Q4 2020 Dicerna Pharmaceuticals Inc Earnings Call

Okay.

Ladies and gentlemen, thank you for standing by and welcome to it and he started now pharmaceuticals full year 'twenty and 'twenty earnings Conference call. As a reminder, the sponge for inches to being recorded at the company's request.

I will now turn the call over to your host Ms. Laurie and Stifel Senior director of Investor Relations at least right now. Please go ahead.

Thank you operator, good afternoon, everyone and thank you for joining us to review day for and its full year, 'twenty and 'twenty financial results and operational highlights.

For anyone who hasn't yet had a chance to review our results we issued a press release after the close of trading today, which is available under the investors and media tab on our website and I certainly.

On Dot com.

And also listen to this conference call via webcast on our website, which will be archived beginning approximately two hours after the call and complete it.

On today's call will be director and as President and CEO, Doug Fambrough, Who'll review, our 'twenty and 'twenty progress and provide updates on our collaboration agreements and introduce our newest internal development program, our Chief Medical Officer, Sriram, Marathi and well discuss upcoming clinical regulatory milestones and our Chief Financial Officer, Doug Pagan will review our full year.

For 'twenty and 'twenty financials, and we also have Jim Weissman, our Chief operating officer, Bob Sharp and Alley, our Chief commercial officer, and Bob Brown, Our Chief Scientific officer available today to address questions during the Q&A session.

Our remarks, we will open the lineup for your questions.

I'd like to remind listeners that management may make forward looking statements on today's call pertaining to the company's financing business and operations, including the discovery development and commercialization of our product candidates and technology platform and the therapeutic potential out there of the success of our collaboration and any potential future.

Collaboration.

Such forward looking statements are subject to risks and uncertainties and could cause actual results to differ materially from those expressed or implied and specialty.

For risks and uncertainties include those relating to our preclinical research and clinical programs and other risks identified under the heading risk factors, including our most recent form 10-Q, and form 10-K, which will be filed with the SEC on this call.

While we may elect to update these forward looking statements at some point and the future and spin.

Particularly disclaim any obligation to do show and hard and change now I'd like to turn the call over to Doug Fambrough, They serve as president and CEO Doug.

Thank you Laura good afternoon, everyone and thank you for joining us 'twenty and 'twenty was a year of success and maturation for dice sirna.

A year of multiple clinical and collaborative successes.

On completion of enrollment and the.

First pivotal trial, a trial that will set the stage for our first NDA submission as a company later this year.

Acceptance were matched by strong momentum behind our pipeline building and discuss.

Research efforts for which we presented for the first time data supporting expansion and the multiple new tissues beyond the liver, which on what multiple potential new disease areas for future pipeline growth looking forward, we'd be 'twenty 'twenty, one as a year of accelerated pipeline growth as well as corporate maturation towards.

Our goal to emerge as a fully integrated commercial entity in 'twenty and 'twenty two.

As a part of our internal pipeline growth efforts, which will be a key area of focus for us and in coming years, we announced today our for internal development program for alcohol use disorder, which is expected to enter the clinic and the third quarter of this year.

$568 million and cash and marketable securities as of December 31, 2020 and.

And a strong payment stream from Orange.

And collaborations and the potential to access.

On the sources of capital, including monetization of our royalty stream and we own on a non banks or on a product and our planned ex U.

S commercial partnership for and it does.

And then.

We have the resources to fund our steady growth trajectory, including the planned launch of net.

And next year.

And so it is that our successes in 'twenty and 'twenty has set us up for an exciting new developments and the coming years.

Some of the most notable of these successes were the positive interim clinical data Readouts first from our open label <unk> III extension trial.

Which carries the essentially the same enrollment criteria and monthly treatment regimen and sorry.

And it all fine ox to clinical trial as a reminder, we saw 100% of the H one patients for each normal urinary oxalate measures at one or more time points and that interim analysis by up to 370% at home and at least three consecutive normal measurements.

With an overall being urinary oxalate and across all ph one ph two patients at day 180 of point for 4 million mould body surface area per day.

And the normal range as defined by the study protocol. We are pleased with it just for rents overall profile to date and class III, particularly within the ph type one population.

Also observed and steady strong activity and ph type two patients with two or three patients reaching normalization at one and more time points and learned a dose range has the potential to be the only RNA therapeutic option and <unk>.

We believe these data and exceeds the bar, we need to hit in order to have a highly competitive product of course as well and we believe we have the potential for best in class profile for treating all three types of ph.

Look forward to top line data from the pivotal for <unk> two trial.

Sure.

As it relates to page three we have initiated our science for single dose study and anticipate data around midyear.

Our plan still remains to include buy X for Dana and early data from our natural history study and.

Our NDA submission and pursuit of an accelerated approval for.

Ph to impeach three remain unaddressed with current therapies and we plan to seek priority review pending data and the first to address the need for these patients.

In addition to our positive Mendoza and data for for.

And the biopsy study, we presented exciting new phase, one and preliminary efficacy data for RG six three for six and a study and patients with chronic hepatitis b infection.

RG six three for six is our proprietary galaxy molecule that knocks down specific genes expressed by the hepatitis B virus, most notably hepatitis B surface antigen. These data were first presented at our R&D day in August and additional follow up data were presented at the 2028 day S. L. P.

