Dicerna Pharmaceuticals, Inc.
Q3 2021 Earnings Call Transcript

Published: 9 Nov 2021

[Operator:]

Good morning, ladies and gentlemen, and welcome to the Dicerna Pharmaceuticals Third Quarter 2021 Financial Results Conference Call. As a reminder, this conference call is being recorded at the company’s request. I will now turn the call over to your host, Kristen Sheppard, Senior Vice President of Investor Relations at Dicerna. Please go ahead.

[Kristen Sheppard:]

Thank you, and welcome to Dicerna’s third quarter 2021 financial results and business highlights conference call. Please note that the press release detailing our results for the third quarter was issued earlier this morning and is available under the Investors and Media section of our website. For your convenience, a replay of today’s call will also be available on our website shortly after we conclude. Joining me for today’s call is Doug Fambrough, our President and Chief Executive Officer; Doug Pagan, our Chief Financial Officer; and Dr. Shreeram Aradhye, our Chief Medical Officer. Before we begin, I’d like to remind everyone that management will be making forward-looking statements on today’s call pertaining to the company’s finances, business and operations, including the discovery, development and commercialization of our product candidates and technology platform and the therapeutic potential thereof and our collaborations in any future collaboration. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Applicable risks and uncertainties include those relating to our preclinical research and clinical development and other risks identified in the risk factors included in our most recent annual and quarterly reports filed with the SEC. The forward-looking statements on this call speak only as of the original date of this call, and while we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so. I’d now like to turn the call over to our CEO, Doug Fambrough. Doug?

[Doug Fambrough:]

Thank you, Kristen. Good morning, everyone, and thank you for joining us. In the third quarter, Dicerna achieved a key milestone in the maturation of our company, one that few biotechs ever attained. We generated strongly statistically significant efficacy data with the clean safety profile in a pivotal clinical trial with our wholly owned nedosiran compound discovered at Dicerna from proprietary technology developed by Dicerna. I am incredibly proud of this. And we believe this success will be the first of many, as there are 15 additional Dicerna molecules at various stages of development being developed by ourselves or by our five global pharmaceutical partners that have chosen to collaborate with us in RNAi. Most of these potential therapeutics utilize our liver-targeted GalXC technology with some of the most recent molecules to enter development utilize our GalXC-Plus technology to target various other tissues. I’m also very excited to begin to share details about our first wholly owned strategic initiative outside the liver in early Q1 2022 when we’re planning a full rollout of that effort. As a reminder, Dicerna has six clinical-stage Dicerna GalXC molecules

[Doug Pagan:]

Thanks, Doug. As mentioned, we are very excited to be advancing our clinical development programs to deliver potential new treatment options for patients and maximize long-term value for our shareholders. Turning to our financials. I’ll begin with our balance sheet. We continue to be in a strong cash position, having ended the third quarter with $646.6 million in cash, cash equivalents and held-to-maturity investments. We continue to believe these amounts, together with projected proceeds from existing collaborations will provide us cash runway into 2025, while we continue to invest in advancing our clinical pipeline, supporting our collaboration partners and expanding our platform technologies. As previously noted, economics from any potential out-licensing arrangements for nedosiran are not factored into our cash runway projection. Moving to the P&L. Revenue for the third quarter totaled $63.0 million compared to $48.9 million in the same period last year. The change primarily reflecting an increase in revenue associated with our collaboration with Novo Nordisk. On to operating expenses. Research and development expense for the third quarter totaled $61.2 million compared to $54.8 million in the same period last year. The change was primarily due to higher facility-related expenses as well as increased depreciation and other expenses. General and administrative expense for the third quarter totaled $22 million compared to $17 million in the same period last year. The change was primarily due to increased rent expense associated with the company’s new headquarters in Massachusetts and an increase in software costs. For our bottom line, net loss was $17.1 million for the third quarter of 2021 compared to $21.8 million for the same period last year. Year-to-date, we have received $76.5 million in milestone, fee and reimbursement payments from our collaboration partners, primarily Roche and Novo, and continue to guide to receiving $83 million for the full year 2021. These payments represent an important source of proceeds and demonstrate the value we expect these collaboration programs to continue to generate as they mature. With that, I would now like to open the call for questions. Operator?

[Operator:]

Thank you. Our first question comes from Jonathan Miller with Evercore. You may proceed with your question.

