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Regulus Therapeutics (NASDAQ:RGLS)

Deutsche Bank 39th Annual Health Care Conference

May 07, 2014 08:40 a.m. ET

Executives

Kleanthis Xanthopoulos – President and CEO

Analysts

Alethia Young

Alethia Young

Great, so this is Alethia Young, analyst with the Deutsche Bank Biotechnology team, we are very lucky to have Regulus from the West Coast over here and we have Kleanthis Xanthopoulos, President and CEO of Regulus. And for those -- many of those you in the room and actually those on the webcast we are going to do some -- mostly we are going to be handling fireside chat in this case. So if you questions just email me directly at alethia.young.@dv.com and then we also have FT that’s called Yorn that's yorn.com/dv and I feel pretty to say how cool Kleanthis is or Emmi or myself or anything you want to say about Regulus, or ask about Regulus and we will respond to those questions anonymously. So with that I guess Kleanthis, we are going to start with but I just want you to give us a background about how you guys such a mature platform and like kind of your story between Alnylam and Isis and how you guys came onto the scene in 2007.

Kleanthis Xanthopoulos

Well thank you and welcome everybody and I am glad we have the opportunity to have dialogue (inaudible) presenting and that’s because there are lot of things that we can cover through a very interesting dialogue and so Alethia is alluding to hear for the audience is how did Regulus’ platform has become so forward-looking and maturing in a relatively short time. And what I am showing here in this slide is essentially the forces that are contributed to that.

We believe our method therapeutic have arrived, they address the diseases at the genetic level and from the very simple prospective that people like Isis have been on the field for over now 25 years developing technologies that directly applicable to what Regulus is doing and likewise Alnylam on the scene for 15 years and they have contributed significantly to the field. The two of them, in 2007, joined forces to create Regulus and that's the formation of the company to capture the idea which was to develop therapeutic against microRNA and therefore for the first time being able to control pathways of human diseases but that idea for the first time and I think unique in biotech history is based on a mature technology and the technology which has been as I said over 25 years now being developed by primarily Isis and Alnylam so we are the beneficiaries of that.

Now, I want to highlight a few things on why we are so excited about RNA therapeutics as any other new big idea, you need to invest into technologies for a considerable amount of time for them to start bringing fruits and we have seen this with therapeutic proteins, we have seen seeing with monoclonal antibodies and we are now seeing with RNA therapeutics. The differences are and similarities between three companies Regulus, Alnylam and Isis are very clear. Although we are overlapping technology that essentially just to give you sense about 80% to 90% of the technology platform that Isis and Alnylam has is directly applicable to what we do. We have to tweak it around specifically for us and that's 10% to 20% delta but overall, we have now very good understanding of how to engineer this RNA therapeutics, how to manipulate and increase or decrease heart lives with pharmacokinetic and pharmacodynamics properties we (inaudible) to the molecule. We understand the (inaudible) specificity as well as the potential liabilities of these molecules and there is a huge clinical database now over 6000 patients we have seen RNA molecules in their bodies. So there is a lot of information that you will hear that directly being applicable to some of our thoughts and that's why we have been able to accelerate our maturation primarily due to the technology that Regulus has developed.

Alethia Young

Great. So maybe we dig a little bit further and see those proper thing, you have gone on here and called RNA therapeutics I mean its heart based, just talk a little bit of how you fit into the world of RNA therapeutics and kind of different kinds of therapeutics out there.

Kleanthis Xanthopoulos

So, let’s start with a big biological question. 60% of our genomes being transcribed yet only 2% of have been translated. So the conventional development of drugs is addressed with 2% translatable genome because we are mostly targeting therapeutic, mostly targeting protein, therapeutic proteins to address the diseases. So there is a hope completely in new space that we are able to address with RNA therapeutics and we specifically have taken and focused on the portion of the genome that being transcribed but not translated and this is the micro-RNA universe, it's about 600 micro-RNAs in the human genome. They selectively control about 50% of the translational ability of our genes. So for the first time now we have the ability to target a single micro-RNA and address the total disease state by targeting the entire pathway.

