Regulus Therapeutics Inc (RGLS) 2013 Q4 法說會逐字稿

Good afternoon ladies and gentlemen, and welcome to the Regulus Therapeutics fourth-quarter and year-end 2013 conference call. My name is Jamie and I'll be your coordinator for today. I would now like to turn the call over to Amy Conrad, Director, Investor Relations and Corporate Communications. Please proceed.

Good afternoon and thank you for joining us. On behalf of Regulus Therapeutics, I would like to welcome everyone to our conference call for the quarter and year ended December 31, 2013. I hope you've all had a chance to review today's press release. If you have not and you need a copy, you can visit our website at www.RegulusRX.com.

Joining me on today's call are Kleanthis Xanthopoulos, PhD, President and Chief Executive Officer; Neil Gibson, PhD, Chief Scientific Officer; and Dan Chevallard, Vice President, Finance and Accounting. Also with us in the room is David Szekeres, our newly appointed Chief Business Officer and General Counsel.

During today's call, Kleanthis will provide introductory remarks including an update on our corporate strategy and our outlook for 2014. Dan will summarize our fourth-quarter and year-end 2013 financial results and Neil will provide an update on our microRNA therapeutic program. Following your questions, Kleanthis will wrap up the call.

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. At this time I would like to turn the call over to Kleanthis.

Thank you, Amy and thank you for joining us this afternoon. 2013 was another good year for Regulus and our achievements continue to solidify our position as the leader in the field of microRNA therapeutics.

Over the last year and recent period, we focused our efforts on advancing our pipeline towards the clinic to drive significant long-term value for the Company and our shareholders. Under our Road to the Clinic strategy for 2013, we outlined several critical corporate goals that focus on identify microRNA candidates for clinical development, advancing our pipeline in a meaningful way, and enabling a smooth transition into a clinical stage company.

Specifically, we set the goal of nominating two microRNA candidates for clinical development, be in a position to file our first application with regulatory authorities by the first half of 2014, and maintain a strong year-end cash position to support these goals.

Today we're pleased to announce that we have successfully achieved our Road to the Clinic goals. We have nominated two candidates for clinical development: RG-101 for the treatment of HCV and RG-012 for the treatment of Alport Syndrome, a life-threatening orphan kidney disease that is driven by genetic mutations.

Our RG-012 program underscores our internal focus on orphan diseases and we hope to continue to expand this portion of our clinical portfolio. We also maintain our strong financial position and exceeded our cash guidance, finishing 2013 with $114 million in cash, cash equivalents and short-term investments.

Following completion of our Road to the Clinic goals, we are now ready to transition our microRNA therapeutic pipeline to the clinic. To successfully navigate entry and progression through the clinical trial process, we have developed our Clinical Map Initiative. This outlines the clear clinical corporate milestone strategy necessary to advance our therapeutic pipeline over the next several years, leveraging our advanced technology platform, our strong strategic alliances and broad intellectual property space.

We've mapped the following goals as the first phase of this initiative. First, establishing a proof of concept with our RG-101 program, which targets microRNA-122 for the treatment of HCV, which we believe may be transformative for Regulus in the field of RNA therapeutics.

Today, we are one step closer to achieving this goal. We are pleased to announce that we've recently received approval from the regulatory authority in the Netherlands to commence dosing in our Phase I clinical trial of RG-101. Later in the call, Neil will provide you with our clinical map for RG-101 and the overall goals for that program.

Second, in addition to establishing human proof of concept results, we expect to initiate the Phase II -- I'm sorry; Phase I clinical study of RG-012 for the treatment of Alport Syndrome in the first half of 2015. We're very excited about this program because it strengthens our internal focus on orphan diseases.

A key component to advancing this program was the recent renewal of our strategic alliance with Sanofi, in which we achieved an additional $10 million in equity investment, bringing their total ownership of Regulus to about 12%.

With this renewal, we're now driving development of the RG-012 program. And Sanofi also increased their interest in our oncology efforts by obtaining opt-in rights to the miR-21 program and gaining opt-in rights to our program targeting microRNA-221 plus 222 for the treatment of hepatocellular carcinoma.

