-21. So we basically pharmacologically pheno-copied the miR-21 knockout data and then, in discussions with Sanofi, our partner, came to the conclusion that patients with Alport syndrome where a good opportunity to really assess the ability of inhibition of miR-21 to improve renal fibrosis and at the same time sort of increase the time to end-stage renal disease. And as Paul mentioned, Alport syndrome patients basically having mutations in the collagen IVa(3), IVa(4) or IVa(5) family of proteins that leads to dysfunctional glomerular basement membrane that creates the stress on the proximal tubular epithelial cells that results in increased levels of expression of miR-21. And there is an animal model of this and we've got beautiful data both as a monotherapy and in combination with ACE inhibitors that inhibition of miR-21 increases the survival of those animals with those mutations. And that was published last year in a JCI paper. So we could send you that PDF if you would like.

[Unidentified Analyst:]

And I do recall the fibrotic observations. And especially on that, do you envision that you can sort of explore other fibrotic indications with your findings in Alport?

[Neil Gibson:]

Yes. That would obviously be the next wave of approaches that we'd take. But we felt Alport syndrome patients or Alport syndrome was a good place to go because of the high percent of patients who subsequently end up with end-stage renal disease.

[Operator:]

Our next question comes from Chris James of FBR & Company. Your line is open, Chris.

[Chris James:]

Just regarding the multidose monotherapy study, will this be in specific patient subtypes and specific genotypes or will this just be in across all the broad subtypes and liver fibrotic issues and cirrhotics and co-infected patients?

[Paul Grint:]

We haven't finalized the design of this yet but based on what I said earlier, what's intriguing to us based on the limited clinical data we have so far is the good response we see in genotype IV patients. And we've talked previously about a potential reason for that based on some of what's known about the sequencing from the GT IV patients themselves and so we will be selective with regard to what are the appropriate patients we're going to treat with monotherapy.

[Chris James:]

And then on RG-125, can you comment on whether this is using the GalNAc conjugation given the nature of NASH as a primary liver disease?

[Neil Gibson:]

Yes, as we mentioned Chris, there is increased levels of expression of 103/107 in patients with NASH or NAFLD. And that was work from Markus Stoffel's group in Zurich. And so in essence, we chose to make the GalNAc conjugate to ensure that we could enrich delivery into the hepatocyte to get at that increased levels of 103/107 that occurs in response to disease progression.

[Operator:]

[Operator Instructions].

[Kleanthis Xanthopoulos:]

Hearing no other questions, let me conclude the call by saying how excited we're about the future prospects of our company. As you heard today, in less than two years, we have nominated three clinical candidates and have initiated two clinical programs and potentially a third before the end of the year in RG-125. Specifically, also for RG-101, I want to make a comment on the commercial opportunity that we see as the landscape of course is changing and with all the information that we extracted out of EASL. As you all know, the total global hepatitis C market is between $0.5 trillion and $1 trillion. We do see a great opportunity for a very versatile, durable and potent compound such as RG-101 that is agnostic to previous treatment histories or fibrotic index, things that we demonstrated in the data we presented at EASL. We think there is a place for RG-101, both in frontline by increasing compliance and shortening the duration of therapy, thus reducing the overall cost of treatment and the duration of treatment. We're thinking that the four-weeks standard design will produce the kind of data that we expect with high SVRH and increased compliance, but also seeing a great opportunity in second line as the 15% or so failure rates that we now recorded in the real world and are attributed to either compliance or resistant associated variants, both things that can be addressed with the injection of RG-101 and the coverage of RAVS or resistant associated variants. Thus, we view that RG-101 has a great potential in the ever-changing HCV landscape. With that, I would like to thank you for joining us on the call this afternoon and we look forward to communicating further progress in the future. Thank you.

[Operator:]

Ladies and gentlemen, this concludes today's conference. Thank you for your participation and have a wonderful day.