So, A: we are increasing the universe, B: we have the ability to provide a completely new unique mechanism of action and that's the uniqueness that we see in micro-RNA therapeutic. Now that's distinctively different than what Alnylam and Isis are doing. Alnylam and Isis have purpose of targeting and challenging a single gene and they do it with two different mechanisms antisense and RNAi and so our universe is a distinctively different and our approaches are also different but the technologies I said before are underlining the therapeutics that we are developing are the same.

So Isis and Alnylam and you have seen they can potentially have competitive programs because it can go after (inaudible) for example trying to even utilize a antisense approach or RNAi approach to knockdown the dream for (inaudible) or any other genome for that matter but we are distinctively and uniquely focusing on microRNA.

Alethia Young

So that’s the good segment and to just talking a little bit about what mircoRNAs and how are (inaudible) target maybe just kind of give us like the one-on-one for everyone in the room.

Kleanthis Xanthopoulos

Yes, I would love to do that and unfortunately for those on the webcast who won’t be able to see a nice video that we have created. And basically what I want to tell you that we have the ability to look a target-specific tissue in specific organ and you can see that the kidney, liver, brain, adipose bone marrow those are all targets that we can easily access and if you are focusing to the cell, what you see is the ribosome doing job translating its specific messenger RNA. The purpose of micro-RNA is to target the messenger RNA and controlling translational phase and what you see there is, there is really that complex of the micro-RNA in the complex of proteins that you are locking the ability of the ribosome to translate a specific messenger RNA through essentially sequence interaction that is stopped of the translation machinery. And that is done in the very dedicated way. You want to make sure that specific messenger RNA is not over translated and that’s how you control the phase in a normal tissue and this is if we shown in the video what we see is ten times more sometimes 20 times more micro-RNA molecules in the same cell and all of the sudden you have abnormal translational inhibition of the ability of the specific messenger RNA to be translated.

So, what we are trying to do now is of course come in we – our target micro-RNA is that you can see there and essentially type A type B axis of the micro-RNA that is going to expressed. It's a very simple pharmacological approach. It has been tested by variety of different other mechanisms. So, essentially what we are doing is we are looking at the disease state, the mirco-RNA is over-expressed 5, 10 or 20 times we create a molecule and RNA therapeutic that's is mirror image of that and we titrating out the axis of that micro-RNA.

It's a very straight forward and very specific way of doing it and we can deliver it very effectively in number of tissues that I mentioned. We can create and decorate the molecule and introduce pharmacokinetic, another pharmacological properties that are suitable for that particular disease.

Alethia Young

Great. So maybe on delivery, can you use any delivery system or do you may be use like maybe like GalNAc kind of, walk us through that kind of process.

Kleanthis Xanthopoulos

It's a very good question Alethia and I want to clarify that we have the flexibility that is 42 hours by the fact that we can either use the single stranded oligone targets and over expressed micro-RNA on in the case of where we want reintroduce the micro-RNA that is lost when we have the loss of phantom leading to disease, we are going to use a double stranded micro-RNA essentially a limit. Depending on the approach we take, we use different deliveries, depending on the target organ we use deliveries. So I am going to describe two different occasions where in one case we are targeting kidney fibrosis. In this case essentially, we don't need to formulate the molecule, it’s a naked, single stranded molecule because we know it's going to end up in the kidney that's the natural way upon where we excrete nucleic acid all of our body’s. So in this case we don't formulate and I will also describe another case where we target specifically hepatocytes and this case we have been able to conjugate it GalNAc so that we can target receptor in hepatocytes and have a significantly better uptake in hepatocytes.

So we have that flexibility. We can use single stranded or double stranded, we can use the formulated, conjugated or not depending on the tissue and that's the beauty of approach that we have that you can afford for us to take different approaches depending on the target.