As you may recall microRNA-21 has been an important microRNA target for us for some time and is considered one of the most validated microRNA targets with an abundance of scientific literature out there.

In 2010 we entered into the original strategic alliance with Sanofi around this target in fibrosis, then expanded the alliances in 2012 for oncology targets and have now focused a relationship on three programs which Regulus is gaining a greater stake in development and greater upside potential in commercialization milestones and royalty payments.

If Sanofi chooses to exercise its option of any of these programs, they would pay us an option exercise fee, reimburse us for a significant portion of our preclinical and clinical development costs on any of these programs, and in addition pay us milestones all the way to approval.

We're also pleased to have an option to co-promote it the United States or receive royalty payments in the mid-10% to 20% range for any of these three programs.

Currently we are planning our clinical map for RG-012 and Neil will provide you with more information on this program and the Alport Syndrome later on the call.

Third, by the end of 2014, we also expect to nominate third microRNA candidate for clinical development. In order to achieve these goals in our Clinical Mapping Initiative, we expect to maintain our strong financial position and guide to [an end] 2014 with at least [$70 million] in cash.

An important component to achieving our goals and maintaining our leadership is retrieving the best talent. Earlier this month we announced that David Szekeres joined us as Chief Business Officer and General Counsel, and he will be a key contributing member of our executive management team. David brings over a decade of legal and deal-making experience with the global life science industry, most recently as Deputy General Counsel, Chief M&A Counsel and Assistant Secretary at Life Technologies Corporation. David's transactional deal experience will be tremendous asset to our team as we continue to mature our Company.

In closing, we had another good year with many achievements. We believe that with the backbone for these achievements is the potential of our emerging product platform based on microRNAs, a recently discovered class of [non-combining] RNAs that control the majority of the genes in the human genome. MicroRNAs have been found to be deregulated in many, if not all decisions that we've looked at, and we believe that modulating them therefore provides a very good therapeutic utility.

We believe that microRNA therapeutics may be the next wave of innovative RNA therapies and may have the potential to totally transform the field of drug discovery.

With those introductory remarks, I'd like to turn the call over to Dan Chevallard, our Vice President, Finance and Accounting, for a review of our fourth-quarter and year-end 2013 financial results. Dan?

Thank you, Kleanthis, and good afternoon. In 2013 we managed our operating costs and working capital in line with our operating plans, which allowed us to exceed our cash guidance for 2013, ending the year with $114 million in cash, cash equivalents and short-term investments compared to $98.1 million in 2012.

Turning now to our full-year 2013 financial results, we recognized revenue of $19.6 million in 2013 compared to $12.7 million in 2012. Revenue in 2013 included approximately $15.4 million from the Sanofi collaboration and license agreement and $4.2 million from other strategic alliances and collaborations. Revenue during these periods consisted of primarily of amortization of upfront payments received from these strategic alliances and collaborations, which we recognized over our estimated period of performance.

Total operating expenses were $37.4 million in 2013 compared to $25.3 million in 2012. Our research and development expenses increased to $29.9 million in 2013 compared to $20.3 million in 2012. This increase was substantially due to costs associated with regulatory filing activities for RG-101 and other programs in 2013.

We expect our research and development expenses to continue to increase as we begin clinical studies and initiate additional IND-enabling regulatory filing activities in the future.

Our general and administrative expenses increased to $7.4 million in 2013 compared to $4.9 million in 2012. This was primarily due to administrative costs associated with the growth of Regulus as well as incremental costs associated with being a public company.

Our net loss for the year ended December 31, 2013 was $18.7 million compared to a loss of $17.4 million in 2012. Our net loss in 2013 included total net, non-cash charges of $1.1 million associated with the change in value of the amended and restated convertible promissory note originally issued to GSK in 2010.

In 2012, net loss included total non-cash charges of $4.7 million. These charges were primarily attributable to increases in the value of our common stock over the respective period. We expect to finish 2014 with at least $75 million in cash, cash equivalents and short-term investments, which includes the recent $10 million equity investment from Sanofi, received in conjunction with the renewal of our strategic alliance.

