Dicerna Pharmaceuticals, Inc.
Q4 2020 Earnings Call Transcript

Published: 25 Feb 2021

[Operator:]

Ladies and gentlemen, thank you for standing by, and welcome to the Dicerna Pharmaceutical's Full-year 2020 Earnings Conference Call. As a reminder, this conference is being recorded at the company's request. I will now turn the call over to your host, Ms. Lauren Stival, Senior Director of Investor Relations at Dicerna. Please go ahead.

[Lauren Stival:]

Thank you, Operator. Good afternoon, everyone, and thank you for joining us to review Dicerna's full-year 2020 financial results and operational highlights. For anyone who hasn't yet had a chance to review our results, we issued a press release after the close of trading today, which is available under the Investors and Media tab on our Web site at dicerna.com. You may also listen to this conference call via webcast on our Web site, which will be archived beginning approximately two hours after this call has been completed.

[Doug Fambrough:]

Thank you, Lauren. Good afternoon, everyone, and thank you for joining us. 2020 was a year of success and maturation for Dicerna, a year of multiple clinical and collaborative successes capped by completion of enrollment in the company's first pivotal trial, a trial that will set the stage for our first NDA submission as a company, later this year. These successes were matched by strong momentum behind our pipeline building and discovery research efforts, for which we presented for the first time data supporting expansion into multiple new tissues beyond the liver, which unlock multiple potential new disease areas for future pipeline growth. Looking forward, we see 2021 as a year of accelerated pipeline growth as well as corporate maturation towards our goal to emerge as a fully integrated commercial entity, in 2022.

[Shreeram Aradhye:]

Thank you, Doug, and thank you all for joining us. Alcohol use disorder is a complex behavioral disorder with huge unmet needs. It is a chronic disorder that is associated with a range of medical, psychological, social, economic, and personal problems. And it was one of the leading causes of preventable death in the United States. It's estimated that 14 million adults in the U.S. experienced AUD, unfortunately, AUD often goes undiagnosed or untreated, in part due to limited treatment options, and willingness to engage in treatment. In fact, it is estimated that fewer than 10% of adults in the U.S. with AUD seek help or treatment, and that a similarly low percentage of those treated actually received pharmacotherapy. Available treatments have generally shown only a modest treatment benefit in the reduction of harmful drinking levels, or maintenance of abstinence with poor patient compliance being a contributing factor. The pathway to AUD recovery is a highly individual experience and each person's journey is unique. We see a critical need and opportunity for a safe, targeted, easy to use pharmaceutical therapy that can be combined with behavioral interventions to help individuals to meet their treatment goals, including reduction in harmful levels of drinking, and our estimates.

[Doug Fambrough:]

Thanks, Shree. We continue to make excellent headway across our collaborative programs. This is another means by which we are expanding our pipeline and expanding the reach of RNAi across therapeutic areas. Our collaboration with Lily continues to progress in the fourth quarter of last year, and kicked off their first Phase 1 study using Dicerna's GalXC technology, targeting ANGPTL3 for the treatment of dyslipidemia. This year, we anticipate an additional IND filing in the second quarter targeting lipoprotein A or LPA for the treatment of cardiovascular diseases. In addition, we have received the formal notification from Lily that they plan to extend the initial research collaboration term, which is excellent news and speaks to the promise of our RNAi technology. A third clinical candidate has been declared in the collaboration and is in preclinical development and we're optimistic for the potential of multiple additional development programs beyond these first three, including both liver targeted and neurodegenerative disease and pain targeted programs. Our development work for Alexion is continuing as planned. And we are pleased to disclose that the first two GalXC candidates are targeting C3 and complement factor Billion to be disclosed at the outset of the year. We anticipate delivering IND supporting packages to Alexion in the fourth quarter of 2021 and in the first quarter of 2022 expectedly after which Alexion will be responsible for any IND or CTA filings in accordance with our agreement. We have also made rapid progress with our partner in Novo Nordisk, although we don't anticipate initiation of a clinical trial this year for a candidate under the Novo collaboration. A tremendous amount of work has already been done and what is a highly collaborative partnership. And we look forward to additional target selections and clinical candidate selections beyond the first clinical candidate we announced at the beginning of the year. Like the Roche agreement, this is a collaboration in which we maintain opt in rights to co-fund development. After Novo has de-risked a candidate in Phase 1 or Phase 2 development, this represents substantial economic upside potential for Dicerna. And with that, I'd like to turn the call over to our CFO, Doug Pagan, to cover financials.