[Jonathan Miller:]

Thanks so much for taking my question guys, and congrats on the progress. Should we expect continued dose response at 12 MPK for the AAT program at AASLD later this week? And on ESTRELLA, would you PR the six-month data on its own? Or are you planning on waiting for the full 48-week data to give us insights into the patient response there?

[Doug Fambrough:]

Hey, Jonathan. this is Doug. We’ll talk about the belcesiran data when it comes out on Friday. Could you repeat the second question? I didn’t quite catch it.

[Jonathan Miller:]

Just on ESTRELLA, would you PR the shorter cohort, the six-month cohort on its own? Or would you wait for the longer the 44-week cohort?

[Doug Fambrough:]

I don’t think we’ve really planned out how we’re going to disclose the data at this point in time.

[Jonathan Miller:]

Okay. Fair enough. Maybe then on extrahepatic. You mentioned the full rollout of your extrahepatic program in early Q1. I think we’ve all been waiting for this a lot. You previously said you’d wait until you were almost clinic-ready before you announce anything. So as we look forward to what’s coming beginning of next year from those programs, what should we be expecting? Is this going to be a whole R&D Day or a PR? How much of the data you are going to present is going to be specific to a particular target versus more broadly on extrahepatic programs and technology. Could you just maybe give us a little color about what we should be looking forward to there?

[Doug Fambrough:]

Sure, I’ll give you a little bit. I mean, I hate to build it up so much. We’ll wait until the new year. I think what we’ll do is we’ll probably do a rollout as part of a kind of year opening corporate presentation. That will go into the therapeutic area that we’re going into our delivery data across cell types in that therapeutic area, the multiple targets of interest and multiple programs that we’re pursuing, the preclinical data that supports a strong belief that these can provide exceptional efficacy in serious unmet medical need, and then we’ll present our timeline to the clinic.

[Jonathan Miller:]

All right. Sure. Thanks. I’ll have back in the queue. Thank you very much.

[Operator:]

Thank you. Your next question comes from Mani Foroohar with SVB Leerink. You may proceed with your question.

[Mani Foroohar:]

Hey, guys. Thanks for taking the question. I have two quick ones. There’s been a lot of debate amongst investors around interest in RNAi platforms broadly in business development. Can you give us a sense of how to think about that strategy? Obviously, developed was the dominant part of the story in 2019. And in the last couple of years, it’s become more focused on your own internally wholly owned assets. How do we think about that balance of out-licensing and partnering assets? Is that just a smaller part of the story now that you don’t need to support the balance sheet that way.

[Doug Fambrough:]

Yes. This is a really interesting question and thinking about how the mix of partnering and proprietary programs drives our strategy is something we think a lot about. And there has been a real change from the 2018, 2019 time frame, where we used a collaboration strategy to build our capabilities and our balance sheet. And we believe we were very successful in doing so. Having been so successful doing so, it wasn’t so important to continue partnering and rather we have turned to focusing primarily on our own programs. And at the same time, managing a shift from the primarily GalXC liver-targeted technology that served for the basis of almost all that partnering to the GalXC, which we’re going to be populating our own pipeline with going forward. Now the interest in RNAi partnering remains very high. We’re not being really responsive to the kinds of requests that we’re getting. But I think RNAi has established itself as a modality, now with multiple approved products and pivotal data sets that show formally a clean safety profile and strong target specific reductions in protein levels, which is really what you asked the technology to do. And that’s been widely noted. So we have a lot of inbound interest, but I don’t think that we really need to do the kinds of collaborations we’ve done before. They do take brain space, they take lab space. Right now, we’re very comfortable with our balance sheet. And so we’re not engaging in discussions around the types of large discovery collaborations that characterized, particularly our Novo and our Lilly relationships. So we’re going to stay focused on our own pipeline and probably think about selective out-licensing of programs that we choose not to invest our own resources in going forward and probably stay away from the large discovery collaborations that we did in the past. That’s not a comment on the demand. I can tell you, pharma is very eager on this technology, but it doesn’t fit our strategy going forward.

[Mani Foroohar:]

Great. That’s helpful. Thanks.

[Operator:]

Thank you. Our next question comes from Luca Issi with RBC Capital. You may proceed with your question.