With that, let me now turn the call over to Neil to provide an update on our recent scientific progress.

Thank you, Dan, and good afternoon everyone.

As Kleanthis mentioned earlier on the call, 2013 was another productive year for us. We were focused on scientific execution and believe that we achieved significant progress in advancing our microRNA portfolio towards the clinic. We're also looking forward to advancing our newly launched Clinical Map Initiative for 2014 and beyond, which focuses on RG-101 and RG-012, and a third clinical candidate to be potentially nominated before the end of this year.

On today's call I plan to focus my comments on RG-101, RG-012 and will provide a general update on the advancement of the remainder of our microRNA portfolio. In 2013 we made significant progress across our therapeutic pipeline. We announced today that we received regulatory approval to commence dosing in our Phase I clinical study for RG-101, a GalNAc-conjugated, anti-miR targeting miR-122 for the treatment of HCV.

At last year's American Association for the Study of Liver Diseases or AASLD, we think we presented data from preclinical studies evaluating RG-101 for in vitro and in vivo [portion phase] pharmacokinetics, pharmacodynamics, toxicology and [safety] pharmacology and inhibition of HCV replication. These positive preclinical data provide the evidence for the favorable properties of RG-101. It's potent, safe and the mechanism appears pan-genotypic and no resistance having been observed to date.

In efficacy studies we have shown that single dose of RG-101 significantly reducing HCV viral load up to two log reduction in a human chimeric mouse model infected with HCV genotypes 1a and/or genotype 3A. Genotype 3A is considered a hard to treat genotype even with current direct-acting antiviral or DAA therapies.

The viral load reduction observed is similar in potency to the oral DAAs in this model, and the duration of action of their [priority] RG-101 supports the potential for a once a month dosing regimen, which we believe may be commercially attractive. These data and the favorable preclinical profile to date supports the advancement of RG-101 into the clinic.

The Phase I clinical study of RG-101 will have four parts. First, a single ascending dose study in healthy volunteers; second, a multi-ascending dose study in healthy volunteers; third, a single dose drug/drug interaction study of RG-101 in combination with an approved DAA in healthy volunteer subjects; and four, a single dose study in HCV patients to assess the safety and viral load reduction which is designed to demonstrate human proof of concept.

The primary objective of the Phase I clinical study of RG-101 is to evaluate safety and tolerability. The secondary objectives are to evaluate pharmacokinetics, viral load reduction and any impact on an oral DAA may have on the pharmacokinetics of RG-101.

Up to approximately 100 healthy volunteers and HCV patients are planned to be enrolled in this Phase I study. The study is being conducted in the Netherlands and dosing is expected to commence in the near term. We continue to be encouraged by this program and believe that RG-101 has the potential to be a best-in-class host factor for the treatment of HCV.

Let me now turn to our second program poised for clinical development, RG-012, an anti-miR targeting miR-21 for the treatment of Alport Syndrome, the life-threatening kidney disease driven by genetic mutations. Alport Syndrome is caused by genetic mutations that affect the type 4 collagen family of proteins. The impact of the mutation in the collagen gene results in disruption for the structure of the glomerular basement membrane, increased expression of miR-21, increased fibrosis in the kidney, loss of renal function, which leads to end stage renal disease and subsequent death. This is a devastating disease with no approved therapy on the market.

We are pleased with the preclinical profile of RG-012 and the results shown to date support our advancement of this compound into clinical development. At the American Society of Nephrology's Kidney Week meeting last year, we presented preclinical data to demonstrate treatment with an anti-miR-21 candidate in a mouse model of the disease that significantly decreased the rate of decline of renal fibrosis, restored expression of the key microRNAs involved in maintaining renal function, and increased the lifespan of the mice up to 50% depending on the genetic backgrounds of the collagen 4A3-deficient mouse.

Today we have a framework of the clinical map for RG-012. In the third quarter this year, we plan to initiate the natural history of disease study, which will allow us to gather greater information about the actual progression of patients with Alport Syndrome, as this is not well described in the current literature.