[Doug Pagan:]

Thanks, Doug. I'd like to briefly walk through the key financial results for the full-year 2020 and directly to our press release outlining the financial results, which was issued today and to our annual report on form 10-K, which will be issued following this call. Net loss for the full-year of 2020 was $112.7 million or a $1.52 per share compared to $120.5 million or a $1.76 per share for full-year 2019. Revenues for the full-year 2020 total $164.3 million compared to $23.9 million in 2019. The year-over-year increase in revenue recognized is primarily attributable to increase activity and associated costs under the various collaboration agreements. As of December 31, 2020, we had approximately $138.5 million of current deferred revenue, which we expect to be recognized over the next 12 months and approximately $336.2 million of non-current deferred revenue expected to be recognized over the following several years. Full-year R&D expense total $205.4 million in 2020 compared to $109.3 million in 2019. The year-over-year increase was primarily driven by a $54.8 million increase in direct external research and development expenses and $32.9 million increase in employee related expenses, which includes salary, benefits and stock-based compensation. As we increase head count to support our expanding pipeline. Full-year G&A expense total $72.1 million in 2020 compared to $42.8 million in 2019. The increase was primarily due a $20.6 million increase in employee related expense as we increase headcount to support our growing operations, as well as a $6 million increase in professional consulting services. We expect operating expense to increase in the coming quarters as we continue to grow headcount to accommodate additional R&D activity and loss readiness, as well as from higher external standards associated with increase activities in the pipeline. During Q4 2020, we received $17.5 million in milestone and reimbursement payments from our collaboration partners. We continue to project receiving over $100 million in collaborative payment received for the five quarter period from Q4 2020 through Q4 2021, and therefore anticipate receiving over $83 million from our existing collaboration for the full-year 2021. These payments represent an important source of proceeds and demonstrate the value of these collaboration programs should continue to generate as immature. As of December 31, 2020, we had $568.8 million in cash, cash equivalent and health maturity investments compared to $348.9 million as of December 31, 2019. Maintaining a strong balance sheet will be a paramount importance as we plan to submit our NDA and the dose range in the third quarter and prepare for potential 2022 commercial launch. During 2021, we anticipate the cash receipts from existing collaborations will be supplemented by other potential sources of funding, including for example, proceeds from a plan ex-U.S. commercial partnership for nedosiran and possible for LT monetization. With the objective of maintaining the balance sheet strength with which we started the current year. That concludes my review of the financials. I would now like to open the call up for questions. Operator?

[Operator:]

Thank you. Our first question comes from the line of Jonathan Miller from Evercore ISI. Sir, your line is open.

[Jonathan Miller:]

Hi, guys. Thanks so much for taking the question, and congrats on all the progress in 2020. When you listed all the it really does look very impressive. I'll start with alcohol use disorder, obviously a huge indication, but as you mentioned, Doug, very challenging to penetrate in the past. Are you thinking of sub populations that are more amenable to treatment here? Do you have any views so far on the sorts of endpoints that are most relevant? How well established is the regulatory path moving forward there, if you could just give us a little more color about how development in AUD is going to look? And then secondly, given that PH2 and 3 are sort of less well understood and no one else is developing that market, how are you thinking of commercialization in those indications as opposed to PH1 just in terms of what the ramp and amount of effort it's going to take to get there is going to be?

[Doug Fambrough:]

Thanks, Jonathan. You put a lot on the table there. We'll answer some of the questions now, and I think we'll go into more detail in March, at the event with Dr. Kranzler. But to start with, you asked about sub populations in AUD, and this is a very diverse indication with millions of people who have alcohol use disorder. So indeed, we are thinking about particular populations that are most applicable, but we do think that all the levels of severity of AUD are potentially addressable with DCR-AUD. But there will be focus. I'm not going to give much detail beyond that. And you asked about endpoints, harm reduction is really critical here. And there has been some evolution in endpoints in AUD, particularly starting in Europe, and it's certainly something that we're seeing in the FDA as well. And a move to thinking about harm reduction, which we think is the right metric and one that is particularly applicable to our mechanism of action. Is there another element there I -- is there another element on AUD, Jonathan? So, with respect to commercializing in PH2 and PH3, we really view this as a singular commercialization effort. The PH patient community has historically not been differentiated into its types. It's really only the advent of PH1-speicific therapy that causes there to be any cleaving of the population. So we do see it as the same effort. My colleague, Rob Ciappenelli, our Chief Commercial Officer, is on the line. Rob, is there anything you'd like to add on that?

