Dicerna Pharmaceuticals Q3 2021 Earnings Call Transcript

Quartr
Provided by Quartr
November 9, 2021

There are 14 speakers on the call.

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, Kristin Shepherd, Senior Vice President of Investor Relations at Tesira. Please go ahead.

Speaker 1

Thank you, and welcome to Dicerna's Q3 2021 Financial Results and business highlights conference call. Please note that the press release detailing our results for the Q3 was issued earlier this 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 Doctor. Sriram Aradhye, our Chief Medical Officer.

Speaker 1

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 and any future collaborations. 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.

Speaker 1

I'd now like to turn the call over to our CEO, Doug Sambrock. Doug?

Speaker 2

Thank you, Kristin. Good morning, everyone, and thank you for joining us. In the Q3, 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 a clean safety profile in In a pivotal clinical trial with our wholly owned nadocerin 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 Various stages of development being developed by ourselves or by our 5 global pharmaceutical partners that have chosen to collaborate with us in RNAi.

Speaker 2

Most of these potential therapeutics utilize our liver targeted Galaxy technology, but some of the most 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 6 clinical stage Dicerna Galaxy molecules: nidosarin for primary hyperoxaluria or PH, valsasarin for alpha-one antitrypsin deficiency associated liver disease or AATLD DCR AUD for the treatment of alcohol use disorder RG6346 for chronic HBV with Roche and ANGPTL3 and LPA targeted programs under our Lilly collaboration. Beyond these clinical programs, we have, as I just mentioned, 10 active core and collaborative preclinical And looking across this entire pipeline of activity, we expect new programs to be entering the clinic on average 1 per quarter over the next 2 years and potentially beyond that at a similar rate. Although

Speaker 3

I want

Speaker 2

to note that our partners have full discretion over submissions And timelines over the nearer term, we expect to deliver packages to support an IND or CTA filing in Q4, potentially followed by 2 additional filings later in the first half of next year. Among all these programs, we believe several large expand in the future into a vast number of indications and meaningfully advance our mission to improve the lives of patients. This is an exciting time for Dicerna and we believe we are well positioned with the cash runway that extends into 2025. Turning now to our recent business highlights. I'll start with nidosiran.

Speaker 2

Of course, the highlight For the quarter was the positive data from our pivotal PHYOX2 study of nidosarin for the treatment of PH type 1 or PH1 that we reported in August. Nidosarin achieved its primary endpoint in the study, demonstrating a highly statistically significant reduction from baseline in urinary oxalate excretion compared to placebo. Dedosiran also met the key secondary endpoint with a significantly higher proportion of patients Achieving and sustaining normal or near normal uOX at 2 or more consecutive visits after day 90 compared to placebo. Additional analysis showed that the uOX reductions were significant in patients with PH1, while there was no consistent pattern of uOX reduction served in patients with PH type 2 or PH2 suggesting additional complexity in PH2 disease biology. We believe these data underscore nidozarin's potential for treating patients with PH1, marking a significant milestone for Dicerna.

Speaker 2

More recently in October, we reported top line results from our PHYOX4 study in which patients with PH type 3 or PH3 were given a single subcutaneous dose of nidosiran or placebo. PHYOX4 met the primary safety endpoint showing nidosiran was Generally safe and well tolerated in patients with PH3. While nidosarin did not meet the pre specified secondary efficacy The endpoint criteria in this trial PH3 patients who were given nidosiran in this study also showed an encouraging trend in urinary to late excretion reduction. Our recent stream of pH data announcements culminated in the selection of PHYOX2 data for a late breaker poster presentation at last week's ASN's Kidney Week, a designation that we believe reflects the importance of the data we have generated for the medical community caring for patients with PH, Which is a great segue for me to highlight Dicerna's continuing commitment to PH patients. While we have refined our near term nidozarin strategy to focused on seeking approval of nadoserine in PH1.

Speaker 2

There is a significant unmet medical need in both PH2 and PH3 and we plan to continue analyzing In terms of our next steps, we remain focused on submitting an NDA for nadoserine in PH1. Subject to our ongoing pre NDA interactions with with the FDA, we are adjusting our plan submission content and currently expect the timing to move from December of this year into the Q1 of 20 Turning to belcesorant, our 2nd most advanced wholly owned clinical stage galaxy RNAi therapeutic Candidate that is in development for the treatment of AATLD. AAT deficiency is a rare genetic condition caused by mutations in the SERPIN A1 gene that encodes AAT that results in disease of the liver and lungs. Due to the And with the severe and progressive nature of AATLD, there is a significant unmet need for a therapy that can directly impact the aggregation of AAT protein in the liver. We're particularly excited about this program as we believe valsisiran has the potential to change the treatment paradigm and prevent the need for liver transplantation, which is currently the only option available to address AATLD.