Scientific conference in November and showing that treatment with multiple doses of RG six three and four six and do see deep and sustained mean production on hepatitis b surface antigen for up to one year. After the last dose the main treatment period for our first three cohorts on the study concluded some time ago, but this stuff.

And he continues and its extended follow up period for patients with at least one log or greater reduction.

H B S antigen from baseline levels.

We are excited by the long duration of H B S antigen suppression induced by RG six three for six and nucleoside suppressed HBV patients observed for the phase one studies and <unk> six three for six has potential to be complementary.

And with other existing and emerging HBV treatment, our collaboration partner Roche will be including RG six three for six in their phase II adaptive design trial expected to initiate this quarter to assess multiple therapeutic combinations, including different mechanisms with the net.

And that's a fine treatment regimens with the potential to deliver a functional cure and we are optimistic about <unk> six three for six as potential as a backbone component of future functional cure combination treatment regimen and.

As a reminder.

China has the right to opt in to co fund development at the initiation of phase III and highly enhanced economics, and the United States and the potential to co promote and the U S as well.

Also in 2020, we presented what we're calling our galaxy plus technology, which extends our R&D capabilities to tissues beyond the liver, including the central nervous system muscle tissue and adipose tissue.

And although we haven't presented data publicly yet and we're having success and other tissues beyond that and including tumor associated immune cells and we look forward to rolling out new proprietary pipeline programs that utilize galaxy plus focused on targets that we believe have a high probability of achieving clinical success and for which we believe our and.

And I will be the preferred treatment modality.

Now before I turn the call over to Sri to discuss our upcoming clinical and regulatory milestones.

I'd like to take a few minutes and introduce our next wholly owned clinical candidates and development program for <unk> for the treatment of alcohol use disorder for this program targets, a broad and diverse addressable population that has been highly underserved by current pharmaceutical intervention, we believe orange.

And on and unique constellation of features on the on potentially brands, including long duration simple administration high target specificity and an excellent safety profile has the potential to be a game changer for the treatment of alcohol use disorder.

<unk> is also a departure from our work and focus to date consistent with our belief that arent and I can be a large market and technology, especially when routed and the science of validated human genomic targets.

Our <unk> program is a perfect reflection of this where the target is aldehyde dehydrogenase, two for ALC H two H.

<unk> II is a key liver enzymes involved and the metabolic breakdown pathway and alcohol.

And people is perfectly healthy lives worldwide and carrying naturally occurring <unk> loss of function mutations.

These mutations cause alcohol and tolerance and on <unk>.

Rising labor rates and alcohol use disorder amongst this population are incredibly low when.

When used as energy and adjunct to behavioral therapy, we believe that our liver specific TCR.

And could result in substantial improvement and treatment outcomes for AEP with the profile that may be attractive to those health care providers and people with AUC and which could be highly differentiated from any current treatment option.

Historically this has been a challenging market and we're well aware that historically there has never been a treatment option for AEG and delivers good efficacy with no side effects and with a long duration of action and are simple administration, which we believe we will achieve with D. C. Our AUT like multiple other markets. It takes the right product.

And we believe <unk> is.

Is the right product for AEP.

We're excited by the prospect of <unk> as a first line pharmacotherapy that is complementary to and to be used in conjunction with behavioral and other approaches to help people with AUT reach their treatment goals.

I will not let Sri touch on the program and more detail and then he will also outline our upcoming clinical and regulatory milestones for 2021 and.

Providing EPS, even deeper and look at our <unk> <unk> program will be hosting a live webinar and next month, so look out for that analysis.

<unk>.

Thank you Doug and thank you all for joining us.

Alcohol use disorder is a complex behavioral disorder with huge unmet needs and it.

It is a chronic disorder that is associated with a range of medical and psychological social economic and personal problems and it was.

And one of the leading causes of preventable death, and the United States.

And is estimated at $14 million adults from the U S experienced.

And unfortunately, often goes undiagnosed and untreated and parks due to limited treatment options and willingness to engage and treatments.

And that it is estimated that fewer than 10% of adults and the U S with AIG CTO for treatment and that is similarly low percentage of those treated.

Actually receive pharmacotherapy.

Available treatments have generally shown only a modest treatment benefit and the introduction of products and drinking levels or maintenance of estimates with poor patient compliance being a contributing factor.

The best way to AUT recovery is a highly individual experience and each person's Jeremy is unique.

We see a critical need and opportunity for increased targeted easy to use pharmaceutical therapy that can be combined with behavioral interventions to help individuals to meet their treatment goals, including reduction in pumps and levels of drinking and our estimates.

Empirically LDH to head for cycles experienced alcohol and tolerance at multiple levels of alcohol and intrigue and overall lower prevalence of alcohol misuse compared with uninfected individuals.

Using galaxy technology <unk> is designed to deliver liver specific knockdown of LDH too.

And given the tolerance of alcohol and moderate the mouse. This approach for us from older small molecule therapies that resulted in a non specific ambition of aldehyde dehydrogenase enzyme activity and other biological processes and the volume.

And preclinical mouse models and liver specific milestone knockdown of the <unk>, two gene and Houston intermediate alcohol and totaled and phenotype and appears to correlate with reduction and heavy alcohol index.