[Rob Ciappenelli:]

Yes, thanks, Doug. Appreciate the question, Jonathan. And Doug said it spot-on. It is the overall PH market, and when you think of it, think about how nascent the overall market is, the state of the science, this tremendous amount of education that needs to be done here regardless of subtype. And appropriate diagnoses and support through genetic testing are also key factors that's going to help physicians not only become aware of this disease, but also make that differential diagnosis. Because these patients have a relatively long patient journey before they're even finally diagnosed with PH. And soon, hopefully we'll have an option for all PH patients through nedosiran, but we still have to finish the PHYOX program and see how that goes.

[Jonathan Miller:]

Thanks so much, guys.

[Operator:]

Thank you. Our next question comes from the line of Yaron Werber from Cowen. Sir, your line is open.

[Brendan Smith:]

Hi. Congrats to the team on all the progress. And thanks so much for taking the question. This is Brendan on for Yaron. Just a couple quick ones from us on HBV here, what can you tell us, I guess, about the potential combo treatments for this Phase 2 that you are discussing from Roche. And maybe how it's kind of reflected in the current treatment option for patients, is the thinking really to target a specific line of therapy for commercial uptake or more to kind of provide optionality in like a pivotal trial and a potential label. Thanks very much.

[Doug Fambrough:]

Hi, Brendan. I think the combination trials that Roche will be kicking off are really designed to identify the combination that yields the highest functional cure rate. And so I would call it exploratory is what the ideal combination is. We have some expectations, but of course the data will have to rule, as it always does in clinical development. So, Roche has identified that they will be initiating, in near-term, combinations of our RG6346 alongside their therapy in combination with a TLR7 agonist. Also in combination with their core inhibitor, their CpAM, and also in combination with Pegasys, their peginterferon product, so three different triple combinations. They will also be looking at extending dosing at two different dose levels of the -- our RNAi plus the Nuk, so that's five treatment cohorts that they've identified so far that will be initiating in the near-term. And again, it's really a horserace to see which gets the highest rate of functional cure.

[Brendan Smith:]

Okay, great, thanks very much.

[Operator:]

Thank you. Our next question comes from the line of Mani Foroohar from SVB Leerink. Sir, your line is open.

[Rick Bienkowski:]

Hey, good afternoon. This is Rick on the line for Mani. Thanks for taking our questions. And so the first one is on AUD, given the preclinical data that have been generated to date for the asset, I was hoping you could provide some details regarding the level of ALDH2 knockdown you'll be looking to reach to produce the therapeutic effect of the duration of knockdown that you're looking for in the clinic, and potentially the dosing schedule for the target product profile?

[Doug Fambrough:]

Sure. So, of course, this is a GalNAc directed liver-specific RNAi molecule. And the class of GalNAc-delivered RNAi molecules has a very consistent potency and pharmacodynamic. We are seeking maximum of suppression of the ALDH2 gene in the liver. And we have seen reproducibly with different molecules targeted at different genes that we can achieve well over 90%-95%-plus reduction, essentially silencing completely the target gene in the liver, so we will be seeking to do that. Similarly, you see an extended duration of effect for RNAi with the pharmacodynamic effect lasting multiple months. It's usually peaking on the order of four weeks or so after the initial administration, and then maintaining a very high level of knockdown for several months, and then slowly decaying over several months beyond that. We are not at this point targeting a particular dosing regimen, but that's something we'll be exploring more deeply, both with respect to what is most appropriate in the market, as well as what we think -- how we see the molecule performing. It may be quarterly; it may make more sense to go with a monthly administration because of the intuitive nature and small doses associated with that. Well, that'll have to emerge during the program. In any event, we do anticipate very high levels of knockdown and the extended duration of effect one has come to associate with RNAi.