[Luca Issi:]

Hello. Great. Thanks so much for taking my question. Congrats on the progress. I have two. one on A1AT, the other one is on hepatis B. So, on A1AT, I think you’re obviously dosing up to 12 milligram per kilogram or roughly 900 milligram assuming the average wage in North America for adult, this appears higher than the 200 milligram that Arrowhead is using in their program. So wondering if you can comment on what’s driving that difference? And then maybe for hepatitis B, if I captured it correctly, you mentioned that you’re anticipating data in 2023 and not 2022. So wondering if you can expand a little bit more on that. Thanks so much.

[Doug Fambrough:]

So for belcesiran, I think we have used pretty much the same dose escalation across all our programs from 0.1 to 12 MPK and the 12 PK cohort is really about showing a safety margin in healthy volunteers. It’s not something we would consider as a clinical dose going forward. As we’ve discussed, we’ve already selected a Phase 2 dose for belcesiran. And we’re very pleased with the profile that it should generate based on modeling and simulation out of the Phase 1 data. I think it’s important to note that chronic dosing is not a single dose, right? So you do get dose additivity, you have a long duration of effect, and that’s something that you can model out. As for differences, there may be differences in molecule potency up or down, but it may be due to the fact we do use different assays, different assay than Arrowhead does in their trial, and it’s not quite an apples-to-apples comparison. We’re achieving the level of knockdown that we target. And we believe we’ve got a convenient simple Phase 2 regimen in our ongoing Phase 2 that we’re dosing and expect that to be a very successful trial. Can you repeat the second question? I didn’t retain.

[Luca Issi:]

Yes, sure. So for hepatitis B, if I captured it correctly, you’re mentioning the next data update on in 2023, and apologies if I didn’t capture it correctly. So wondering why we’re not getting any data in 2022.

[Doug Fambrough:]

So the trials began enrolling last year, and there’s a 48-week dosing period in a 24 weeks basically 1.5 years. We expect that given some guidance from Roche that at least some of the cohorts will complete enrollment before the end of this year. But then you’ve got that 72-week period before data. We haven’t been given any guidance from Roche about an interim update. If they provide one, obviously, we’ll pass that on. But otherwise, that’s just the time frame of this trial to try to achieve functional cures with a 48-week dosing period and then a 24-week period off drug during which you need to maintain no viral markers in order to qualify for functional care.

[Luca Issi:]

Super helpful. Thanks so much, Doug.

[Operator:]

Thank you. Our next question comes from Stephen Willey with Stifel. You may proceed with your question.

[Stephen Willey:]

Yeah. Good morning. Thanks for taking the questions. I was maybe just wondering staying on HBV if, Doug, you could maybe comment a little bit on, I guess, some of the updated data that we’ll be seeing at AASLD. I know that they’ve presented their 48-week stopping rural data. I think the combo of an siRNA and nucleon side analog looks to be pretty interesting and just wondering what that provides in terms of read-through to your asset and the Roche development program.

[Doug Fambrough:]

Yeah. Hi, Steve. Thanks for asking that question. I thought that was super cool. That exceeded my expectations for 48-week of siRNA and nucleon to have 20% of the patients achieve the stopping rule. I think that bodes very well for the possibility of a substantial rate of functional cures, particularly in a triple combination context, particularly when an immune activator is included. And there are two cohorts like that in our study with Roche, one with interferon and the other with TLR7, a liver-specific TLR7 agonist. It remains to be seen what sort of rebounds you’ll have coming off drug. I am a little skeptical that just suppression with siRNA and nuc is going to provide a functional cure by itself, but to see it be so powerful in that high percentage of patients over 48 weeks, suggests to me that within a triple combination, you could have really impressive levels of functional cure. So I was really excited to see that data. I think there is a pretty direct read-through to what other siRNAs against HBV could do. So I really saw that as a harbinger, I think, some really exciting data in the future from us and our colleagues in the industry.

[Stephen Willey:]

That’s helpful. Thank you. And then just with respect to ESTRELLA, can you remind me, patients are not allowed to receive augmentation therapy in the study, correct?

[Doug Fambrough:]

I’m going to pass to Shree to talk about how that’s going to work in our trial.

[Shreeram Aradhye:]

Yes, in fact, we are just about to start allowing the inclusion of patients on augmentation therapy in ESTRELLA. That will be part of the modification to the current protocol, but we fully expect to enroll people on augmentation.