In general, we envision and <unk> will provide a functional guardrail.

Real time physiological feedback that may help boost <unk>.

Avoid harmful levels of alcohol intake and give them the time and space they need to pursue day recovery.

With the safety profile of our Galaxy platform shown and our other development programs to date, including monthly or even less frequent dosing and liver specific target knockdown and we believe <unk> could be a mobile convenient and safe approach to treating <unk> that may expand the reach of pharmacologic.

Apparently do many more people who could benefit from it.

We plan to file an IND for <unk> midyear and into the clinic shortly thereafter.

Our phase one study plans to enroll healthy volunteers and was included for assessment of logos alcohol interactions confirmed pharmacodynamics.

And the target profile that is consistent with preclinical models of liver specific LDH to lockdown and.

And the observed alcohol interaction and humans with naturally occurring <unk> deficiency.

We have confidence that our approach will generate important golden level information for all.

And our phase one program that will be directly translatable to ABB.

We're very enthusiastic about this new program and plan to close on additional calls with our guests therapeutic expert so for Henry counselor weaker and March to discuss the VCR and more detail.

Moving on initial study plans and the challenges of treating and youll be and its human and societal costs and importantly, the opportunities for improvement and what is a complex treatment landscape for ABB.

Both the credit limits and professor of Psychiatry, and director of the center for studies of addiction, That'd be University of Pennsylvania's Perelman school of Medicine and.

Our research focuses on the genetics and pharmacological treatment of substance dependence with a particular emphasis on precision addiction medicine, and we're very excited that he has agreed to join us to discuss our efforts in developing this year.

And for alcohol use disorder.

Now I'll take a moment to update you on our alpha one antitrypsin deficiency associated liver disease program.

As many of you know placer.

As a reminder, while and entered into an agreement last April to collaborate on our phase one clinical candidates in development.

At the outset of 2021 and careful evaluation of all data to date for both programs.

We announced that we have selected the buy sort of a molecule bill tessera for further development of the phase II.

Both molecules, where well designed and demonstrated competitive target knockdown on the <unk> protein, but ultimately we chose vocera.

We plan to release initial interim phase one data sometime mid year and additional results from an appropriate medical meeting later in 2021.

It was <unk> deficiency associated liver disease or <unk>.

And is caused by the production of abnormal protein by the <unk> of the surf and <unk> and may lead to chronic liver disease, culminating and cirrhosis liver failure or cancer.

No treatments exist for <unk> other than liver transplantation.

And is estimated at 120000 individuals and Europe, and 63000 individuals and the U S carriers as easy genotype with debt.

About 10% are diagnosed with <unk>, representing a significant opportunity for increased identification and diagnosis and treatment of individuals with this disease.

We are on track to initiate our phase II study and patients and the first half of this year.

This is a multiple dose randomized placebo controlled double blind study of compressor and to evaluate the safety Tolerability, PK and PD and adult patients with <unk>.

And.

The study will comparable for us around the placebo and parallel cohorts of six and 12 months and duration as.

Part of this trial will evaluate share.

Histology and a variety of exploratory biomarkers to assess the effects of the assessor and on AAC liver disease activity.

And we will be discussing with regulators the ultimate endpoint for pivotal trial based on the data collected from our phase II study.

Finally for the dossier and as Jeff mentioned, we are on track to receive felt line based on mid year or on and also have a pivotal trial for which we will be looking to achieve our primary endpoint demonstrating a greater percentage reduction in urinary oxalate from baselines and the doctor and versus placebo based on the reduction in 'twenty for you ask for.

Baseline using an area under the curve between day might be and day 180.

Our ongoing open label extension study has shown promising data to date and both ph one ph two patients where we saw a 70% mean maximal reduction in urinary oxalate at day 180 for all patients and the study.

As part of our overall filed for development program. We have also begun building and our clients for single dose trial of <unk> and it also room to evaluate safety Tolerability and PK PD and patients with ph three.

Our goal is to demonstrate substantial reduction of urinary obsolete and these participants and includes these data along with early data from our natural history study and phase III is our NDA submission planned for the third quarter and support of a potential accelerated approval and ph suite.

And as the most recently diagnosed for MS ph and this is known for data both disease progression and wealth of infections and disease. So we expect the additional work moving needed portfolio.

We also plan to initiate the <unk> seven trial and patients with ph, one ph to and end stage renal disease, and the playoffs, HOS ultimate author and and each of zero for six in the first half of this year.

While we see them and lumpy available for inclusion and our initial NDA submission. This year, we plan to submit supplemental filings expeditiously. Following the conclusion of this expense.

I'd now like to turn the call back over to debt volume growth to touch on progress across our various pharma collaboration.

Thanks Sri.

We continue to make excellent headway across our collaborative programs. This is it.

And other means by which we are expanding our pipeline and expanding the reach of RNA on across therapeutic areas.

Our collaboration with Lilly continues to progress and the fourth quarter of last year and they kicked off their first phase one study using debt service Galaxy technology targeting <unk> three for the treatment of Dyslipidemia. This.

And this year, we anticipate and additional IND filing and the second quarter targeting lipoprotein or LP day for the treatment of cardiovascular diseases and edition. We have received formal notification from Lilly that they plan to expand the initial research collaborations term, which is excellent news and speaks to the promise of our RNA <unk>.