[Rick Bienkowski:]

Got it, that's helpful. And I did have an additional question about the alpha-1 antitrypsin study. I was hoping that maybe you could elaborate on some of the endpoints that you're planning to present in the interim readout, could we expect to see the degree of the reduction of Z-AAT polymer, total Z-AAT burden or any other potential metrics for overall liver health?

[Doug Fambrough:]

Shree, would you like to talk about the points?

[Shreeram Aradhye:]

Yes, sure, Doug. So as you can imagine, our goal is to look at, first, beginning with reductions in serum A1AT, but the focus, of course, is on understanding the effects of belcesiran on what's happening in the liver. So we will be looking at -- planning to look at the measuring protein in the liver. We will be looking at histology using traditional and ways of looking at distribution, any elements of information, what's happening to fibrosis. And in addition, we will include a series of serum biomarkers to put them all together and to identify an opportunity for coming up with potentially a score that could be used to assess impact of belcesiran on liver disease. In addition, we will include imaging biomarkers using measures of liver stiffness, if you will, like MR Elastography as well as Fibroscans, so the typical combinations of both histology and non-invasive imaging and serum biomarkers to assess liver disease activity both six months and 12 months.

[Rick Bienkowski:]

Great. Thanks for taking our questions and congrats on all the progress.

[Doug Fambrough:]

Thanks.

[Operator:]

Thank you. Our next question comes from the line of Luca Issi from RBC Capital. Sir, your line is open.

[Luca Issi:]

Terrific. Thanks so much for taking my question. And congrats on the progress is great. Maybe first on PH3, I think you mentioned that you're planning to include PH3 as part of nedosiran NDA package. My understanding that the end for PHYOX 4 is actually fairly small, I think it's only six patients there. So, wondering what gives you confidence that such data can be sufficient for approval. And then maybe for the cardiometabolic, you mentioned , obviously multiple companies in the space here, Arrowhead, Ionis, Therapeutics and a bunch of others, I think you did a great job in differentiating for primary hyperoxaluria, how are you thinking about differentiation for N3 and LPa? Thank you.

[Doug Fambrough:]

So, you like to start on PH3, I will take that. So, indeed PHYOX4 is a single dose study in six subjects up to nine, but six, that is the range, that will have a placebo control. So, our goal there is to convincingly demonstrate that we are able to lower urinary oxalate. The endpoint, as you recall, is a 30% reduction on two consecutive visits a month apart. And that will be the first evidence that nedosiran can lower your nedosiran in PH3 years of disease. If we show meaningful reductions in urinary oxalate, knowing that mechanistically the importance of lowering oxalate as the primary source of renal injury, our arguments for an accelerated approval would be based on combining the results of Uox reduction with data that is available from the literature that is now emerging showing that the H3 carries risks of stone rates as well as renal insufficiency that was previously unrecognized. But these are things that we still need to discuss, it will really depend upon the magnitude of effect, we demonstrate in PHYOX4 and it will then need to serve as the basis of the potential accelerated approval with the recognition that additional work will be necessary both from our ongoing Natural History study, as well as any additional commitments to follow our subjects, longer-term to see impact on clinical outcomes, but I think the key message is that we'd expect this to be a discussion with the FDA around a potential accelerated plan.

[Doug Pagan:]

So, Luca, with respect to the cardiovascular targets, we obviously made the decision several years ago to seek a development partner to pursue those and there were a number of issues on our mind when we decided not to pursue them on our own. They include the fact that there are other modalities that are more advanced developments, targeting these types of targets, that there are current drugs on the market with patients are often on poly therapy and managed, these are constantly large populations, very large sales forces, differentiation, I think is challenging and probably at the margins of the clinical data and to generate that requires large, long and expensive trials. And rare populations have may have special needs. But there has been a history of those markets not enjoying the rare disease economics because they've been undercut by the larger population products. So, it may be that one can successfully navigate that complex environment. But we made the choice several years ago that a really established strong player like Lilly would be far more capable of navigating those orders. So we've really left it to Lilly, with respect to the mechanism, RNAi turns off transcript in liver. So if you're using GalNAc targeted RNAi, they're sort of, it is what it is right, you're going to be achieving a very strong level of silencing, with the pharmacodynamics we prescribed in the absence of using a different target for example, there are really aren't good avenues for mechanistic differentiation, it's really going to be execution differentiation. And as I mentioned that that's something where I think scale is a huge benefit. And that's not -- scale is not what we bring to the table as our core competence. So, our friends at Lilly, I think they're going to do a good job with.