[Stephen Willey:]

Okay. And can you say whether or not that was a regulatory directed protocol change? Or was that something that you guys just work through internally?

[Shreeram Aradhye:]

No, it was something that we decided because we know that, that’ll be a population of clear interest for the product in the future.

[Doug Fambrough:]

We recently did the validation of the assay that allows us to separate the augmented protein from the endogenously produced Z protein. You need to distinguish those, so you need a validated assay for that. So with that coming online, we can now adjust our enrollment.

[Stephen Willey:]

All right. Very helpful. Thanks for taking the questions.

[Operator:]

Thank you. Our next question comes from Yigal Nochomovitz with Citigroup. You may proceed with your question.

[Yigal Nochomovitz:]

Hi, Doug and team. Thanks for taking the questions. Doug, can you help us understand a little bit better the path forward in PH2 and PH3. I’m just wondering if you were able to ascertain why the PH2 results were inconsistent and as well why the PH3 patients didn’t need statistical significance. And more generally, how do you plan to proceed with further development in PH2 and PH3? Will that become the responsibility of a future out-licensing partner? Thanks.

[Doug Fambrough:]

Sure, Yigal. This is something we have thought a lot about. It was quite a surprise that the drug was not effective in PH2 and PH3 the way it was in PH1. We did assemble a group of KOLs and did really a deep dive into the biology. And as part of that generated a series of hypotheses about what might be going on. Now I call these hypotheses. This is an ultra-orphan disease. There’s been a limited amount of research on the disease. So there’s a speculative nature to some of these hypotheses. Now for some of them, they’re hard test and/or imply no role for nedosiran. For others, they are testable within the context of our PHYOX3 open-label study and potentially suggest a role for nedosiran in treatment. And we do intend to pursue those hypotheses to see if we can develop a role for nedosiran by certain adjustments. I’m not going to go into the specifics of the hypotheses, but suffice it to say, we can explore them in the context of the current open-label study, which we have patients with PH2 and PH3 roll over our own tool. So as to the responsibility for us or the partner that will be, it’s part of the discussion with our commercialization partner. But we have a commitment to these patients. It has really been one of the really exciting parts of the program for us that we could address all patients with PH2 and PH3. So to the extent we can explore it in PHYOX3 with credible hypotheses that suggests to roll for nedosiran, we want to make sure that happens, and we’re moving to pursue them.

[Yigal Nochomovitz:]

And can I just clarify, for PH1, the intention is to retain the rights for that population. Is that correct?

[Doug Fambrough:]

We are in the process of out-licensing commercialization rights to nedosiran globally.

[Yigal Nochomovitz:]

Okay.

[Doug Fambrough:]

So, we cover all indications. So really, it’s the same call point, it’s patients presenting with very similar symptom profiles. So there wouldn’t be any distinction between out-licensing PH1, 2 or 3. But we are seeking a global commercialization partner. We’re well in discussions. We look forward to making an announcement when that is concluded, but the interest has been quite strong with multiple parties.

[Yigal Nochomovitz:]

Okay. And then can I just ask a different question. You’ve got an impressive number of discovery programs. I think you said 20 or more. Is there any theme there in terms of therapeutic area? Or are you looking broadly across the therapeutic manner? If you could just give us any sense as to what you’re working on there.

[Doug Fambrough:]

So it is quite broad. The discovery programs under both the Lilly and the Novo Nordisk and Roche collaborations are dominated by liver targeted. So Roche is focused on things primarily for the treatment of HBV. I’ve characterized our Lilly collaboration programs in the liver as tend to be focusing on cardiovascular but also sort of cardiometabolic. And the NOVO collaboration is a sort of NASH and cardiometabolic oriented. And so there’s a broad number of programs using the GalXC technology that are like that. The neurodegeneration and pain part of our Lilly collaboration is -- also has several programs associated with it, and they target various areas within the CNS from spinal cord up to the various regions of the brain. And then we have our own programs there is GalXC preclinical program, but most of those are GalXCs. And our initial focus will be rolling out. There is a therapeutic area theme, large market. We think we’ve got a really exciting angle that RNAi is particularly well suited to that we’ll roll out as I discussed at the beginning of Q1. So there’s a fair amount of breadth there. It’s a majority GalXC, minority GalXCs at this point in time. But as the Novo and Lilly collaborations in particular, as those programs move to the clinic, it will shift to more GalXC-Plus than GalXC. And some of them will face attrition at the discovery level. Our Novo collaboration, for example, is designed to be exploratory about targets. So have a more discovery programs than Novo intends to take into the clinic. But RNAi actually -- it’s very easy, literally, in about a month, we can generate a tool to do therapeutic activity work in animal models. And so out of Novo’s sort of genetic biological discovery work, they identify targets, we generate the tools. There’s a joint look at therapeutic activity and then programs will move forward. So there’s going to be attrition in these discovery stage programs. Having said that, I don’t expect much attrition in the preclinical development pipeline, once molecules have been nominated. And as I’ve noted, there are 10 of those in the pipeline. And that’s what supports the sort of won a quarter over the next couple years and probably similar rate going beyond that. It’s just that we need more programs to enter development if they’re going to be INDs two years out, right? Those haven’t entered development yet. So we don’t expect very much attrition amongst that group of 10. It’s amongst the 20 though, there will be attrition.