Speaker 2

In July, we announced interim results from our Phase 1 study of belcesiren, which met our objective demonstrating strong dose dependent reductions in serum completed active treatment dose cohorts of 0.1, 13 and 6 milligrams per kilogram, valsasiran was found to have an acceptable safety profile and was generally well tolerated. The final 12 milligram per kilogram dose cohort in this trial has now been completed. We will be presenting these results at the upcoming American Association For the Study of Liver Diseases, liver meeting later this week. The key takeaway is that the data were consistent with the previously reported interim results, including a favorable safety profile as has been reported to date and further support these further support our decision to move forward with the delsesserin clinical program. In June, we initiated the next phase of development for valsesserin, advancing to patient dosing in our Phase 2 AUSTRELLA trial.

Speaker 2

This is an important milestone in our efforts to bring valsesserin to patients with AATLD. Astrla is a randomized multi dose Double blind, placebo controlled study evaluating falcisiran safety, tolerability, pharmacokinetics and pharmacodynamics for the treatment of AATLD. The Astrela Phase 2 study includes a 24 week cohort and a 48 week cohort to be conducted in parallel, each with up to 27 participants who have a diagnosis of PIZZ type AAT deficiency and AATLD. Turning to our newest candidate in clinical development, DCR AUD, it is an investigational Galaxy The RNAi therapeutic for the treatment of alcohol use disorder or AUD. AUD is characterized by the inability to stop or control alcohol use Despite social, occupational or health consequences, many individuals with AUD do not receive treatment and Currently available pharmacotherapies are not widely prescribed.

Speaker 2

There are an estimated 14,000,000 individuals in the U. S. With AUD, out of which fewer than $1,400,000 received treatment of any kind. To address this unmet need, we recently initiated a randomized Double blind Phase 1 study of DCR AUD to evaluate the safety, tolerability pharmacokinetics and pharmacodynamics of single ascending doses of DCR AUD and up to 36 healthy volunteers over a 24 week observation period. The trial is also assessing the interaction between DCR AUD administration and alcohol consumption using standardized ethanol interaction and assessments performed serially over the trial's duration.

Speaker 2

We remain steadfast in our belief that this program has the potential to generate a novel treatment for individuals with AUD and we look forward to sharing interim results from the trial later in 2022. Now turning to clinical stage programs being developed by partners. Our RG6346 program in collaboration with Roche continues in multiple cohorts within their Phase 2 ADAPTIVE trial in chronic HBV with different cohorts exploring different multidrug combinations. Based on the nature of that trial, we expect data in 2023. As a reminder, Dicerno retains a right to opt into program for Phase 3 development.

Speaker 2

The 2 Lilly partnered Galaxy programs targeting ANGPTL3 and LPA continue in Phase 1 development at Lilly. With so much to look forward to in terms of clinical and corporate milestones, We're still only getting started here at Dicerna. We are committed to building on our progress by advancing our existing portfolio of candidates and unveiling our next wave of innovations to deliver strategic value for all our stakeholders, most importantly, the patients who motivate our mission. To that end, we are proud to sponsor Alpha-1 Awareness Month this month and hyperoxylorrhea week, which officially began on Monday. With that, I'll now turn the call over to Doug Pagan to review our financial results for this quarter.

Speaker 2

Doug?

Speaker 4

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 Q3 with $646,600,000 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.

Speaker 4

As previously noted, Economics from any potential out licensing arrangements for nadoserine are not factored into our cash runway projection. Moving to the P and L, revenue for the Q3 totaled $63,000,000 compared to $48,900,000 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 Q3 totaled $61,200,000 compared to $54,800,000 in the same period last year.

Speaker 4

The change was primarily due to higher facility related expenses as well as increased depreciation and other expenses. General and administrative expense for the Q3 totaled $22,000,000 compared to $17,000,000 in the same period last year. The change was primarily due to increased rent For our bottom line, net loss was $17,100,000 for the Q3 of 2021 compared to $21,800,000 for the same period last year. Year to date, we have received $76,500,000 in milestone, And we will now be conducting a reconciliation of our collaboration partners, primarily Roche and Novo and continue to guide to receiving $83,000,000 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.

Speaker 4

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.