[Luca Issi:]

Terrific. Thank you so much.

[Operator:]

Thank you. Our next question comes from the line of Stephen Willey from Stifel. Sir, your line is open.

[Stephen Willey:]

Yes, good afternoon. Thanks for taking the questions. Just a quick question on the AUD program, so I know we've talked a little bit about the development plan, and we're going to get some more color, presumably at webinar next month. But is this a program that you feel you can independently take across the finish line from a regulatory perspective? And I know it's a little bit of kind of a specialty niche market, is this something for which you have commercial aspirations?

[Doug Pagan:]

Yes, that's a good question, Stephen. It does, what's the old saying about future, predictions are difficult, particularly about the future, I certainly think that we're growing to a scale where we can push this across the finish line on our own, whether we choose to or not, physician that we'll have to face. But I think it's certainly within our capabilities. I think the most effective marketing of the product probably will be beyond something that we can do 100% on our own and there are different call points that one can think about here, including psychiatric call point and very importantly for growth of the market broader call point than that in the CPU community, and I do not see us going into the CPU community. So I think it is right for commercial collaboration for us. But I don't think we require a development partner in the indication. So it's something that we intend to maintain a very strong economic state, and not something that we're seeking to just generate PSC and half-life. This is the core program that we're going to invest in, and we intend and hope to reap the economic rewards from it.

[Stephen Willey:]

Got it. That's helpful. And maybe just one collaborative question, I guess is there any kind of change of control provision that impacts the Alexion collaboration? And I guess is there a scenario by which the C3 and the CFB drug come back to you, and I guess if so are those targets you'd be interested in?

[Doug Pagan:]

So, there is not a change of control trigger. That means, they would definitely come back to us. With respect to what might happen, I think there are a lot of possibilities for what might happen. But I'm confident that these programs are going to move forward, because we do see C3 and CFB as very interesting targets to move forward. So it is conceivable that there won't be any change in the relationship. It's also conceivable that there will be some sort of re-jiggering, and we'll just have to work with our friends at Alexion and I expect after Q3, there'll be friends at AZ as well to figure out what the path forward is, and there may be a change, but I think both programs are very likely to proceed along their timelines and enter the clinic.

[Stephen Willey:]

Okay. And then maybe just one last quick, potentially stupid financial question, so the $100 million in recognized revenue that you're talking about here over this five-quarter period, is that a combination of both incremental milestones and the recognition of deferred revenue or is that just some incremental milestone payments on top of the deferred that we should expect getting forward?

[Doug Fambrough:]

I'll pick that up, , but the $100 million that we quote over that five-quarter period, we just cash in the door, the revenue recognition associated with the collaboration and so that number is, that's just the cash going into the bank account number and independent accounting for as revenue. And so when Doug is quoting the deferred revenue, that's really cash that's already in the bank, and about shows up as revenue on the line. Does that clarify for you?

[Stephen Willey:]

Yes, I just wanted to make sure that it was indeed incremental cash coming in the door. Okay, very helpful.

[Doug Pagan:]

Stephen, just to further the point, there will be tables in the MD&A section that make it very clear, specific cash in hand by partner and it's an order to help understand how the deferred revenue unfold, but its pure cash.

[Stephen Willey:]

Okay, great. Thanks for taking the questions.

[Operator:]

Thank you. Our next question comes from the line of Ed Arce from H.C. Wainwright & Company. Sir your line is opened.

[Ed Arce:]

Great. Thanks for taking my questions and congrats on all the progress, continuing to expand both internal and collaborative programs. Just one question for me, a lot of them have already been answered, but on your A1AT program for belcesiran, just thinking longer term as you move towards potential approval and collaboration in a few years, obviously this asset is targeted towards the liver effects, independent of the lung effects for these patients. I'm just curious how you think about the benefits to patients in the liver and how that could benefit as a compliment or even synergistic clinical benefit to these patients and how that could impact your overall marketing strategy and positioning? Thanks.