[Yigal Nochomovitz:]

Thank you very much for the comprehensive answer.

[Operator:]

Thank you. Our next question comes from Yaron Werber with Cowen. You may proceed with your question.

[Brendan Smith:]

Hi. Thanks very much for taking the questions. This is Brendan on for Yaron. Just a quick one for us on the Lilly collaborations actually. So, given that there are a couple different compounds that they’re targeting ANGPTL3 and LPa, was just wondering, first, what you’re able to tell us about, mechanism of action or even the target sequence for your compounds that Lilly sets them apart. And then understanding that a lot of it is at the discretion of Lilly, but when we might start seeing some data from either of those studies? Thanks very much.

[Doug Fambrough:]

So, I don’t think I can comment on particular sequences as some folks may recognize RNAi is very robust. There are a lot of sequences in the gene that are responsive. Some are better than others. We do go through a process of trying to identify the best ones and there is a bit of an IP. I don’t know, Scuffle that sort of goes on around sequences. And we certainly believe we’ve identified things that are very active and have FTO. People may recall that it was sequence IP against the HAO1 gene that led to our owning a royalty on the Oxlumo product. We believe we are avoiding that situation with the sequences we’re using in LPA and ANG3 and frankly, all of the other programs that we’re working on. I really can’t comment on the data or the time lines, that is the purview of Lilly. I am led to believe that things they take into Phase 2, they just tend to present the Phase 1 data of and I look forward to that coming to pass.

[Brendan Smith:]

Okay. Thanks very much.

[Operator:]

Our next question comes from Ed Arce with H. C. Wainwright. You may proceed with your question.

[Thomas Yip:]

Hi. Good morning, everyone. This is Thomas Yip asking a couple of questions for Ed. First, perhaps, can you share the thoughts on the competitive dynamics of being the second entry on the PH1? And then also, can you go over some details of interaction with the FDA ahead of the NDA filing?

[Doug Fambrough:]

Sure. I’ll take the first part of that. And then with respect to interactions, I’m going to pass over to Shree to answer that question. So there is a lot of unmet medical need in PH1, and there are many patients, both in the US and ex-US that have yet to be diagnosed. So we expect the patient universe to be growing as diagnosis increases. We believe our monthly self-administered prefilled syringe dosing regimen provides a particularly convenient and empowering dosing regimen for patients that are sort of customer research, so to speak, as we believe, shows to be something that’s highly desired. So we think combined with the data that we have in PH1, there’s a pretty compelling rationale for people to choose nedosiran who are freshly diagnosed. When it comes to patients that are currently diagnosed, of course, many of those are in process or have already gone on Oxlumo. The data for Oxlumo suggests that about 50% of patients do not achieve their oxalate reduction goal of normalization. And we think that those patients are likely going to be open to trying an alternative product to see if they can achieve their goal. For patients who are well controlled and achieving normalized oxalate on Oxlumo. I think it’s fairly unlikely you’ll see the switch in that case based on convenience alone. So I think that’s really how the landscape sort of plays out. And to the extent that we really are having a lot of interest in that program for commercial out-licensing. I think that story is resonating with the potential commercialization partners. Shree, do you want to talk about our interactions with the FDA?

