Q3 2021 Dicerna Pharmaceuticals Inc Earnings Call
Okay.
Good morning, ladies and gentlemen, and welcome to the Doctor 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 Chris.
And Shepherd senior Vice President of Investor Relations at <unk>. Please.
Please go ahead.
Thank you and welcome to today's <unk> third quarter 2021 financial results and business highlights conference call. Please note that the press release detailing our results for the third quarter with 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, <unk>, President and Chief Executive Officer, Doug Pagan Chief Financial Officer, and Dr Test Sriram, <unk>, 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 companys finances business and operations, including the discovery development and commercialization of our product candidates and technology platform and the therapeutic potential thereof in our collaborations and any fees.
Sure 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.
Our 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 would now like to turn the call over to our CEO, Doug Fambrough Doug.
Thank you Kristen good morning, everyone and thank you for joining us in the third quarter dice sirna achieved a key milestone in the maturation of our company one that few biotechs ever attained we generated strong lease statistically significant efficacy data with a clean safety.
Profile and a pivotal clinical trial with our wholly owned nodosa and compound discovered at ICR enough from proprietary technology developed by dice startup I am incredibly proud of this and we believe this success will be the first of many as there are 15 additional dye sirna molecules at various stages of.
<unk> being developed by ourselves or by our five global pharmaceutical partners that have chosen to collaborate with us and RNA.
Most of these potential therapeutics utilized our liver targeted galaxy technology, but some of the most recent molecules to enter development utilize our galaxy plus technology to target various other tissues.
I'm also very excited to begin to share details about our first wholly owned strategic initiatives outside the liver in early Q1 2022, when we're planning a full rollout of that effort.
As a reminder, <unk> sirona has six clinical stage die startup galaxy molecules.
The dose of <unk> for primary Hyperoxaluria or ph Bell <unk> for Alpha one antitrypsin deficiency associated liver disease or a T. L D.
Do you see our <unk> for the treatment of alcohol use disorder or.
<unk> 6346 per chronic HBV with Roche.
And <unk> III and LPGA targeted programs under our Lilly collaboration beyond these clinical programs. We have as I, just mentioned 10 active core and collaborative preclinical development programs as well as over 20 discovery research stage programs in multiple tissues or cell types and looking across.
This entire pipeline of activity, we expect new programs to be entering the clinic on average one per quarter over the next two years and potentially beyond that at a similar rate.
Although I want to note that our partners have full discretion over submissions and timelines over the near term, we expect to deliver packages to support an IND or Cta filing in Q4 potentially followed by two additional filings later in the first half of next year.
Among all of these programs, we believe several large billion dollar market opportunities exist with significant potential to fulfill unmet medical need. We believe this creates the opportunity for dice sirna to dramatically expand in the future until a vast number of indications and meaningfully advance our mission to improve the lives of patients this is and.
Exciting time for dice sirna, and we believe we are well positioned with the cash runway that extends into 2025.
Turning now to our recent business highlights I will start with no dose around.
Of course, the highlight for the quarter was the positive data from our pivotal <unk> study at nodosa rent for the treatment of ph type one or <unk> that we reported in August the dose of <unk> achieved its primary endpoint in the study demonstrating a highly statistically significant reduction from baseline and.
<unk> oxalate excretion compared to placebo.
The dose and also met the key secondary endpoint with a significantly higher proportion of patients achieving and sustaining normal or near normal you ox at two or more consecutive visits after day 90 compared to placebo additional analysis showed that the <unk> reductions were significant in patients with ph one while there were.
No consistent pattern of <unk> reduction observed in patients with ph type two or ph too, suggesting additional complexity in ph to disease biology, we believe these data underscore the dose or its potential for treating patients with ph, one marking a significant milestone for <unk>.
More recently in October we reported topline results from our <unk> four study in which patients with ph type three or ph three were given a single subcutaneous dose of <unk> or placebo fly ups for met the primary safety endpoint showing the dose <unk> was generally safe and well tolerated in patients with <unk>.
<unk> III, while on the dozer and did not meet the pre specified secondary efficacy endpoint criteria. In this trial <unk> three patients who were given the dose in the study also showed an encouraging trend and urinary oxalate excretion reduction.
Our recent stream of ph data announcements culminated in the selection of <unk> two 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 that <unk> continuing commitment to ph patients. While we have refined our near term the dosing strategy to focus on seeking approval of the dozer in ph. One there is a significant unmet medical need in both ph to ANP is three and we plan to continue analyzing both of these datasets.