RG-012 may be a transformative therapy for Alport Syndrome patients, but the clinical and regulatory path is unclear. Our learnings from the planned natural history of disease study and our ongoing discussions with the regulatory agencies will help us establish clinical endpoints for our upcoming trials amidst the unclear clinical path.

We do know that there is a preliminary biomarker of renal disease known as glomerular filtration rate or GFR, which may be an appropriate clinical end point. And we will continue to assess this as we learn more about the progression of disease through our natural history of disease study.

In addition to looking at GFR and other renal biomarkers for clinical endpoints to our study, we also have the ability to look at other exploratory biomarkers. Additionally, through our Regulus microMarkers technology, we also have the ability to investigate microRNA levels in both the serum and the urine to help us refine the potential clinical endpoint.

Once we have identified appropriate clinical endpoints for our trials, we expect to conduct Phase I clinical study of RG-012 in healthy volunteers and transition to Alport Syndrome patients to evaluate the effects of inhibiting miR-21. Currently, we are manufacturing drug product and conducting additional toxicology studies prior to entering into clinical development with RG-101 in the first half of 2015. This is a critical goal in our Clinical Map Initiative, and we look forward to reporting progress on this exciting program over the coming year.

We continue to make progress with our exploratory efforts to identify attractive new microRNA targets that will fit with our internal expertise and align with our focus on oncology and orphan diseases. We also communicated today our intent to nominate a third clinical candidate for development before the end of the year, which may come from these efforts or from a partner target or program.

Over the last year, we have streamlined our strategic alliances and believe that we've strengthened those relationships to help us advance candidates into clinical development. We gained full control of RG-101 from GSK, we gained greater control of RG-012 from Sanofi, and we announced today that we rebalanced our efforts with AstraZeneca by terminating the miR-33 program for atherosclerosis and focusing on our miR-103/107 metabolic program and our miR-19 oncology program.

We and AstraZeneca chose to terminate the miR-33 program due to certain technical challenges with the program and increasing complexity in the competitive landscape for atherosclerosis. We continue to collaborate with AstraZeneca on additional targets, namely miR-103/107 for metabolic disease and miR-19 for oncology. AstraZeneca also has replacement rights for the miR-33 target.

We are pleased with the successful relationship we have built with AstraZeneca, and believe that their continued commitment to RNA therapeutics will enable us to build a meaningful clinical pipeline. We look forward to communicating additional progress from this alliance in the future.

Turning now to our proprietary portfolio, I'd like to provide you with a brief update on the programs that fit within our focus on oncology and orphan diseases. In our miR-10b program for the treatment of glioblastoma or GBM, critical experiments are still ongoing and we are currently assessing early microRNA candidates.

As we mentioned earlier in the call, with the recent renewal of our strategic alliance, Sanofi gained opt-in rights to our miR-221/222 program for the treatment of hepatocellular carcinoma. We have identified potent lead candidates and are working to optimize our ability to deliver those lead molecules using the lipid formulations for the GalNAc-conjugation technology that we are utilizing for RG-101.

To close out the therapeutic pipeline review, we also continued to make significant progress with our biomarkers technology platform. Earlier this year, we announced that we expanded our efforts here and established Regulus microMarkers, an R&D division designed to support our growing therapeutic pipeline, our strategic alliance partners and our collaborators, and which is aimed at identifying microRNAs as biomarkers for disease.

We have developed a highly reproducible proprietary platform from extracting, profiling and analyzing microRNAs, and have successfully applied this platform to identify microRNAs that are dysregulated compared to healthy in human samples. We plan to demonstrate the value of the Regulus microMarkers technology by identifying microRNA biomarkers in test and patient populations of specific indications such as our miR-221/222 program for HCC.

In 2012, we founded a research collaboration with Biogen Idec focused on the discoveries of microRNAs as biomarkers for multiple sclerosis. We're currently working out the next phase of our relationship with Biogen around biomarkers and hope to report additional progress in the near term.

To summarize, 2013 and the recent period has been very successful for the advancement of our microRNA therapeutic pipeline. We've established a clinical map for RG-101 and RG-012 and look forward to reporting further progress over the coming year.