[Doug Fambrough:]

Yes. Let me try and get into that. Shree step in if there're things you want to add. There are really two different diseases here. They have the same cause, but they're different diseases. There is a lung manifestation, that's treated by pulmonologists and it has a standard of care, and if a new treatment is going to come along, it needs to compete with that standard of care. We have a liver disease, that's treated by a different physician group, different target organ, and currently there is no standard of care for it, but there will become one. Patients with liver disease are going to want the best care for their liver patients with longer than I want the best care for the lung. Obviously there is an overlap in these patient populations, but there are patients that are lung only, and there are patients that are liver only. And so, I think the synergy between them is there is a marketing synergy for sure, because the lung patients are more parents, given that people don't feel their liver decline in the same way they feel their lung decline. And so, there is an enrichment for lung patients amongst the current liver patient that are there. So, to the extent they're already in a system of augmentation through the three existing augmentation providers, there is potential marketing synergy there. For the liver -- from a medical perspective, though I really think you got to ask, what is the best treatment option for the liver, and what is the best treatment option for the lung? And I don't think it matters so much with their exam drug or not. It really is what's going to do the best. And we think RNAi because of its ability to give a constant and very high suppression of the misfolded protein, really has the potential to be the best liver treatment and be standard of care in the liver.

[Ed Arce:]

Okay, great. That's helpful.

[Operator:]

Thank you. Our next question comes from the line of Mayank Mamtani from B. Riley Securities. Sir, your line is open.

[Mayank Mamtani:]

Thanks for the comprehensive pipeline update and appreciate you taking your questions. I'm going to see so much visibility into your partner programs. So, maybe Doug, starting there on the Roche HPV program, obviously encouraging for them to include your program in the ongoing study with a number of different alternative combinations there, I just want to kind of ask you if between the different options, is there any one, or do you think you have more confidence and given obviously, it's a busy kind of landscape. It's so challenging to have that off treatment, functional care data, any comments you can derive the betrayed Doug on that?

[Doug Fambrough:]

Yes, I'm often happy to speculate. Of course my opinion doesn't matter, right? There'll be the data, but I know of course we all recognize that. We look at the history of treating HPV and it doesn't vary a bit by genotype, but where there has been success, albeit at a low rate in achieving functional cure, that's been in . And I view that as the crack in the door, so to speak. And there's a real question that there can you widen it? And I think it stands to reason that if you suppress that antigen, which is the tolerizing agent immunosuppressive activity HPV, then you're likely to increase the activity of the NUC interferon company. And so I think the most straightforward way to think about it is NUC RNAi and interferon or some other immunoactive agent. So that would say that amongst Roche's three triple combos, and I think it's more likely that the interferon or the TLR7 arm are would perform. Now, obviously interferon has a well-known downside, and it would be great to replace it with something better and it maybe a TLR7 agonist is the something better, maybe there's something else earlier in the pipeline. I think the optimism around core inhibitors has waned a bit as the core inhibitors in combination with NUC haven't really shown a differentiated activity. So, it is harder to see why adding RNAi to that combination to put is going to all of a sudden become a whole lot better. So we have a predilection to thinking that we're likely to succeed in the immunoactive combinations, but it's a clinical experiment and we'll see what happens.

[Mayank Mamtani:]

Yes. Thank you, Doug. That was very helpful. And so, just to clarify the initial label for nedosiran, are you targeting having all PH 1,2,3, just that PH 3 was going to be more accelerated approval and the other two are going to be full approvals. Is that kind of the goal for 2022?

[Doug Fambrough:]

Yes, I think we have agreement on what the basis of approval for PH 1 and PH 2 phase, so that is in a different place than are continuing on PH 3 where for the reasons I described, we've recognized that it will be an accelerated type of approval with the commitment to do additional work is what our expectation is spending data.

[Mayank Mamtani:]

Okay. And last question, just a step back question, maybe for you Doug, and also as you think about the spend trajectory going from last year to this year. Are you kind of talking about a little bit of a strategy shift here that you are thinking about larger prevalent diseases in a different way. And we should kind of expect to hear from you more programs like AUD, some others that might be sitting in their pipeline maybe you've not invested in again?