Speaker 5

Congrats on the progress. Should we expect continued dose response at 12 MCK for the AAT program at It will be later this week. And I guess on EASTRAYA, would you PR the 6 month data on its own? Or are you planning on waiting for the full

Speaker 2

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

Speaker 5

Just on Astraea, would you PR the shorter cohort, the 6 month cohort on its own or would you wait for the longer the 44 week cohort?

Speaker 2

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

Speaker 5

Okay, fair enough. Maybe then on extrahepatic, you mentioned the full rollout of your extrahepatic program in early Q1. I think we've I've 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?

Speaker 5

Is this going to be a whole R and D day or a PR? How much of the data you I'm going to present is going to be specific to a particular target versus more broadly on extrahepatic programs and technology.

Operator

Could you just maybe give us

Speaker 5

a little color about What we should be looking forward to there?

Speaker 2

Sure. I'll give you a little bit. I mean, I hate to build it up So much. We are we'll wait until the New Year. I think what we'll do is we'll probably do a rollout as part of That kind of year opening corporate presentation.

Speaker 2

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

Speaker 6

strong belief that

Speaker 2

these can provide exceptional efficacy in efficacy in this area of unmet medical need and then we'll present our timeline to the clinic.

Speaker 5

All right. Sure. Thanks. I'll hop back in the queue. Thank you very much.

Operator

Thank you. Our next question comes from Mani Ruhae with SVB Leerink, you may proceed with your question.

Speaker 7

Hey, guys. Thanks for taking the question.

Speaker 8

I guess I have 2 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, business development was the dominant part of the story In 2019, and over the last couple of years, it's become more focused on your own internally wholly owned assets. How do you think about that balance out licensing and partnering assets?

Speaker 8

Is that just a smaller part of the story now that you don't need for the balance sheet that way?

Speaker 2

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 timeframe 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 Galaxy The liver targeted technology that served for the basis of almost all that partnering To the Galaxy Plus, 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.

Speaker 2

But I think RNAi has established itself as a modality now with multiple products and pivotal datasets that show formally a clean safety profile and strong target Specific reductions in protein levels, just 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 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 our 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.

Speaker 2

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.

Speaker 8

Great. That's helpful. Thanks.

Operator

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

Speaker 9

Great. Thanks so much for taking my question. Congrats on all the progress. I have 2, one on A180, the other one on hepatitis B. So on A180, I think you're obviously dosing up to 12 milligram per kilogram or roughly 900 milligram assuming the average weight in North America for adult.

Speaker 9

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 capture 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.

Speaker 2

So for valsisiran, I think We have used pretty much the same dose escalation across all our programs from 0.1 to 12 MPK and the 12 MPK 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 valsasiran 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 that belong 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 assays than Arrowhead does in their trial, and it's not quite an apples to apples Comparison.

Speaker 2

We're achieving the level of knockdown that we target and we believe we've got a convenient Simple Phase 2 regimen and 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 it.

Speaker 9

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

Speaker 2

So the trials began enrolling last year and there's a 48 week dosing period in a 24 week, so about basically a year and a half. We In fact, that the 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 1, obviously, we'll But otherwise that's just the timeframe 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

Operator

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

Speaker 10

Yes, 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 Janssen data that we'll be seeing at AASLD, I know that they've presented their 48 week Stopping rule data, I think the combo of an siRNA and nucleoside analog looks to be pretty interesting and just Wondering what that provides in terms of read through to your asset in the Roche development program?

Speaker 2

Yes. Hi, Steve. Thanks for asking that question. I thought that was super cool. That was exceeded my expectations for 48 week of siRNA and new colon, to have 20% of the patients achieve the stopping rule.

Speaker 2

I think that bodes very well for the possibility of a substantial rate of functional particularly in a triple combination context, particularly when an immune activator is included. And there are 2 cohorts like that in our study with Roche, 1 with interferon and the other with TLR7, a liver specific for our 7 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 SI RN A and Nuc is going to provide a functional cure by itself, but to see it be so powerful And that high percentage of patients over 48 weeks suggests to me that within a triple combination you could have really impressive levels of functional Sure. So I was really excited to see that data.

Speaker 2

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 of some really exciting data in the future from us And our colleagues in the industry.

Speaker 10

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

Speaker 2

I'm going to pass to Shri to talk about how that's going to work in our trial.

Speaker 3

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

Speaker 10

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

Speaker 3

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

Speaker 2

We recently did the validation of the assay that allows us to separate the augmented protein from the indogenously produced The 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.