Alethia Young

And also if I am not mistaken right you have access to the kind of the Isis and Alnylam delivering technologies that you are (inaudible)

Kleanthis Xanthopoulos

That's correct. So, we have talked about in 2007 Isis and Alnylam came together and created Regulus part of that creation in the founding agreement between the two companies was that all the technologies that are applicable for micro-RNA therapeutic will exclusively and automatically become property of Regulus. So we do have access to the three ways collaboration. And it goes the other way around as we develop our own technologies that 10%, 20% that I was discussing before, if their applications for in the antisense or RNAi those technologies will be available to Isis and Alnylam respectively.

To give you an example, the compound that we have in the clinic right now in phase I, that target hepatocytes incorporates the most advanced technology from Isis The Chemistry 2.5 and GalNAc conjugate from Alnylam. So delivery technology from Alnylam the best Chemistry from Isis that combination frankly is superb and it's the first time that this combination has been tested in human. So we are excited about that.

Alethia Young

Yes, it's interesting, kind of proof of concept for them, very helpful for them, yes, on what you are doing. You know I barely knew what micro-RNA was a year ago and now I get all these medical meetings now always to the discussion of it and what kind of pre-clinical so that kind of, how do you like what diseases are the implicated in and then we will dig little bit further onto how you think about selection of target.

Kleanthis Xanthopoulos

So, we have an explosive biological knowledge when it comes to micro-RNA. So to give you a sense, the first human micro-RNA was described in 2001 and that year we had three tier review publications. Last year, I think we were low close to 6,500 review publications, so we are in explosion stage in terms of all the information that is coming and I am connected to micro-RNA biology and we do know that in a sense there hasn’t been a single disease that we haven’t found microRNA being implicated in.

Now, implication versus follicle stem cell target is a big distance between the two but there is clearly a lot of interest and understanding the role of microRNA in diseases. How we prioritize our targets has been from day one the biggest issue for Regulus and in fact it was as I jokingly talk we have been in the organization, the biggest problem we have got what not to do, how to do pick the best programs that you can prosecute when you have 600 other competing for attention. And given our size, our budget, and our focus we think between our own partnering programs and as you know we have four very-very significant partners clients, GlaxoSmithKline, astrazeneca, Bigen (inaudible) and of course Sanofi, we try to balance these and then we have in any given time between six and eight programs that are ongoing.

So how do we prioritize that? We look for phenotypic evidence. We do look for chemical evidences and microRNA, dysregulated microRNA associated with the disease state and potentially clinical outcomes. We then look for genetic evidence, a lot of either knock outs or other kind of experiments that give us a sense of the criticality of that particular microRNA of and the disease and finally we approach this from pharmacological perspective. We look to incubate or mimic that microRNA and see if we can correct the disease. So there is a lot of work that goes into prioritizing and credential on the particular microRNA before it becomes fully baked program.

Alethia Young

If you say me I will get segway, so maybe just talk a little bit about the key programs you have in the clinic right now or go into the clinic next 12 months and the time line around those offer.

Kleanthis Xanthopoulos

Yeah we have been very fortunate to advances, I said the pipelining in relatively short period that we have been around. We have one clinical program in Phase 1 that is targeting a microRNA called 122, it's the major microRNA in deliver and to be hijacked by Hepatitis C. in order to stabilize the viral genome and potentially replicate, we expect clinical proof of concept on all this program in the end of the year and we won’t see -- for the first time the pan-genotypic in that is administered once a month in conjunction with any direct anti-viral that has the ability to suppress the viral replication very, very effectively. So we expect to see in multiple genotypes, both genotype 1 and genotype 3 and as we know genotype 3 is hard to treat. We expect to see data on a mono-therapy outcomes of these studies before the end of the year.

And for us this is a very interesting program. It is a platform from validating. We are not and to be franchise company but we think it's a very important to demonstrate the clinical utility of inhibiting of microRNA. We expect to do that before the end of the year.