<unk>.

A third clinical candidate has been declared and the collaboration and is in preclinical development and we're optimistic for the potential of multiple additional development programs beyond these first three including both liver targeted and neuro degenerative diseases pain targeted program.

Our development work for Alexia on is continuing as planned and we are pleased to disclose that the first two galaxy candidates are targeting C. III and complement factor b, because we disclosed at the outset of for the year, we anticipate delivering and supporting packages to Alexia on and the fourth quarter of 2021 and and the.

First quarter of 2022, respectively, after which alexia on will be responsible for and the IND or Cta filings and accordance with our agreement.

We have also made rapid progress with our partner and Novo Nordisk, Although we don't anticipate and initiation of clinical trials. This year for a candidate under the Novo collaboration for.

Tremendous amount of work has already been done and what is a highly collaborative partnership and we look forward to additional target selections and clinical candidates selections beyond the first clinical candidate we announced at the beginning of the year.

Like the Roche agreement. This is a collaboration and which we maintain opt in rights to co fund development. After Novo has de risked a candidate and phase one or phase two development.

This represents a substantial economic upside potential for a nicer.

And with that I'd like to turn the call over to our CFO for gone to cover financials and Doug.

Thanks, Doug.

I'd like to briefly walk through the key financial results for the full year 2020 and directly to our press release outlining the financial results, which was issued today.

And to our annual report on form 10-K, which will be issued following this call.

Net loss for the full year of 2020 was $112 $7 million for.

For $1 52 per share compared to a $125 million for $1 70, 676 per share for full year 2019.

Revenues for the full year, 2020 totaled $164 $3 million compared to $23 $9 million and 2019.

The year over year increase and revenue recognized is primarily attributable to increased activities and associated costs under the various collaboration agreement.

As of December 31, 2020, we had approximately $138 5 million.

Current and deferred revenue, which we expect to be recognized over the next 12 months and approximately $336 2 million of non current deferred revenue.

We expect it to be recognized over the following several years.

Full year, R&D expense totaled $205 $4 million, and 2020 compared to $109 $3 million and 2019.

The year over year increase was primarily driven by a $54 8 million increase from direct external research and development expenses.

And $32 $9 million increase and employee related expenses, which include salaries benefits and stock based compensation as we increased headcount to support our expanding pipeline.

Full year, G&A expense totaled $72 $1 million, and 2020 compared to $42 8 million and <unk>.

And 19.

The increase was primarily due to a $26 million increase and employee related expense as we increased headcount to support our growing operations.

As well as a $6 million increase in professional and professional consulting services.

We expect operating expense to increase in the coming quarters as we continue to grow head count to accommodate additional R&D activities and launch readiness as well as from higher external spend associated with increased activities and the pipeline.

During Q4, 2020, we received $17 5 million and milestone and reimbursement payments from our collaboration partners.

We continue to project, receiving over $100 million and collaborative payments and fee for the five quarter period from Q4 2020 through Q4 2021.

And therefore and anticipate receiving over $83 million from our existing collaboration for the full year 2021.

These payments represent an important source of proceeds and.

And demonstrates the value of these collaborative and collaboration programs should continue to generate and has been mature.

As of December 31, 2020, we had $568 8 million and cash cash equivalents and held for maturity investments compared to $348 9 million as of December 31, and 2019.

Maintaining a strong balance sheet will be of Paramount importance as we plan to submit our NDA on a dose range in the third quarter and.

And prepare for a potential 2022 commercial launch.

During 2021, and we anticipate cash receipts from existing collaborations will be supplemented by other potential sources of funding, including for example proceeds from our planned ex U S commercial partnership for and the dose range.

And possibly possible for royalty monetization with.

With the object with the objective of maintaining the balance sheet strength with which we started the current year.

That concludes my review of the financials I would now like to open the call up for questions operator.

Thank you and as a reminder, if you want to ask a question just press Star and then the number one on your telephone and again this press star and then the number one on your telephone keypad and so we draw your question press the pound key please standby, while we compile the Q&A roster.

Yes.

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

Hi, guys. Thanks, so much for taking the question and congrats on all the progress in 2020, when you looked at all like that it really does look very impressive.

I'll start with alcohol use disorder, obviously, a huge indication, but as you mentioned Doug for challenging to penetrate in the past are you thinking of sub populations that are more amenable to treatment here do you have any view so far on the sorts of endpoints that are more most relevant how well established as the regulatory path moving forward. There. If you could just give us a little more color about.

How development and that your day is going to look.

And then secondly.

Given that <unk>, two and three year sort of less well understood and known.

What else is developing that market. How are you thinking of commercialization in those indications as opposed to ph one just in terms of what the.

Ramp and amount of effort is going to take to get there is going to be.

Thanks, Jonathan do you put a lot on the table there.

Answer some of the questions now and I think we'll go into more detail on March.

With Doctor Kranzler, but to start with you asked about sub populations and AUC and this is a very diverse indications with millions of people who have alcohol use disorder. So indeed, we are thinking about particular populations that are most applicable, but we do think.

And that all levels of severity of AEP are potentially addressable with TCR AED.

It will be focused and I'm not going to get much detail beyond that.