Further as part of our discussions to out license the commercialization of nodosa rent in terms of our next steps we remain focused on submitting an NDA for <unk> and ph one subject to our ongoing pre NDA interactions with the FDA. We are adjusting our planned submission content and currently expect the <unk>.
To move from December of this year into the first quarter of 2022.
Turning to Bell Susser, and our second most advanced wholly owned clinical stage Galaxy RNA therapeutic candidate that is in development for the treatment of <unk>.
L D.
<unk> deficiency is a rare genetic condition caused by mutations in the surface a one gene that encodes AAP that results in disease of the liver and lungs due to the severe and progressive nature of L.
There is a significant unmet need for a therapy that can directly impact the aggregation of proto.
Protein in the liver, we're particularly excited about this program as we believe bell Susser and has the potential to change the treatment paradigm and prevent the need for liver transplantation, which is currently the only option available to address L. D.
In July we announced interim results from our phase one study of <unk>, which met our objective demonstrating strong dose dependent reductions in serum <unk> in healthy volunteers with administration of a single dose of <unk> in this analysis of the four completed active treatment dose cohorts.
0.1136 milligrams per kilogram <unk> 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 has been reported to date and further support. These further support our decision to move forward with the Delta El <unk> clinical program.
In June we initiated the next phase of development for Bell <unk> advancing to patient dosing in our phase II Estrella trial. This is an important milestone in our efforts to bring <unk> to patients with a L. P. S.
<unk> is a randomized multi dose double blind placebo controlled study evaluating <unk> safety Tolerability pharmacokinetics and pharmacodynamics for the treatment of a T. L T.
The Estrella Phase III study includes a 24 week cohort and a 48 week cohorts to be conducted in parallel each with up to 27 participants who have a diagnosis of P. ICC type deficiency and.
L D.
Turning to our newest candidate in clinical development <unk>.
It is an investigational galaxy RNA therapeutic for the treatment of alcohol use disorder or <unk>.
<unk> is characterized by the inability to stop or control alcohol use disorder, despite social occupational health consequences. Many individuals with <unk> do not receive treatment and currently available pharmacotherapy are not widely prescribed.
There are an estimated 14 million individuals in the U S with <unk> out of which fewer than one 4 million received treatment of any kind.
To address this unmet need we recently initiated a randomized double blind phase one study of <unk>.
To evaluate the safety Tolerability pharmacokinetics, and Pharmacodynamic dynamics of single ascending doses of <unk> and up to 36 healthy volunteers over a 24 week observation period.
The trial is also assessing the interaction between <unk> administration and alcohol consumption using standardized ethanol interaction assessments performed serially over the trials duration.
We remain steadfast in our belief that this program has the potential to generate a novel treatment option for individuals with <unk> 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 RG six 346 program in collaboration with Roche continues in multiple cohorts within their phase two adaptive trial in chronic HBV with different cohorts exploring different multi drug combinations.
<unk> on the nature of that trial, we expect data in 2023.
As a reminder, distomata retains the right to opt into this program for phase III development.
The two Lilly partnered galaxy programs targeting <unk> III and LPGA continue in phase one 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 <unk> Sirona. We are committed to building on our progress by advancing our existing portfolio candidates and unveiling our next wave of innovations to deliver strategic value for all our stakeholders. Most importantly, the patient.
Who motivate our mission to that end, we are proud to sponsor Alpha one awareness month this month.
Hyperoxaluria 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 Doug.
Thanks, Doug as mentioned, we are very excited to be advancing our clinical development programs to deliver a 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.
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 nodosa and 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 facilities 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.
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 of 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.
Thank you as a reminder to ask a question you will need to press star one on your telephone to withdraw your question press the pound key please standby, while we compile the Q&A roster.
Our first question comes from Jonathan Miller with Evercore you May proceed with your question.
Thanks, So much for taking my question guys and congrats on the progress.
Should we expect continued dose response at 12 and PK for the AAD program at <unk>.
Later this week.
And I guess on Australia 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.
Hey, Jonathan This is this is Doug.
We'll talk about the bell Susser and data when it comes out on Friday could you repeat the second question I didn't quite catch it.
Just on Australia.
Would you PR the shorter cohort the Sigma cohort on its own or would you wait for the longer the 44 week cohort.