We have nominated another compound. We are putting the regulatory documents now to initiate phase 1. This is called Alport Syndrome, it is a kidney fibrosis disease, it’s lethal and an orphan disease effecting on a minimum 20,000 patients in the U.S. Some estimates bring out up to 50,000 and lethal number in Europe. We expect to file regulatory documents before the end of the year and initiative a study as early as the first quarter of next year.

Importantly, (audio gap) the significant is that we are studying natural history of disease studies for Alport Syndrome to measure a number of bio-markers that we think are going to be very useful in deciding which endpoints to prosecute in the clinical trials so we are going to undertake. The FDA has been very-very receipting on this. We actually have now a date for pre-IND meeting on June 2nd, less than 30 days from today to discuss all these and discuss how we are going to both execute the natural history of disease study but also what are our clinical plans. And before the end of the year, we expect to nominate the third clinical candidate for a number of programs most likely oncology since we have at least three programs on oncology ongoing and so in a sense we expect to have three clinical programs in 2015. So to paraphrase Alnylam we are going to have free buy system.

Alethia Young

Great. So just going back to kind of the proof of concept possibly at the end of the year, I mean I does note that you guys with the platform company also but just in your mind like what are the three major things we should be looking for the – like how do we link proof of concept and what are the three major points we should be looking for in that dataset?

Kleanthis Xanthopoulos

So particularly for RG-101 which is the molecule that targets 122 Hepatitis A you are going to be looking at the single-dose in patients either of genotype one or genotype three, and we are going to be looking at the viral load reduction over 28 days. So we want to make sure that we have at least very significant viral load reduction number again it's mono therapy so we are looking at as an equal efficacy in both GP1 and GP3 to justify the pan-genotypic nature of the program which we have seen in the number of preclinical works that we have done and importantly also take into consideration the overall safety and overall tolerability of the program.

For us, the fact that we have – we expect to show clinical utility is the validating of our platform, is validating of all of our efforts of how we engineer our compounds, how we administer them, what doses we use and also importantly having open the dialogue with the Regulatory Authorities that we can now replicate these as you can see for compound and program number two and program number three. So there are multiple things that you should expect to hear before the end of the year in regard to this program and then we will see how that in the future we know that it can be at least additive to existing therapies so we can combine it with any direct anti-viral because there are no (inaudible)interaction so obviously it’s completely and unique different mechanisms but for us the major goal is demonstrate the utility of the platform and ultimately find a way to get these programs into the hands of somebody who is interesting in attribute to combine with other aids and for clinical utilities.

Alethia Young

Great. So just going to the platform again and safety you bring up an important point, like what you think is kind of the biggest safety thoughts for us and like what's the hurdle that you are overcoming? You talked a little bit about the kidney and you targeting in Alport. So just give us a little bit of play of how think about de-risking safety?

Kleanthis Xanthopoulos

So I mentioned in the beginning that 25 years of work and platform development has been tremendously been beneficial to us. Between Isis which being the pioneer in this phase but also at least half of dozen of another companies now that have programs in the clinic and that includes Alnylam, Sarepta, a number of other companies. We have had over 50 clinical trials have been conducted over the past 15 years there is a record now database so at least 6000 patients, some people estimates that to be significantly higher. So we know the (inaudible) and liabilities as any other pharmaceutical so we know what to expect when we introduce (inaudible) into human. And so that's very, very beneficial as we design the molecule to try to avoid some of the potential liabilities that nucleic acid may have but other than that, and once we engineered things into the molecule for example how to escape compliment activation, once we have all these and we know how to do this pre-clinically, the rest of the toxicology not different than any other pharmaceutical development. So we do the classical, preclinical toxicological work that is known for any other pharmaceutical agent. And we monitor the responses, the benefit and the risk like any other pharmaceutical drug.