With that, I'll turn the call back over to Kleanthis for closing remarks.

Thank you, Neil. In closing 2013 was an extremely productive year for us and we had a very busy start for 2014. We have significantly matured as a Company and are ready to enter clinical development. We completed our goals on the Road to the Clinic and have launched our Clinical Map Initiative to clearly define our clinical plans.

Under the initiative we've mapped out very aggressive goals to rapidly advance our microRNA candidates in clinical development, which we believe will drive long-term value for our shareholders. Later this year, we expect to demonstrate human proof of concept results from our RG-101 program, which we believe will validate our microRNA technology and may be transformative for us in the overall RNA therapeutics space.

We also expect to further advance our second clinical candidate RG-102 (sic RG-012 -- see Press Release) for the treatment of Alport Syndrome by conducting a natural history of disease study and planning for a Phase I clinical study in the first half of next year.

Lastly, we expect to nominate a third microRNA candidate for clinical development by the end of 2014.

With these important upcoming catalysts, we believe that 2014 will be another exciting year as we advance our programs and continue to build a meaningful clinical portfolio.

With that, I'd like to thank you again and we're now ready to take your questions.

(Operator Instructions) Jim Birchenough, BMO Capital.

Congratulations on all the progress. A couple questions, just first on the Alport Syndrome program, I'm trying to get a sense of what period of time with this natural history disease study do you expect to learn what patient population to target. You have to have, I guess, a broad sense of the natural history to target it on some portion of it over a reasonable people of time. Could you just talk us through that?

Hey Jim, this is Neil. We're going to look at the progression of disease in Alport patients over a minimum of 12 months, going out for as long as 18 to 24 months.

And is that -- are you looking at a certain subset of patients that are pre-dialysis or earlier in the continuum or is it a broader term?

Yes, what we are planning to do is look at patients who have stage III chronic kidney disease. It's thought that those patients have a reasonably consistent decline in GFR and would allow us to get an appropriate way of looking at the efficacy of the molecule. So we're going to try and enrich the natural history study for patients in Stage III chronic kidney disease and use those patients also in our proposed efficacy study.

Great. And then just a question on one-to-one; when you get to the point of testing and HCV patients, do you expect to enroll patients who have failed approved DAAs like Sovaldi?

As this is being done in the Netherlands, at the moment it's likely that the patient population will either be sensitive or insensitive or naive to interferon. But a number of the patients are not likely to have received the oral DAAs that have been approved in the US.

And when do you think you might gain that type of experience, Neil?

The second half of this year is when we anticipate being able to get human proof of concept in HCV patients. And in that study, we'll have a mix of genotype 1 and genotype 3 patients. So we'll get a real good handle on what the level of viral load reduction is in both these specific genotypes.

Got it. And I guess I'm just trying to understand in terms of getting a sense of activity in patients who have failed existing DAAs, that may require study in the US. When might that happen?

That would be potential design of a Phase II study. So the single-dose HCV study is likely to read out in the second half of this year, as I mentioned. So more than likely, the Phase II study would be a 2015 type of study.

One of the primary objectives of the study is to demonstrate oncogenic activity in a safe way, obviously, and well-tolerated. So that's the goal of this study. We expect to hit that milestone before the end of the year and we'll have a combination of at least one DAA.

The question you're asking about, potential cell body failures, that's going to be addressed in -- as Neil said, after that, probably in 2015. And also, to your first question, to clarify, the natural history disease study is going to be going in parallel with Phase I. So they're not going to be sequential of course. We are going to be continuing at study as we enter into Phase I, which we plan to do in the first half of next year.

And Kleanthis, I think just a final question -- strategically, as you're building out the biomarker part of the business, how do you think about that as a separate revenue-generating business? And is that something you think should stay part of Regulus or does it become a separate business? How are you thinking about that?

We've been very surprised with the success of the biomarker technology, Jim. So those are subject to intense discussions internally. Part of the broad expert team that David Szekeres is bringing to the table is understanding this part of our business quite well.