I don't think we've really planned out how we're going to disclose the data at this point in time.
Okay fair enough maybe.
Maybe then on extra hepatic you mentioned the full rollout of your extra hepatic program in early Q1, I think we've all been waiting for this a lot.
You've previously said you'd wait until 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 PR, how much of the data.
Present is going to be specific to a particular target versus more broadly on extra hepatic programs and technology could you just maybe give us a little color about.
What we should be looking forward you there sure I'll give you a little bit.
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.
Ah kind of Youre opening corporate presentation that will go into the therapeutic areas 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 our strong belief that these can provide excel.
<unk> efficacy in this area of unmet medical need and then we will present, our timeline to the clinic.
Alright sure. Thanks, I'll hop back in the queue. Thank you very much.
Thank you. Our next question comes from mining grew hard with Seb Leerink. You May proceed with your question.
Hey, guys. Thanks for taking the question.
I have two quick ones theres been a lot of debate amongst investors around.
Interest in R&R platforms broadly in business development.
Can you give a sense of how to think about that strategy. Obviously volatile is the dominant part of the story.
2019, and over the last couple of years become more more focused on your own internally wholly owned assets.
How do we think about that balance.
Out licensing and partnering assets.
That just took a smaller part of the story that was you don't need to support the balance sheet that way.
Yes. This is this is a really interesting question in 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 our collaboration strategy to build our <unk>.
<unk> abilities, and our balance sheet and we believe were very successful in doing so having been so successful doing so.
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 primarily galaxy liver targeted.
Technology that sort.
For the basis of almost all of that partnering to the Galaxy plus which we're.
Couldn't be populating, our own pipeline with going forward now.
Interest in R&D I partnering.
Her main preparing hi.
We're not being really responsive to the kinds of requests that we're getting but I think our NII has established itself as.
As a modality now with multiple approved products and pivotal data sets.
That show uniformly a clean safety profile and strong target specific reductions in protein levels, just really what you asked the technology to do and Thats 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 spaces.
Take lab space right.
Right now, we're very comfortable with our balance sheet.
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 are choose not to invest our own resources and going forward and probably stay away from the largest discovery collaborations that that we did in the past that's not a not a comment on the demand I can tell you farmers.
Is very eager on this technology, but it doesn't fit our strategy going forward.
Great a couple.
Thanks.
Thank you. Our next question comes from Luca <unk> with RBC capital You May proceed with your question.
Oh, great. Thanks, so much for taking my question. Congrats on all the progress I have two one on <unk> one on hepatitis B so on <unk> I.
I think youre, obviously dosing up to 12 milligram per kilogram of roughly 900 milligram, assuming the average weight in North America for adult this appears higher than the 200 milligram bid 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 correctly you mentioned that.
Youre anticipating data in 2023, and not 2022, so I'm wondering if you could expand a little bit more on that thanks. So much.
So for Bell Susser, and I think we have used pretty much the same dose escalation across all our programs from 0.1% to 12, and PK and the 12 and 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 have already selected a phase II dose for both us around and we're very pleased with the profile that it should generate based on modeling and simulation out of the phase one data I think it's important to note that.
Chronic dosing is not a single dose right. So you do get those sensitivity with a long duration of effect and that's something that you can model out.
As for differences there may be differences in the molecule potency up or down but it may be due to the fact, we do use different assays different assay then 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 III regimen in our ongoing phase two that we're dosing and expect that to be very successful trial.
Can you repeat the second question I didn't retained.
Yes, sure so corporate items be captured correctly, you were mentioning the next data update can be 2023, and apologies if I didn't capture correctly. So I'm wondering why we're not getting any data in 2022.
So the trials began enrolling last year and there was a 48 week.
Dosing period, and at 24 weeks about basically a year and a half we expect that the.
Given some guidance from Roche that at least some of the cohorts, we 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.
They provide one obviously, we'll we'll pass that on but otherwise it's just the time frame of this.
Trial to try to achieve functional cures.
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 a functional cure.
Super helpful. Thanks, So much Doug.
Thank you. Our next question comes from Stephen Willey with Stifel. You May proceed with your question.
Yes. Good morning, Thanks for taking my questions.
With maybe just wondering staying on HBV.
Doug you could maybe comment a little bit on I guess some of the.
Updated you answered data that we'll be seeing.
I know that they've presented there.
48 week.