Alethia Young

So I am going to open it up just to see if anyone has any questions on the webcast or in the room. I am just going to check my blog, if there is any. Okay. I am going to take on questions (inaudible) so just maybe talk a little bit about the role of the microRNA planning in Alport and describe Alport, it’s pretty rare disease.

Kleanthis Xanthopoulos

Yes. So the focus that we have is around the specific microRNA called microRNA-21 and for those of you who may remember we published critical paper in nature about four, five years ago, demonstrating the actual critical role of 21 in cardiac fibrosis at the time. So we knew that if you induce cardiac fibrosis in mice, 21 was the driver we also shown in that paper that if you can incubate them the over-expressed in 21, you can not only reverse the cardiac hypertrophy but also reverse the fibrosis in this particular mouse model system.

Since then we focused a large and as we said we are doing a lot of translational work and demonstrated the microRNA-21 is uniquely over-expressed in number of fibrotic conditions. So essentially we find that every fibrotic condition in human so whether it's liver fibrosis, pulmonary fibrosis or kidney fibrosis, and we see a very significant over-expressed from 21. So for a variety of reasons, we don't have the time to focus, here we decided to prosecute the kidney fibrosis and very quickly got into looking into outputs because and we published a lot, it's in our website, people can go and look at all these and a variety of studies both generically knock outs of 21 (inaudible) fibrotic conditions in these mice but we are also shown that we can inhibit fibrosis in a variety of these kidney models.

So Alport came to our attention for a couple of reasons. One is the lethal orphan disease, so as I said before, a minimum of 20,000 patients in the U.S. potentially up to 50,000 there is no proved therapy, frankly there is nothing out there because genetic mutation based on collagen 3A, families of protein and essentially it's a very well defined population. There is multiple of course like many other genetic disorders. There is more than one mutations that particularly can identify in human population but the unique thing about is this is that nearly adolescence you are going to start seeing the effects of that mutation that effect kidney and hearing loss and progressively all of the patients can end up with end-stage renal disease. So they are going to get on dialysis, and there is very little to be done and essentially kidney transplant if not always of course condition to all the risk but not always address the case.

So there are genetic mice models of the human disease. We have exactly the same phenotype, they have the same kind of open the text and we have demonstrated in these mice now on multiple occasions that we are able in time-dependent and dose-dependent ways to inhibit 21 and reverse the histological phenotype that we see, improve by at least 80% of the kidney function and equally important extend the life of these mice by 50%. Underlying to what I have said and should have highlighted before is that ultimately it’s a lethal disease as you can imagine since all of these patients end up having end-stage renal disease. So by the 4th decade we see over 80% of these patients on end-stage renal disease.

So huge on mathematical need, a very well defined population genetically there is now foundation that is working closely with us. We announced a couple of things back in March. We are going to have a close association with the Alport Syndrome Foundation's patients group, very excited about the work we are doing. So we clearly think we are going to have a lot of benefits in them helping us or essence with the natural history of disease study as well as recruitment of patients. So that was one of the reasons that we looked at that huge opportunity of the non mathematical need and tremendous amount of preclinical work that justifies that 21 is a very-very prudential target in this space.

We have very good compound in RG-012 and as I said we are putting together all the preclinical works to be able to file the regulatory authorities application to start clinical trials for that compound.

Alethia Young

How you view as to diagnose Alport?

Kleanthis Xanthopoulos

You know part of Alport Syndrome Foundation is of course the awareness campaign but once the physician is aware, it’s a very easy to see the genetic prospect can be done very quickly but once you are aware of the symptoms and because genetically transmitted because we see first most cases we see initial hearing loss and impediment there but ultimately protein urea and kidney function being deteriorated over the time. It's very straight-forward.

Alethia Young

So maybe I will ask some, just to go back a little bit to the, I mean you know the environment (inaudible) and I am very interested in what the refractory market might look like here but where do you see it's like commercial opportunity for RG-101, how do you think the market is going to shape up from that two to five years?