Speaker 11

All right.

Speaker 10

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.

Speaker 7

Hi, Doug and team. Thanks for taking the questions. Doug, can you help us And 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 meet statistical significance. And more generally, how do you plan to proceed with further development in PH2 and PH3?

Speaker 7

Will that become the responsibility of a future out licensing partner? Thanks.

Speaker 2

Sure. Aaron, 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.

Speaker 2

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 nadoserine. For others, They are testable within the context of our PHYOX3 open label study and potentially suggest a role for nidosiran in treatment.

Speaker 2

And we do intend to pursue those hypotheses to see if we can develop a role for nadoserine 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 from the PH2 and PH3 rollover on to. So as to the responsibility for us or the partner, that would 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, INPHYX3 with credible hypotheses that suggest rolfriendosiran, We want to make sure that happens and we're moving to pursue them.

Speaker 7

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

Speaker 2

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

Operator

Okay.

Speaker 2

So that would 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 licensing PH1, 2 or 3. But we are seeking a global commercialization partner. We're well in discussions.

Speaker 2

We look forward to making an When that is concluded, but the interest has been quite strong with multiple parties.

Speaker 7

Okay, thanks. 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?

Speaker 7

Or are you looking broadly across the therapeutic map? If you could just give us any sense as to What are you working on there?

Speaker 2

So it is quite broad. The Recovery programs under the 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 tend to be focusing on cardiovascular, but also sort of cardiometabolic. And the NASH the Novo collaboration is sort of NASH and cardiometabolic oriented.

Speaker 2

And so there's a broad number of programs Using the Galaxy technology that are like that. The neurodegeneration and pain part of our Lilly collaboration It 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 that are there is Galaxy Preclinical program, but most of those are Galaxy Plus 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 will roll out as Discussed at the beginning of Q1. So there's a fair amount of breadth there.

Speaker 2

It's majority Galaxy, minority Galaxy Plus 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 Galaxy And some of them will face attrition at the discovery level. Our Novo collaboration, for example, is designed to be exploratory about targets. So we'll have a discovery more discovery programs than Inovo intends to take into the clinic. But RNAi actually it's very easy.

Speaker 2

Literally in about a month we can generate a tool to do therapeutic activity work in animal models. And so out of Novo's For 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.

Speaker 2

And that's what supports the sort of 1 a quarter over the next couple of 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 2 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.

Speaker 7

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.

Speaker 12

Hi, thanks very much for taking the questions. This is Brandon on for Yaron. Just a quick one for us on the Lilly collaborations actually. So I mean given that there are a couple of different compounds that they're targeting Ngp, TL3 and Lp,

Speaker 13

I

Speaker 12

was just wondering First, what you're able to tell us about, I guess, mechanism of action or even the target sequence for your compounds that really 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.

Speaker 2

So I don't think I can comment on, particular sequences as some folks may recognize. Our AI 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.

Speaker 2

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 -one gene that led to our owning a royalty on the oxalumabroduct. 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 timelines that is the purview of Lilly. I am led to believe that things they take into Phase II they tend to present the Phase And data of and I look forward to that coming to pass.

Speaker 12

Okay. Thanks very much.

Operator

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

Speaker 13

Hi, good morning, everyone. This is Thomas Yip asking a couple of questions for Ed. First, perhaps can you share Your thoughts on the competitive dynamics of being the 2nd entry in RNAi for PH1? And then also can you Go over some details of interaction with the FDA ahead of the NDA filing?

Speaker 2

Sure. I'll take the first part of that and then with respect to the interactions, I'll pass over to Shri to answer that question. So there is a lot of unmet medical need in PH1 and there are many patients both in the U. S. And ex U.

Speaker 2

S. That have yet to be diagnosed. So we expect 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 nidosiran who are freshly diagnosed.

Speaker 2

When it comes to patients that are currently diagnosed, of course, many of those are in the process or have already gone on The data for OXOLUMO 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 oxalumab. 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 we really are having A lot of interest in that program for commercial out licensing.

Speaker 2

I think that story is resonating with the commercialization potential commercialization partners. Sreed, do you want to talk about our interactions with the FDA?

Speaker 3

Yes. Thanks Doug. So as you know, in August, we revised our strategy to on seeking approval for nidosiran 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, nidosiran 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.

Speaker 3

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.

Speaker 13

Okay, got it. Thanks. Thank you for the additional details. Perhaps another question For TCR AUC, while Phase 1 is ongoing, can you share some initial thoughts On possible efficacy endpoints for Phase 2 and beyond?