And you asked about endpoints and harm reduction is really critical here and there has been some evolution and endpoints and AEG, particularly starting in Europe, and and certainly something that we're seeing and the FDA as well and.

And the move to thinking about harm reduction, which we think is the right metric and one that is particularly applicable to our mechanism of action thereof is there another element there.

For us.

And the other element on John.

Got it.

So with respect to commercializing and ph two and ph three.

And really view this as a singular commercialization effort.

H patient community and has historically not been differentiate and into these types.

It's really only the advent of ph one specific therapy that causes there to be any cleaning of the population.

So we do see a debt at the same effort my colleague Rob <unk>, Our Chief commercial officer is on the line Rob is there anything you'd like to add on that.

Yes, Thanks, Doug appreciate the question Jonathan and.

Hey, Doug hit it spot on it is the overall ph market and when you think of it think about how nascent.

The overall market is the state of the science there is tremendous amount of education that needs to be done here for <unk>.

<unk> subtype and appropriate diagnosis and support through genetic testing are also key factors that's going to help.

Physicians and the only become aware of this disease, but also make that differential diagnosis because these patients have a relatively long patient journey for there.

Moving.

And finally diagnosed with ph and soon hopefully we will have an option for all ph patients during the dose range, but we still have to finish the buyback program and see how that goes.

Thanks, so much guys.

Thank you. Our next question comes from the line of BRL and wherever.

And from Calvin Sir your line is open.

Hi, Congrats on the team on all the progress and thanks very much for taking the question. This is Brendan on for you Ron just a couple of quick ones from us on HBV here, what can you tell us I guess about the potential combo treatments for this phase II that youre discussing from Roche and.

Maybe how it has kind of reflected and the current treatment option for patients is the thinking really to target a specific line of therapy for commercial uptake or more to kind of provide optionality and like a pivotal trial and the potential label. Thanks very much.

Hi, Brendan.

The combination trials that Roche will be kicking off are really designed to identify the combination that yields for the highest functional cure rates and so I would call. It exploratory as what the ideal combination is we have some.

And some expectations for the course of the data and we'll have to rule as it always does and clinical development. So Roche has identified that they will be initiating and near term combinations of RG six three for six alongside their nuc therapy and <unk>.

Combination with CLR seven agonist.

Also in combination with their core inhibitor and their CPAP and also in combination with <unk> peg interferon products for three different triple combinations and we'll also be looking at extended dosing at two different dose levels of the.

Our RNA on.

The nukes. So that's five treatment cohorts that they've identified so far that that will be initiating in the near term and and it gets really a horse race to see which gives the highest rate of functional cure.

Okay, great. Thanks very much.

Thank you. Our next question comes from the line of money for <unk> from SVP Leerink, Sir Your line is open.

Hey, good afternoon, and this is Rick on the line from Mani Thanks for taking our questions and so.

On the first one is on <unk>.

Alright, and then given the preclinical data that have been generated to date for the assets I was hoping you could provide some details regarding the level of LDH.

<unk> knockdown and you'll be looking to reach to produce the therapeutic effects.

And you have knocked down that you are looking for and the.

And.

And potentially the dosing schedule for the target product profile.

Sure. So of course this is.

Gal Mac.

And interacted liver specific RNA molecule and the class of <unk> and Bluebird RNA molecules has a very consistent potency and pharmacodynamics.

Our seeking maximum on suppression of the <unk>, two gene and the liver and and.

We have seen reproducible Lee with different molecules targeting.

Different genes that we can achieve well over 90%, 95% production essentially silencing completely the target gene and deliver so we will be seeking to do that similarly, you see and extended duration of effect for RNA on with the pharmacodynamic effects lasting multiple months.

And it's usually peaking on the order of for weeks or so after the initial administration and then maintaining a very high level of knockdown for several months and then slowly be kang of for several months beyond that.

We are not at this point targeting a particular dosing regimen, but that's something we'll be exploring more deeply both with respect to what is most appropriate and the market and as well as what we think how we see the molecule performing it maybe quarterly it may make more sense to go with a monthly administration.

Administration, because as <unk> and <unk>.

<unk> nature, and small doses associated and if that will go up that will have to emerge and turning the program and any event and we do anticipate very high levels of knockdown and the extended duration of effect one has come from associated with RNA line.

Got it that's helpful and I did have an additional question about the Alpha one Antitrypsin study.

I was hoping that maybe you could elaborate on some of the endpoints and Youre planning to present for the interim readout could we expect to see the degree of debt.

And the reduction of.

And if your polymer total.

Burden or any other potential metrics for overall liver health.

True would you like to talk about it went on.

Yes sure Doug.

So as you can imagine our goal is to look at for US beginning with reductions and certainly wanted to zero in on 18.

But the focus of course is on understanding the effects of the emphasis on whats happening and the liver so.

We'll be looking at planning to look at.

Measuring protein and November.

And we'll be looking at histology using traditional screens and.

And just looking at for Colombia distributions and the evidence of information on what's happening and diagnosis and.

And in addition, we will include a series of serum Biomarkers.

We've been altogether.

And to identify and opportunity for coming up with potentially.

For that companies use.

Assess impact on surface and I don't remember.

In addition, we will include imaging biomarkers using.