[Shreeram Aradhye:]

Yes. Thanks, Doug. So as you know, in August, we revised our strategy to focus on seeking approval for nedosiran for the treatment of PH1. We believe that the potential approval is supported by a clinical data package that consists primarily of the data from PHYOX2 in which, as you know, nedosiran achieved strong statistical significance for efficacy in PH1. Subject to our ongoing discussions with the FDA, we intend to submit additional efficacy data from our open-label extension study, PHYOX3. We are currently processing the data and believe that we have collected all the data we need to file. So given this and subject to our ongoing discussions with the FDA, we expect to submit our NDA in Q1 of 2022 versus the original plans for December this year.

[Thomas Yip:]

Okay. Got it. Thanks. And thank you for the additional details. Perhaps another question from us for DCR-AUD. In Phase 1 is doing, can you share some initial thoughts on possible efficacy end points for Phase 2 and beyond?

[Doug Fambrough:]

So the nature of the way DCR-AUD works is it provides physiological feedback to patients who are consume alcohol when they’re in the process of treatment to help themselves limit their alcohol consumption. And so the really relevant endpoint is what we would call a harm reduction endpoint, where it reflects that people have fewer days where they drink heavily. This is as opposed to abstinence not starting to take a drink. Absence would be appropriate for something that works at the level of trying to reduce cravings, whereas DCR-AUD working at the level of providing feedback for those who give into their cravings is one where you would expect to see fewer days of heavy drink. And so the reduction in heavy drinking days, also sort of, as I said, now as a harm reduction endpoint is what we’ll be tracking in Phase 2 and what we expect will likely be the regulatory endpoint for approval in the US and Europe.

[Thomas Yip:]

Got it. Perhaps one quick one. Does the cash run rate include the spending for the new extrahepatic program?

[Doug Fambrough:]

Yes. It does include the preclinical programs that we’ll announce as well as all of everything that’s in the pipeline today. We have planned a fairly aggressive introduction of new programs and our spending over the next several years, and that is fully included in our runway calculations.

[Thomas Yip:]

Got it. Understood that. Thank you for questions, and we look forward to the viewing of the new extrahepatic program.

[Operator:]

Thank you. Our next question comes from Madhu Kumar with Goldman Sachs. You may proceed with your question.

[Madhu Kumar:]

Good morning, everyone. So thinking about alpha-1 antitrypsin, PiZZ liver disease kind of at a big picture level, what do you guys consider a clinical proof of concept for kind of clinical benefit in the setting of that disease?

[Shreeram Aradhye:]

Hi, Madhu. It’s Shree. You know that this is a rare disease. So I think that the evidence of efficacy is going to come from looking at improvements in liver histology, soluble biomarkers and imaging given that the actual clinical endpoints of progression of ascites, hepatic encephalopathy need for liver transplantation are going to be hard to track in a clinical trial. Those are eventually the outcomes that matter. But in this program, I think establishing that our therapeutic hypothesis that reducing the mutant protein in the liver results in restoration of hepatic homeostasis and a return either reduction in progression or reversal of some of the injury will be predictive of the clinical outcomes. But the primary basis is going to be on the basis of improvements in liver function, histology and other markets.

[Madhu Kumar:]

Yes. Sure. So on that point, how do you think about the variability in liver fibrosis in Z AAT patients? And how much like the kind of more biochemical type parameters, things like Z polymer formation, the globule deposition are going to be kind of more useful surrogates compared to fibrosis, histology assessment per se?

[Shreeram Aradhye:]

Yeah. I know you follow the NASH literature. So we know that the hard end point of scores and changes in those with high placebo responses are a challenge. So I actually fully expect, and that’s how ESTRELLA has been designed that it will be the concordant movement in a beneficial direction for a variety of biomarkers that include both the soluble ones that we described, histological ones like reductions in globule reduction in inflammation, reductions in liver enzymes and an imaging biomarker like we are using MRE as an option as well as fibro scan to look at sort of overarching what’s happening in the liver as a whole in terms of reductions in fibrosis or tissue resistance, if you will, to ultrasound. It will be a collection of those parameters. And I think that’s part of the core discussions that we expect to have with regulators. We also expect to learn from what our competitors plan to do.

[Madhu Kumar:]

Okay. And then one last one. On the nedosiran NDA submission, so you mentioned kind of pending ongoing pre-NDA interaction with the FDA. Is there any specific issue that’s been raised as part of the kind of pre-NDA discussions? Or is it just kind of like standard processes of NDA filing?