Speaker 2

So the nature of the way DCR AUD works is it provides physiological feedback to patients who are To 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 that reflects that people have fewer days where they drink Heavily. This is as opposed to abstinence not starting to take a drink. Abstinence 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 drinking. And so the reduction in heavy drinking days Also, as I said, known as a harm reduction endpoint is what we will be tracking in Phase 2 and what we expect will likely be the Regulatory endpoint for approval in the U.

Speaker 2

S. And Europe.

Speaker 13

Got it. Perhaps one quick one. Does The cash runway included spending for the new extrahepatic program?

Speaker 4

Yes, it does include the preclinical programs that we'll announce as well as all of everything that's in the pipeline today.

Speaker 2

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.

Speaker 13

Got it. Understood. Thank you again for taking our questions, and we look forward to the unveiling of the new extra hepatic program.

Operator

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

Speaker 11

Good morning, everyone. So thinking about alpha-one and atripsin, PIZZ liver disease, kind of at a big picture level, What do you guys consider clinical proof of concept for kind of clinical benefit in the setting of that disease?

Speaker 3

Hi, Madhu, it's Sri. I mean, you know that this

Speaker 11

is a rare disease.

Speaker 3

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 the return Either reduction in progression or reversal of some of the injury will be predictive of the clinical outcomes. The primary basis is going to be on the basis of improvements in liver function, histology and other markers.

Speaker 11

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

Speaker 3

Yes, I mean, I know you follow the NASH literature. So we know that the hard endpoint of EPS scores and changes in those with high placebo responses are a challenge. So I actually fully expect and that's how Astellas 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 you 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 FibroScan 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 dose 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.

Speaker 11

Okay. And then one last one. On the nadosiran NDA submission, so you mentioned kind of pending ongoing pre NDA interactions 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?

Speaker 3

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.

Speaker 3

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.

Speaker 11

Okay. Thank you so much, everyone.

Operator

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

Speaker 6

Hi, this is Yuan Zhi on for Mayank. Congratulations on the progress in the last quarter. Just a follow-up on the HBV questions. 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?

Speaker 6

Thank you.

Speaker 2

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 recognize there are 4 genes in the HBV genome, 3 of which are structural and one of which is regulatory. And the way the genes overlap And the transcripts for the genes map out, one has the option of sort of trying to hit all 4 at

Speaker 3

the same time

Speaker 2

We're hitting 3 out of the 4. And of course, we evaluated that during our development. The Janssen program, It's 3 out of the 4 as I understand it using 2 siRNAs and a ratio that hasn't been disclosed to my knowledge, whereas we use a single one that targets 3 out of the 4. 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 in mice, it's not an active ongoing infection, but viral replication intracellularly. And saw a distinct difference between 3 versus 4 gene suppression based on The status of this one, this 4th regulatory only protein and when you don't silence it and you have an overabundance of that regulatory protein in the mouse model that 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 Nuke takes care of very effectively.

Speaker 2

We I'd say we didn't see as dramatic a difference in our Phase 1 human study single dose. Well, 4 doses actually In patients, but it was a limited duration study, but we're still evaluating the duration there. To the extent that that VALS model shows An actual regulatory difference between 34, the implication is that we should get better Sustained S suppression and potentially a better human immune response due to that suppression from the 3 versus 4. 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.

Speaker 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 3 versus 4 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.

Speaker 6

Yes. Thanks for the helpful color. I understand NIO case is very important as the part of the combination. Just want to hear your comment or thoughts. If you could add another part another arm of therapy to the combo therapy you have, What would be an ideal one to generate more synergies?

Speaker 6

Thank you.

Speaker 2

The ideal third combination partner along and drive T cell mediated elimination of infected cells that carry CCC DNA. That is the to the extent we have proof of how to generate functional cure, the proven way Nuc and Interferon Being that proof a small number of patients, but we believe that with an siRNA particularly given its suppression of S, you can really drive that number up. So I think that's the way to go. There are 2 triple combination cohorts like that in the clinical program that Roche is Pursuing with RG-six thousand three hundred and forty six, one with Peg interferon, PEGASYS, of course, their long time interferon product and the second with their in development Liver activated TLR7 agonist.

Speaker 6

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.

Speaker 2

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 with some really Thanks, Stephanie. So I feel really good about our prospects here. Thanks a lot.

Speaker 2

Bye bye.

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Earnings Conference Call
Dicerna Pharmaceuticals Q3 2021
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