Bedroom.

Business, if you will.

Like MRI elastography as well as five years guidance.

Typical combinations of.

Both <unk> and noninvasive imaging and serum biomarkers and assess where disease activity.

And those six months and 12 months.

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

Thanks.

Thank you. Our next question comes from the line of Luca IC from.

RBC capital Sir your line is open.

Terrific. Thanks, so much for taking my question and congrats on all the progress and the great.

Maybe the first on ph three.

Mentioned and Youre planning to include ph, three as part and the dose for an NDA package my understanding and for fireworks for is actually fairly small I think it's only six patients. There. So I'm wondering what gives you confidence.

Such data could be sufficient for approval and then maybe for the cardio metabolic you mentioned and three as well as LP Little a obviously multiple companies and Ms Stacy or arrowhead.

Silence therapeutics at a bunch of others. So I think you did a great job and differentiator for primary Hyperoxaluria. How are you thinking about differentiation for <unk> III and I'll feel like thank you.

So we want to start on th sales.

So it will be indeed filed for is a single dose study.

And six subjects.

Two 9% to fix.

But is there any debt will have a placebo control. So our goal there is to convincingly demonstrate that we are able to.

Lower urinary oxalate.

And the endpoint as you recall is a 30% reduction on two consecutive visits for months apart.

And that would be the force evidenced and also on Ken Miller and the auction.

And PHP and the disease.

And we show meaningful reductions in urinary oxalate and knowing that.

Mechanistically builds and importance of lowering oxalate as the primary source of renal injury.

Our arguments for and accelerated approval will be based on combining the results. You'll also production with data that is available from the literature that is now emerging showing that BHP carries risks still rates as well as unit and sufficiency that was previously unrecognized.

But these are things that we still need to discuss and will really depend upon.

And.

The magnitude of effect, we demonstrated and <unk> four and it will then need to serve as the basis for potential accelerated approval with the recognition that additional work will be necessary. Both from our ongoing natural history study as well as and the additional commitments to follow on subjects longer term to see impact on clinical outcomes.

But I think the key messages that we would expect this to be.

For discussion with and.

And potential accelerated plan for fall.

So luca with respect to the cardiovascular targets. We obviously made the decision several years ago to seek good development partner and to pursue those and there were a number of issues on our mind, when we decided not to pursue them on our own.

They include the fact that there are other modalities that are more advanced and developments.

Targeting these types of targets.

Current drugs on the market to the patients are off and on colleagues therapy and manage that these are constant and large populations for very large sales forces differentiation I think is challenging and probably at the margins of the clinical data and to generate that requires large law.

Long and expensive trials and.

And rare populations have.

And they have special needs, but there has been the history of those markets not enjoying for rare disease economics, because they've been undercut on the larger population products. So that it may be that one can successfully navigate the complex environment, but we made the choice several years ago that really is.

Establishing strong player like Lilly will be far more capable of navigating those water. So we really left it to Lilly with respect to the mechanism RNA turns off a transcript and the liver. So if youre using gallon that targeted RNA I E, they're sort of growth.

And I answered and that you're going to be achieving a very strong level of silencing with the pharmacodynamics. We described.

And the absence of using a different target for example.

There are.

Really arent good avenues for mechanistic differentiation, and it's really going to be execution differentiation and as I mentioned and that that's something where I think scale is it.

Huge benefit.

And that's not scale is not what we bring to the day as our core confidence so.

<unk>.

Our friends at Lilly I think are going to do a good job on this.

Terrific. Thank you so much.

Thank you. Our next question comes from the line of Steven <unk> from Stifel. Sir Your line is open.

Yes, good afternoon, thanks for taking the questions.

Just a quick question on the.

Hey, you day program is so.

And I know, we talked a little bit about the development plan and we're going to get some more color presumably at the webinar next month.

Is this a program that you feel you can independently take across the finish line from a regulatory perspectives and.

And then I know, it's a little bit of kind of a specialty niche market is is this something for which you have commercial aspirations.

Yes, that's a good question, Steve and it does.

What's the old saying on future.

Predictions are difficult, particularly about the future I certainly think that we are growing to a scale, where we can push this across the regulatory finish line on our hot weather and whether we choose to or not.

And that will have to face, but I think it's certainly within our capabilities.

Thank the most effective marketing and product probably will be beyond something that we can do 100% on our own and there are different call points and that one and think about here, including psychiatric call point and and very importantly for growth of the market a broader call point and that with the GP community and I do not see is growing and to the GP community.

So I think it is right for commercial collaboration for us.

I don't think we are.

And we will require a development partner and the indication. So it's something that we intend to maintain a very strong economic stake and not.

And not something that we're seeking to just generate POC and out license and this is a core program that we're going to invest and and we intend and hope to.

Bcf for the economic rewards from it.

Got it that's helpful and.

Yes.

Maybe just one collaborative question.

I guess.

Is there any kind of change of control provision that impacts the alexia on collaboration and.

Yes.

Is there a scenario by which the C three and the CFB drug and come back to you and I guess, if so are those.

Target you'd be interested in.

And.

So there is not a change of.

Control trigger and that means.

And they would definitely come back to us.

With respect to what might happen and I think there on a lot of possibilities for what might happen, but I am confident that these programs are going to move forward, because we do see C III and CSP and.