Yes.
Stopping rule data.
The combo of <unk>, RNA and nucleoside analog looks to be pretty interesting and just wondering what that provides in terms of read through to you.
Our asset.
The Roche development program.
Yes, Steve Thanks for asking that question I thought that was Super Bowl.
That was exceeded my expectations for 48 week of <unk> in Nuc alone.
To have 20% of the patients achieved 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 include.
And there are two cohorts like that in our study with Roche, one with interferon and the other with <unk> in liver specific telos seven agonist.
It remains to be seen what sort of rebound youll have coming off drug I am a little skeptical that just suppression with SCR at Nee 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 with in a triple combination you can 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 <unk> against HBV could do.
So I really solve that is.
A harbinger I think of some really exciting data in the future from us in there.
Our colleagues in the industry.
That's helpful. Thank you and then.
Just with respect to Australia.
Can you remind me.
<unk> are not allowed to receive augmentation therapy in this study correct.
In the past history to talk about how thats going to work in our trial and in fact, we are just about to start allowing the inclusion of patients on augment patient therapy in Australia that will be part of the modification to the current protocol would be what we fully expect to enroll people on augmentation.
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.
So it was something that we decided because we know that that'll be a population of clear interest for.
For the product in the future.
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 can get a validated assay for that so with that coming online we can now adjust our enrollment.
Alright very helpful. Thanks, taking the questions.
Okay.
Thank you. Our next question comes from the local mortgage with Citigroup. You May proceed with your question.
Hi, Doug and team. Thanks for taking the questions. Doug can you help us understand a little bit better the path forward in ph two and ph three I'm. Just wondering if you were able to ascertain why the ph to results were inconsistent and as worldwide page three patients didn't meet statistical significance.
And more generally how do you plan to proceed with further development in ph to ph three will that become the responsibility of our future out licensing partner.
Thanks.
Sure This is Ed.
Something we have thought a lot about it was quite a surprise.
The drug was not effective in ph to on page three of the way. It was in ph. One we did assemble a group of Kols ended 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 has 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 are hard to test.
And or imply no role for and it does around for others.
They are testable within the context of our <unk> III open label study and potentially suggest a rule from the dos around and treatment and we do intend to pursue those hypotheses to see if we can develop a role for <unk>.
By certain adjustments I'm not going to go into the specifics of the hypothesis hypotheses, but suffice it to say we can explore them in the context of the current open label study.
We have patients with ph to MPS III rollover onto.
So.
As to the responsibility for us or the partner that will be part of the discussion with our commercialization partner, but we have a commitment to these patients and it has really been one of the really exciting parts of the program for us that we could address all patients with ph <unk> III. So to the extent, we can explore it and finance.
Three with credible hypotheses that suggested Wilfred.
We want to make sure that happens and we're moving to pursue them.
And can I just clarify for ph one the intention is to retain the rights for that population is that correct.
We are in the process of out licensing commercialization rights to dos around globally.
Okay. Okay.
I'll cover all indications so really it's the same.
It's call point patients presenting with very similar.
Symptom profiles, so there wouldn't be any distinction between out licensing page one two or three.
We are seeking a global commercialization partner well and discussions we look forward to making an announcement win win that is concluded but the interest has been quite strong with multiple parties.
Okay. Thanks, and then can I just ask a different question you've got an impressive number.
Burberry 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 Matt if you could just give us any sense as to what.
What we're working on there.
So it is quite broad the discovery programs under the Lilly and 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.
Clearly.
Collaboration programs and deliver us.
Tend to be focusing on cardiovascular, but also sort of cardio metabolic and Nash.
<unk> collaboration is sort of Nash in cardio metabolic oriented and so theres a broad number of programs using the galaxy technology that are like that.
Neuro degeneration 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 that are there as 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 RNA is particularly well suited.
Two that will rollout disc.
As discussed at the beginning of Q1, so there's a fair amount of breath there.
It's the 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'll shift to more Galaxy plus then galaxy.
And some of them will face attrition at the.
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 then.
Novo intends to take into the clinic.
Arnie I actually.
It's very easy and literally in about a month, we can generate a tool to do therapeutic activity work in animal models.
So out of Novo's <unk>.
Genetic biological discovery work they identified targets, we generate the tools.
There is 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 Ive noted there are 10 of those in the pipeline.
And that's what supports the sort of one 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 theyre going to be two years outright haven't entered development yet so.