[Doug Fambrough:]

Well, I think the - perhaps the most important message I was fairly explicit about, which is that we're not just looking at orphan disease. We have the biotech industries has been flowering and ways to approach diseases. But there are in our analysis diseases where the qualities of RNAi that constellation of features looks like it's the most appropriate. And when you combine that with targets and opportunities enabled by RNAi that look like there pretty likely to work that you would have some competence that you have a higher than industry average probability of success. That's where we're trying to look. There're some orphaned things in there, but there's some large market indications in there. And that is - we have a formalized internal process led by Bob Brown, our Chief Scientific Officer to evaluate various opportunities draws on the internal resources that are out, large given our growth of our company as well as our strong resources. And it's a somewhat diverse set of indications, but they're united by this confidence that, hey, this is probably really going to work. This is a great target, and RNAi really looks like the best way to go at it. And then, there're some work that in there, but there are also some, some non-orphan. So that is, that's how we're thinking about building the portfolio. We will roll out more indications beyond AUD in the coming quarters. And I think you'll see those threads that go through the future programs. In addition, you can see how they thread through the historical program.

[Mayank Mamtani:]

Got it. Thanks so much for taking my question and it seems like 2021 has been really excited. Good luck.

[Doug Fambrough:]

All right.

[Operator:]

Thank you. And our next question comes from the line of Keay Nakae from Chardan. Sir, your line is open.

[Keay Nakae:]

Yes. Thanks, Doug. For AUD in terms of measuring knock down of ALDH2 is something like a fetal hide to a good proxy, or is there something more specific that you'd be looking to measure?

[Doug Fambrough:]

Well, I will start, and I think Shree can supplement the answer here. And what they were not going to be doing is poking people in the liver. So we're not going to get an ALDH2 knock down. But as I alluded to in another context before RNAi has been very reproducible. So I think we can have a base level of confidence that we're going to achieve pretty good knock down of ALDH2, it aldehydes the transient bio marker. And that makes it somewhat challenging to use as a very firm basis for analysis. So we won't be hanging our hat solely on that. And ultimately the most important thing here is response to alcohol challenge. So that is really going to be the most important aspect. Shree, do you want to push that out?

[Shreeram Aradhye:]

Yes, the PH marker will be like a redirection, and we'll be looking at marker. We would open the publisher facial flushing, heart rate, happy to feel. So we'll look at them all interaction study as a primary marker of RTD. We will have metabolism measures. But I think our primary goal is to done with the onset and offset of -- in response to a small alcohol challenge.

[Keay Nakae:]

Okay. And then, in talking about perhaps a prevalence of $14 million, but with a goal to initially target some subgroups. Can you give us a sense of what the below hanging through subgroup is as we're trying to model, what this opportunity is worth?

[Doug Fambrough:]

Yes, so we'll flush that down, but at some at the 18th, but obviously the key group is the group that's currently receiving pharmaceutical intervention. That's number one. That's about 1% of the population. That's about 140,000 individuals. There is a much larger group 10 times that size on the order of one and a half million people who are seeking some form of treatment, 90% of them are given pharmaceutical treatment. However, we believe that DCR-AUD has the potential to become commonly used option amongst that group in conjunction with the behavioral therapy that they're currently getting. So that low-hanging fruit there, 1.3 million, 1.5 million people that are already being recommended for treatment. It just don't have a good pharmaceutical option. So I think that's where we start in thinking about the values far. And you can see now even a parcel that there needs to be a very valuable product.

[Keay Nakae:]

Okay. Thank you. That's really helpful.

[Operator:]

Thank you. That concludes our question-and-answer session. I would now like to return the call over to Doug Fambrough for closing remarks. Sir, please go ahead.

[Doug Fambrough:]

Thank you. With two Phase 2 studies of RG6346 and belcesiran were expected to start this year and at least two INDs potentially to be filed on our highly productive collaboration activities. We're going to continue to turn out candidates and importantly, our NDA submission on the horizon. I got a lot ahead of us this year. It's going to be a very exciting year of execution and growth. I think it's transformative actually, as we go through the NDA filing process. So in addition towards some conferences in March we hope you all will join us for our webinar on March 18th on DCR-AUD. We'll discuss that program in more detail with Dr. Henry Kranzler of U Penn. We got a lot going on here today and we look forward to keeping you all updated as we continue to build towards the fully integrated commercial stage biopharmaceutical company. Thank you again for joining us tonight and have a wonderful evening.

[Operator:]

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.