So we'll have a clear strategy over the next quarter or two that we'll be able to communicate. But in the meantime, collaborations with Biogen and other pharmaceutical companies are ongoing. Our own efforts on a number of disease that we are looking for biomarkers now in blood, serum, and urine are giving us a very high level of confidence that this is a very valuable asset of Regulus that will find a way to ultimately monetize above and beyond what we're doing now.

Great, thanks for taking the questions.

Simos Simeonidis, Cowen and Company.

Kind of following up on what Jim was asking on the clinical and commercial plan for RG-101. So Kleanthis and Neil, you are planning to start Phase II trials, assuming the Phase I is successful, and your two proof of concept in the US in 2015. Is that correct?

Simos, to clarify that, that's a good question. Our stated objective is we want to demonstrate human proof of concept with 101. We have so many opportunities that I hope you got a glimpse from what Neil was saying on how microRNAs operate in so many different diseases, that we want to and our objective is to ultimately find a home for someone who is an HCV franchise and needs a pan-genotypic agent on top of a number of DAA oral agents that they are applying.

So, we do not intend to on a unilateral setting start a Phase II trial. We'll come to the proof of concept, validate the approach and we already have started a number of discussions, potentially finding the appropriate home for RG-101.

I see. That's very helpful. And then again, going on what Jim was asking about 012, and you might not be able to answer the question yet. But in terms of where you think there might be a fit for this drug in the course of the disease, or how it would help patients -- that it would delay them from going to dialysis, it would extend life by preserving function? And I know it's too early because we've only seen the animal experiments, but how do you think this drug may work and may help these patients?

Based on the preclinical studies, Simos, we are anticipating the inhibition of miR-21 in patients with Alport Syndrome will actually delay the progression of disease.

Okay, okay. And then Neil, finally a couple of more for you. On the new targets you announced tonight on your AZ partnership, can you tell us a little more about what 103/107 in metabolic disease and 19 are implicated in? What type of tumors for 19 and what types of metabolic diseases in 103 and 107?

Yes, so 103/107 is a highly expressed microRNA in hepatocytes and adipocytes. So it's really thought to play an important role in modulating glucose control, and we're looking at the effects of inhibition of that specific microRNA in metabolic disease.

For the miR-19 program, a lot of the focus has been on lymphoma. And in part, miR-19 is activated or increased in its expression as a result of myc amplification. And myc amplification is a very common genetic lesion in lymphoma giving us a reasonably clear path with how we can advance this type of mechanism when we have a potential clinical candidate.

Okay, great. Well, thanks for taking the questions and congrats on the progress.

Alan Carr, Needham & Company.

Can you talk about the -- with respect to the Alport's program, are we going to be seeing any more preclinical data at conferences over the course of the year?

And then also what's the scale of the natural history of the disease study? And can you comment on what's the limiting factor to starting the Phase I trial? Thanks.

Let me start with the initiation of the Phase I trial, Alan, and it's basically currently manufacturing the drug substance to allow the GLP toxicology studies to get completed. So in essence that timeframe is what will drive the filing of the regulatory documents towards the end of this year, with the anticipation that we'll be starting dosing in human early in 2015. So that's the key there.

For the natural history disease study, we're really looking there to get a sense of maybe between 30 and 50 patients on a number of different clinical endpoints over the course, as I mentioned, of at least 12 months and more likely be 18 to 24 months.

Alan, to add to the third part of your question, between Sanofi, Glax, Genzyme and Regulus we have a lot -- a plethora of preclinical experiments done on multiple sides, multiple times with our lead compound, indicating a very significant improvement in histology, improvement in kidney function, and more importantly, extension of survival of these mice carry the exact genetic mutation as do the humans. And you will -- we have the full intention of both in publishing in scientific journals as well as participating in many of the upcoming scientific conferences presenting additional data.

Okay, great, thanks very much.

(Operator Instructions) Greg Wade, Wedbush.

Good afternoon, let me add my congratulations as well on a very busy year and thanks for taking my questions.

Neil, can you help us to understand what will define proof of concept in the Alport setting? Is it going to be the same endpoint that you would need to demonstrate, do you think, for approval or something different?