[Shreeram Aradhye:]

Well, I mean, look, you know the process, right? We got our PH1 data. They were very strong. As part of our normal routine. We engage with the division for the discussions on now the NDA is getting ready. It’s an ongoing discussion. We got feedback, no concerns on safety, and we are evaluating additional information that we believe we’ve already collected. And that’s the sort of active process that’s ongoing right now.

[Madhu Kumar:]

Okay. Thank you so much, everyone.

[Operator:]

Thank you. Your next question comes from Mayank Mamtani with B. Riley Securities. You may proceed with your question.

[Yuan Zhi:]

Hi. This is Yuan Zhi for Mayank. Congratulations on the progress in the last quarter. Thank you for taking our questions. A follow-up on the HBV questions. I understand the exact targeting position in the HBV genome is different. Can you remind us your target and any potential different impact you would expect versus Janssen’s program? Thank you.

[Doug Fambrough:]

Sure. Thanks for bringing this difference up. There is some molecular differentiation between our approach and the approach of the program that Janssen is developing. So as I think many people who are deep in HBV recognized, there are four genes in the HBV genome, three of which are structural and one of it is regulatory. And the way the genes overlap and the transcripts where the genes map out, one has the option of sort of trying to hit all four at the same time or hitting three out of the four. And of course, we evaluated that during our development. The Janssen program, it’s three out of the four, as I understand it, using two siRNAs and a ratio that hasn’t been disclosed to my knowledge, whereas we use a single one that targets three out of the four. We did a pretty deep analysis in what we believe is the highest fidelity mouse model of HBV, recognizing this is not a mouse virus. But there are techniques that you can do to generate viral replication in mice. It’s not an active ongoing infection, but viral replication intracellularly. And saw a distinct difference between three versus four gene suppression. Based on the status of this one, the sports regulatory only protein. And when you don’t silence it and you have an overabundance of that regulatory protein in the mouse model, it led to a longer duration suppression of S and a deeper suppression of S antigen. And this is due to sort of toggling between producing s antigen decoy particles are producing actively infected virus, of course, which now takes care very effectively. I’d say we didn’t see as dramatic a difference in our Phase 1 human study single dose – well, four doses actually in patients, but it was a limited duration study. But we’re still evaluating the duration there. To the extent that, that value model shows an actual regulatory difference between three and four, the implication is that we should get better sustained suppression and potentially a better human immune response due to that suppression from the three versus four. This may be a subtle difference at the margins or it may be an important difference. We’ll see when it comes down to functional cure rates in the Phase 2. But we’re pretty confident, at least at the animal model level that we’ve tapped into some real viral biology around the regulation of S by targeting three versus four and having relative overabundance of that regulatory protein in order to maximize the chance of the patient’s immune system mounting a successful response against the virus, which we think is critical for the ultimate functional cure and truly eliminating the virus from the body.

[Yuan Zhi:]

Yeah. Thanks for the helpful color. I understand nuc is very important as the part of the combination. Just want to hear your comment on thoughts if you could add another arm of therapy to the combo therapy how, what would be an ideal want to generate more synergies.

[Doug Fambrough:]

The ideal third combination partner alongside sRNA and NUC is an immune system activator to help refresh the exhausted immune response and drive T cell mediated elimination of infected cells that carry cccDNA. That is the – to the extent we have proof of how to generate functional cure, the proven way, nuc and interferon being that prove a small number of patients. But we believe that with an siRNA, particularly given the suppression of S, you can really drive that number up. So I think that’s the way to go. There are two triple combination cohorts like that in the clinical program that Roche is pursuing with RG6346, one with peginterferon with Pegasus. Of course, they’re long-time interferon product and the second with their in development, liver-activated TLR7 agonist.

[Yuan Zhi:]

Yes. Thanks for the color. Thank you.

[Operator:]

Thank you. And I’m not showing any further questions at this time. I would now like to turn the call back over to Doug Fambrough for any further remarks.

[Doug Fambrough:]

Thanks, everyone, for paying attention today and all your questions. We’re in a really strong position financially. We’re in a strong position with our technology and our pipeline is some really exciting stuff coming. So I feel really good about our prospects here. Thanks a lot. Bye-bye.

[Operator:]

Thank you. This concludes today’s conference call. Thank you for participating. You may now disconnect.