Kleanthis Xanthopoulos

We have some wonderful combinations for direct and (inaudible) also demonstrating 90% plus viral response but those are of course in clinical studies and very well defined populations in terms of genotype. So we think in real world there is a need for difficult to treat patients, for infected patient, HIV and HCV where potentially combinations of direct antiviral maybe problematic as have seen with several clinical trials in the past. We can say genotypes anywhere from GT3 to GT6 could be problematic also. They may not reach that kind of high level of SVR and of course refractory or (inaudible) patient et cetera, et cetera. So what we are looking here is for a compound that can be injected once a month, this would be very easily done because the patient goes to the doctor to follow the blood-work for viral load reduction. The doctor is incentivize because this increases compliance obviously, it's the simple injection of 1 ml or so is going to anticipating and in combination with direct antiviral we think we are going to have a much better outcomes, and B: potentially to treat those kind of patients.

Alethia Young

So I am going to ask you a big picture question but maybe over let's say 2018, where you do think Regulus will be in and how do you think about like kind of how many targets per year your platform can kind of generate?

Kleanthis Xanthopoulos

Yes, we model that constantly and revisit that theme at least once a year. We want to be a company that has a combination of programs that we own and other that we are advancing with our partners. Our goal is to have our own ultimately commercialization so by 2018 we should be thinking very seriously about commercializing some of the compounds. We think we are going to have compounds in various – probably at least three to four clinical programs that are advancing nicely and at any given time as I alluded before, we are going to have at least preclinical programs. So by 2018, the size of the organization will be slightly higher than it is today and we think we are going to be prosecuting let’s say at least about eight program at that time.

Alethia Young

And so we have been, a lot of times talk about this but your partnership (inaudible) maybe just kind of give us a flavor for that what you are doing there.

Kleanthis Xanthopoulos

Yeah. So as a byproduct of something that we are thinking about how to describe the fiber basins so that we can go to a very specific population and indeed its over-expressed in the microRNA to give you an example, we interest in hepatocellular carcinoma, when you look at that hepatocellular carcinoma and the molecular level there is at least six or seven different diseases. And when you look and focus at this specific microRNA that are over-expressed for example 221 or 21 we see about 15% of the hepatocellular carcinoma is over-expressed, it’s not particular target. So if you are designing an RNA therapeutic that says I am going to titrate down the over-expressed 21, I want to focus on this 15% of the hepatocellular carcinoma patients that do over-expressed 21. Now, there is no need of going to the rest who are actually do not show that because the molecular mechanism of that cancer is different. And so with that in mind, we developed a method to very rapidly essentially with 100-150 micro units of blood we able to titrate and see which basin over-expresses that particular microRNA. So that we started those efforts three-four years ago and ended up developing a beautiful technology that is now essentially in cartelize where we can with that minimum amount of example, we can titrate expressing over 260 microRNAs and start obtain signatures. So we started a business, we announced at the beginning of the year and the Bio-Markers and the Biogen collaborations around that where for the first time we titrated about 400 for the first time in history I think if you look at 400 multiple sclerosis patient samples and we are able to analyze that from the perspective of microRNAs being expressed in other regulated and obtained a signature that allows us to say you have the disease or you don't. And so that was the very good first step and now discussing what the next phase is going to be with that collaboration but as you can imagine, these biomarker platform has utility in just about everything and for us it's a great, great way to stratify the patient that we are interest and enrolling in clinical trials hopefully.

Alethia Young

Great. It seems like the business could take a lot of its own but of it's own but Kleanthis I really appreciate you coming here today and join us and having the chat. So until we see again.

Kleanthis Xanthopoulos

Absolutely. Thank you and I appreciate the opportunity to have dialogue.

Question-and-Answer Session

[No formal Q&A session for this event]

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Source: Regulus Therapeutics' (RGLS) CEO Kleanthis Xanthopoulos Presents at Deutsche Bank 39th Annual Health Care Conference (Transcript)
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