And then secondly with respect to the 10b program in GBM, could you just maybe highlight for us the nature of the experiments that are ongoing, if there's been any particular challenges you are trying to overcome and whether you think this will be the last set of preclinical work before you are able to figure out which drug might go into the clinic? Thanks.

So, for the endpoint question on patients with Alport Syndrome, Greg, we have really been looking at a number of different endpoints. There's obviously the GFR -- the glomerular filtration rate that I talked to. And that's a discussion that we would need to have with the agency as to whether that would be an acceptable endpoint for subsequent approval.

But clearly it's an endpoint that we could use in terms of helping us make a subsequent investment decision into a potential registration study. But also we are going to back that up by looking at a number of the different approved or FDA-approved renal biomarkers and study those in the natural history of disease setting, and to see which ones potentially give a nice signal to noise.

An example, beta-2 microglobulin, KIM-1, NGAL -- these are three of the seven approved renal biomarker tests that are available for us to look at to see whether they provide a good signal to noise.

And thirdly, we'll be looking at exploratory biomarkers including understanding the micron expression, as I talked about earlier, either in serum or in urine, as well as looking at for instance urinary peroxides which we know in the preclinical studies were highly elevated in the progression of disease in the mutant mouse. And our inhibition of miR-21 actually dramatically reduced the level of urinary peroxide. So there is multiple levels to what we could do from the endpoint question.

And obviously looking at it from, one, the decision to add additional investment into the program and, two, the discussion with the regulatory authorities as to what may be an approvable endpoint for key areas we are going to focus upon.

For the 10b program, in essence we've been -- we see interesting phenotypic changes with some of our lead molecules. But the challenge in the program has been really to define what's the right target messenger RNA that we are -- or set of messenger RNAs that we can use to help us with our pharmacodynamic endpoint, and to really understand by what mechanism modulation of 10b may be driving progression of GBM and in which specific segment of GBM that is occurring, whether the mesenchymal patients or the proneural patients.

So we've got a number of challenges to surround that target messenger RNA readout that we're trying to solve at the moment.

Great, thanks. If I could just a quick follow-up with respect to GFR in Alport, another rare disease that affects the kidney, GFR can be a little misleading where there's a hyper-filtration period followed by decline in GFR. Are you aware in the natural history of Alport whether it's a steady decline in GFR or these patients might go through a hyper filtration period as well? And thanks for taking my questions.

Greg, let me make a few comments about this. As you very well are aware, the Alport Syndrome is now getting a lot more publicity. We saw a frenzy of media coverage just yesterday with a report originally on television with ABC, Good Morning America and the expectation that there is a lot of patients out there. Estimates now up to 60,000 in the US; a lot more than we originally had anticipated.

And more importantly, the reason I am making those comments is that the Alport Syndrome Foundation of the United States is working very closely with us. You're going to hear more about that in the future. We've already been networked to KOLs. We're gathering their wisdom in terms of comments like this, whether DFR would be appropriate biomarker or not.

So we basically are going to cover all bases, as we think that this is a great entry point for microRNA treatment. And this has, of course, a rather huge upside potential if we identify treatment.

So we are not going to be focusing on one or two biomarkers; going to be everything that the KOLs are suggesting. We can do that very effectively in a short period of time during the course of the disease. Neil, did you want to add something?

Just to add, Greg, we do know that there are multiple different mutations that drive the progression of Alport Syndrome. And the type of mutation can strongly influence the rate of progression. So that's something we're very aware of and are actually incorporating that thinking into how we think about the design of our subsequent studies.

Great, thanks. Sounds like you have a lot of endpoints to look at, so there will be no shortage of measurements to make. Thanks.

At this time I am showing no further questions. I would now like to turn the call back over to Kleanthis Xanthopoulos for closing remarks.

Thank you again for joining us on the call this afternoon, and as we stated, we're very pleased with our recent accomplishment. We look forward to communicating further progress with you. Thanks again for your time this afternoon.

Ladies and gentlemen, that does conclude the conference for today. Again, thank you for your participation. You may all disconnect. Have a good day.