It's very interesting targets to move forward so.

It is conceivable that there won't be any change and the relationship. It's also conceivable that there will be some sort of rejiggering and we'll just have to work with our friends at Alexia on and I expect.

After Q3.

It will be for instance.

And as well.

Figure out what the path forward is and there may be a change, but I think both programs are very likely to proceed along their timelines and entered the clinic.

Okay, and then maybe just one last quick.

Potentially stupid financial question.

So.

$100 million and recognized revenue that youre talking about here over this five quarter period is is that a combination of both incremental milestones.

And the recognition of deferred revenue or is that just some incremental milestone payments on top of the deferred debt, we should expect for remodels.

I'll kick that off and on that.

And I forgot and do you want to step into the $100 billion that we quoted on that five.

Quarter period, just cash and detour.

Hi.

The revenue recognition associated with the collaborations and how shall we say for Roque.

And okay.

And so that number is and Thats just the cash going into the bank account number and as independent accounting for and as revenue and so.

And when Douglas quoting the deferred revenue and Thats really cash that's already and the bank and about what shows up as revenue on the line does that clarify for you Yeah and I just wanted to make sure that it was indeed incremental cash coming on the door okay.

Yes, Steve it's very helpful.

Just to further the point there will be tables, and the MD&A section that make it very clear and specific cash and by partner and it's.

And in order to help understand how the deferred revenue unfolds, but it's a pure cash.

Okay, great. Thanks for taking the questions.

Yes.

Thank you. Our next question comes from the line of Ed Arce from H C Wainwright and company Sir Your line is open.

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

Continuing to expand both internal and collaborative programs.

Just one question for me a lot of them have already been answered but.

And on your <unk> program for <unk>.

So for one.

Just thinking.

Longer term.

As you move towards potential.

Approval and collaboration and a few years obviously.

Asset is targeted towards the liver effects independent of the long effects for.

For these patients.

Curious how you think about.

The benefits to patients and deliver and how that.

Could benefit.

Complement the reason.

Synergistic.

Clinical benefit to these patients and how that could impact your overall.

Marketing.

And I guess strategy and and positioning.

Thanks.

Yes, let me try and kind of get into that three step and there is.

And things you want to add.

There are really two different diseases here and they have the same cause but they're different diseases.

Lung manifestations, it's treated by Pulmonologists and it has a standard of care.

And.

And do treatment is going to come along and needs to compete with that standard of care, we have a liver disease.

And the street by a different physician groups and different target, Oregon and currently there is no standard of care for it but there will become one.

Patients with liver disease are going to want the best care for it.

Their liver patients with long and doesn't want the best care for the month, obviously and there's an overlap and these patient population, but there are patients that are long only and there are patients that are on liver only and so I think the synergy between them.

Is there is a marketing synergy for sure because of the lung patients are more apparent.

And given that people don't feel their liver decline and the same way they feel theyre long decline and so there is an enrichment for lung patients amongst the current liver patients that are there so to the extent they are already in our system of augmentation through the three existing argumentation providers there is potential market.

<unk> net.

For <unk>.

Deliver.

From a medical perspective, though I really think you got to ask what is the best treatment option for deliver and what is the best treatment option for the loan and I don't think it matters so much with her and same genre.

It really is what's going to do the past and we think RNA eye because of its ability to give a constant and very high suppression of the misfolded protein really has the potential to be the best liver treatment and be the standard of care and the liver.

Okay, Great that's helpful on that.

Thank you. Our next question comes from the line of Miami from one tiny from B Riley Securities. Sir Your line is open.

Thanks for the bumping and flip guideline update and appreciate you taking my questions All day and day to see so much visibility and be above net programs. So maybe debt starting day on the on the HBV program.

Obviously in <unk>, Inc for them being new and you'll draw down and the ongoing study with a number of different automotive combination there.

And I just wanted to ask you is between the different options is there is there any one or do you think you'll have more confidence and given obviously, it's a busy kind of landscape. It's very challenging to have that off peak day functional and carrier data.

And any comment you can provide would be paid on debt.

Yes, op and happy to speculate of course, my opinion doesn't matter right and it'll be the data but of course, we all recognize that.

We look at the history of treating HBV and it doesn't vary a bit by genotype, but where there has been success, albeit at a low rate and achieving functional cure, that's been and nuke plus interferon and it hasnt been nukes alone.

And.

And I view that as.

And the crack in the door so to speak and there is a real question is there can you can you widen it and.

It stands to reason that if you suppress S antigen.

As the tolerating agent immunosuppressive activity and HBV and then you are likely to increase the activity.

And nuc interfere on content.

And so I think the most straightforward way to think about it is.

Duke arent AI and interferon for some other immuno active agent.

So that would say that amongst roche's three triple combos, I think it's more likely that the interferon or the DLR seven arm.

And would perform and obviously interferon has and well known downsides and it would be great to replace it with something better and it may be a <unk> seven agonist for <unk>.

Better and maybe theres something else over there and the pipeline.

I think the optimism around core inhibitors has waned a bit as the core inhibitors in combination with nuke haven't really shown and differentiated activity. So it is harder to see why adding R&D on cars and that combination duplicity Pam.