So we don't expect very much attrition amongst that group of 10.
Amongst the 'twenty, though there will be attrition.
Thank you very much for the comprehensive answer.
Thank you. Our next question comes from your own Weber with Cowen You May proceed with your question.
Hi, Thank you very much for taking the question Brennan on for you Ron just a quick one for us on the Lilly collaboration is actually so I mean, given that there are a couple of different compounds that they are targeting <unk> three <unk> LP little a.
Was just wondering first what youre able to tell us about I guess mechanism action or even the target sequence for your crop pounds that really sets us 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.
Thanks very much.
So.
I don't think I can comment on specific ULA sequences.
As.
Some folks may recognize.
RTI has very robust there are 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 dunno scuffled, it sort of goes on around around sequences.
And we certainly believe we've identified things that are very active and have FTE.
People may recall that it was sequence IP against the Hai one gene that led to our owning a royalty on the ox limo product we.
We believe we are avoiding that situation with the sequences, we are using an LTA and ancillary 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'm led to believe that things they take into phase II. They just tend to present the phase one data.
Yeah.
I look forward to that coming to pass.
Okay. Thanks very much.
Thank you. Our next question comes from Ed Arce with H C. Wainwright you May proceed with your question.
Hi, Good morning, everyone business kind of your best guess couple of questions.
Okay.
So can you share some thoughts on the competitive mix.
The second entry.
Th. One then also thank you.
Over.
The telescope interaction with the FDA.
The NDA filing.
Sure I'll take the first part of that and then with respect.
Our actual Passover to Sri to answer to answer that question. So there is a lot of unmet medical need in ph, one and there are many patients both in the U S and ex U S that have yet to be diagnosed so we expect the patient.
Universe to be growing.
Doses increases we believe our monthly.
<unk> administered.
Pre filled syringe dosing regimen provides particularly convenient and empowering dosing regimen for patients.
Our.
Customer research so to speak.
Believe shows to be something that is highly desired. So we think combined with the data that we have in ph. One there is a pretty compelling rationale for people to choose the dose around who are freshly diagnosed when it comes to patients that are currently diagnosed of course many of those are in the process or have already gone on ox Lou mow the data for <unk>.
<unk> 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 online Shlomo.
It's fairly unlikely youll see the switch in that case based on convenience alone.
So.
I think that's really how the landscape.
Plays out and to the extent, we really are having a lot of interest in that program for a commercial out licensing I think that story is resonating.
With the commercialization potential commercialization partners.
Do you want to talk about our interactions with the FDA yeah. Thanks, Doug.
So as you know in August we revised our strategy to focus on seeking approval for and that also ran for the treatment of ph one.
We believe that the potential approval is supported by our clinical data package.
That consists primarily of the data from <unk> two in which as you know it also achieved strong statistical significance for efficacy in ph one.
Subject to our ongoing discussions with the FDA, we intend to submit additional efficacy data from our open label extension study <unk> III.
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 of this year.
Okay.
Okay got it thanks.
Okay.
Thank you the additional details.
That's another question.
From us for PCR in UK.
Okay. Just wondering can you share some initial thoughts on possible efficacy endpoints for phase.
Yes.
So the nature of the way <unk> works is it provides physiological feedback to patients who are consume alcohol.
When they are in the process with treatment to help themselves limit their alcohol consumption.
So the really relevant endpoint is what we would call harm reduction endpoint.
It 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 D. C are working at the level of providing feedback for those who get into their cravings.
One where you would expect to see fewer days of heavy drink.
So the reduction in heavy drinking days also sort of as I said notice of harm reduction endpoint is what we will be tracking in phase two and what we expect will likely be the regulatory endpoint for approval in the U S and Europe.
Okay.
Got it.
One quick one.
The cash runway.
Thanks.
Sure Patrick program.
Yes. It does include the preclinical programs that we will announce as well as all of everything thats 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.
Got it.
Thank you, Okay, let's get our questions, we look forward to be a fair way.
Thanks, Rob.
Sure.
Thank you. Our next question comes from Madhu Kumar with Goldman Sachs. You May proceed with your question.
Good morning, everyone. So thinking about alpha one antitrypsin Z 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.
Hi, <unk>.
I mean, 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 <unk>.
<unk> hepatic encephalopathy lethal that were transplant patients 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 and deliver results.
Restoration of hepatic homeostasis in the return.
The reduction in progression or reversal of some of the injury.
We'll be predictive of the clinical outcomes with the primary basis is going to be on the basis of the improvements in liver function histology and other markers.
Yeah sure so on that point how yep.
Do you think about the variability and liver fibrosis in Z E T patients and how much like the kind of more biochemical type parameters things like the polymer formation. The globule deposition are going to be kind of more useful surrogates compared to fibrosis histology as such.
<unk> per se.
Yes, I mean, I know you follow the match literature. So we know that the hard endpoint of at scores and changes in those with high placebo responses are a challenge so I actually fully expect and Thats. How estrella has been designed that it would be the concordance movement in a beneficial direction.
For a variety of Biomarkers that include both the.
Soluble once they do describe histological ones like reductions in globule.
<unk> inflammation reductions in liver enzymes and a imaging biomarker like we are using MRI as an option as well as fiber scan to look at sort of overarching what's happening and deliver as a whole.
Reductions in fibrosis or tissue resistant 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.
Okay, and then one last one and then it goes to an NDA submission. So you maintain kind of pending ongoing pre NDA interactions with the FDA is there any specific issue that's been raised is.
Part of the kind of pre NDA discussions or is it just kind of like standard processes.
The NDA filing.
Well I mean look you know the process side, we got our ph one data they were very strong as part of our normal routine we engage with the division for the.
The discussions are 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 have already collected.
And that's.
That's the sort of active process thats ongoing right now.
Okay. Thank you so much everyone.
Thank you. Our next question comes from my Yang from Antonio with B Riley Securities. You May proceed with your question.
Hi, This is Andrew.
Congratulations on the progress seen in the last call Kurt. Thank you we will take our questions just a follow up on the HPV infections understand the exact target team positioning the HBV genome is different can you remind us your target and on a potential different the impact you would expect.
Versus Johnson's program. Thank you.
Sure. Thanks for bringing this difference up there is some molecular differentiation between our approach and the approach of the program that Johnson is developing.
So as I think many people who are deep in HBV recognize there are forgings in the HBV genome three of which are structural and one of it is regulatory and the way the jeans overlap and the transcripts for the genes map out.
One has the option of trying to hit all four at the same time.
We're hitting three out of before and of course, we evaluated that during our development beyond <unk> program. It's three out of the four as I understand it using two <unk> and a ratio that hasnt been.
Disclose to my knowledge, whereas we use a single one that targets three out of the floor. 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.
There are techniques that you can do to generate viral replication.
In mice.
On an active ongoing infection, but viral rapid replication intracellular Lee and.
Saw a distinct difference between three versus four genes depression.
Based on.
The status of this one the sports regulatory only protein and when you don't silence. It and you have an over abundance of that regulatory protein in the mouse model. It led to a longer duration suppression of S.
And the 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 takes care of very very effectively.
We.
Say, we didn't see as dramatic of a difference in our phase one human studies single dose.
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 balanced model shows.
And the 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.
It's maybe a subtle difference at the margins or it may be an important difference.
We will see when it comes down to a functional cure rates in the phase two 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 are getting three versus four and having a relative overabundance of that regulatory protein.
In order to maximize the chance of that.
Patients immune system mounting a successful response against the virus, which we think is critical for the ultimate functional cure and true truly eliminating the virus from the body.
Yes. Thanks for the helpful color understand Neil is very important as the part of the combination just want to assure you I'll call them fast.
You could add another part another arm of <unk> therapy to E.
Tom will share with you how what would be ideal want to generate more synergies. Thank you.
The ideal third combination partner alongside <unk> in Nuc is an immune system activator.
To help refresh the exhausted immune response 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 prove a small number of patients.
But we believe that with an S irna, particularly given its suppression of S. You can really drive that number up.
So.
I think thats the way to go there too.
Triple combination cohorts like that in the clinical program that Roche is pursuing with RG 63461, with peg interferon Pegasus of course their longtime interferon product.
The second with there in development liver activated T <unk> seven agonist.
Yes, thanks for the color. Thank you.
Okay.
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.
Thanks, everyone for paying attention today and all your questions. We're in a really strong position financially when our strong position with our technology and our pipeline with some really exciting stuff coming.
So I feel really good about our prospects here. Thanks, a lot bye bye.
Yeah.
Thank you. This concludes today's conference call. Thank you for participating you may now disconnect.
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