Is going to all of a sudden become a whole lot better so.

We are proud of election to thinking that we're likely to succeed and immuno active combinations, but.

And it's a clinical experiment and.

We'll see what happens.

Yes.

Thank you Doug that was very helpful and.

And just to clarify the initially and moving forward.

And then.

Are you are you targeting having all BH, one dude see just that BHG.

<unk> III is going to be more accelerated approval and yes. They do are going.

And to be full approval does that kind of the goal for Duane Duane Dewey.

I think we have we have agreement on what the basis of approval for ph one ph two is so.

That is and the different place than our thinking on the BHP where for.

For the reasons I described we recognize that.

It will be on.

And accelerated type of approval with the commitment to do additional work is what our expectation and spending data.

Okay and.

Last question just to step back question, maybe for you Doug and also as you think about the spend trajectory going from last year the BCA.

Are you are you kind of talking about a little bit of a strategy shift and that.

You are thinking about them.

And diseases and a different way and we should have we should kind of expect to hear from you more.

Programs like <unk>.

And some others that might be sitting on your pipeline maybe.

And maybe maybe you've not invested and again.

Well I think.

Perhaps the most important message I was fairly explicit about which is that we're not just looking at orphan disease.

Hi.

Yes.

Biotech industries, and flowering and ways to approach diseases, but there are and our analysis diseases, where the qualities of Rei that constellation and features looks like it's the most appropriate and when.

And you combine that with.

Targets and opportunities enabled by R&D and either it looked like there.

Pretty likely to work that you would have some confidence that you have a higher than industry average.

<unk> ability and a success.

That's where we're trying to look there is some work and things from there, but there are some large market indications and there and that is we have a formalized internal process led by Bob Brown, our chief scientific officer to evaluate various opportunities draws on it and the internal resources are reasonable.

Recent from large scale growth of our company as well as external resources and it is.

And with diverse set of indications, but they are United by this confidence that hey, this is probably really going to work is a great target and R&D I really looks like the best way to go at it.

And as I said for some work and in there, but there are also some for some non orphan so.

And.

And that's how we're thinking about building the portfolio, we will roll out more indications beyond <unk> and the coming quarters and.

I think you'll see those threads.

Go through the future programs addition, you can see how the threat through the historical programs.

Got it. Thanks, so much for taking my question and then and it seems like maybe up to and to anyone is going to be very exciting and good luck.

Alright.

Thank you and our next question comes from the line of Keith K from share done Sir Your line is open.

Oh, yes, thanks, Doug for for <unk> in terms of measuring.

Knockdown of LDH too.

Is something like <unk>.

A good proxy or is there something more specific debt you'd be looking to measure.

Well I'll start and then I think streak and for them.

From that the answer here and one thing, we're not going to be doing with folk and people and deliver so we're not going to get and <unk>.

<unk> knockdown, but.

As I.

And I alluded to it in another context for R&D I has been very reproducible.

So I think we can have a base level of confidence that we're kind of achieved pretty good knockdown of <unk> two.

Hey, aldehydes, the transient biomarker and that snakes is somewhat challenging to use as a very firm basis for analysis, and we won't be hanging our hat solely on that and ultimately the most important thing here is.

Bonds to alcohol challenge.

And it's really going to be and most important asset true do you on it.

Just on the PD marker will be excellent.

On the directions and.

And we're looking at.

And welcome to publish that.

For the rigs facial flushing of and it's.

Country.

And field. So we will do a formal and ethanol interaction study and society to be more thorough of our BD.

We will have metabolic measures.

Our primary goal is to and that will be offset and offset from infection.

And response to me.

And our challenge.

Okay and then.

And talking about.

Perhaps a prevalence for $14 million, but.

And with a goal to initially targets on subgroups.

Can you give us a sense of.

What's the low hanging fruit subgroup is as for trying to model what.

This opportunity is worth.

Yes.

Flesh this out but.

At summit.

On the 18th but obviously the key group and the group is currently receiving pharmaceutical intervention.

Debt to number one that's about 1% of the population and that's about 140000 individuals share.

And as much.

Much larger than the 10 times that size on the order of one 5 million and people who are seeking some form of treatment, 90% of them are getting and pharmaceuticals.

However, we believe that <unk> has the potential for that comes commonly used for option amongst that group and conjunction with the behavioral therapy that they're currently getting so that low hanging fruit there.

One three and $1 5 million people that are already being recommended for treatment.

Don't have a great pharmacy options. So I think that's where we start and.

And thinking about values for this product and you can see how even our parcels and such there needs to a very valuable product.

Okay. Thank you that's really helpful.

Sure.

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

With two phase III studies of RG six three for six and belts SRAM and expected to start this year and at least two and.

<unk> potentially to be filed.

On our highly productive collaboration activity, we're going to continue to churn out candidates and importantly, and our NDA submission on the horizon. How can we got a lot of habit for this year to go and be very exciting year of execution and growth.

Forward it accurately as we go through the NDA filing process.

So in addition to on some conferences in March we hope you all will join us for our webinar on March 18 on <unk>.

<unk>.

That program and more sales with Doctor and Henry brand for Us.

We've got a lot going on here at the nicer and on and we look forward to keeping you all updated as we continue to build towards the fully integrated and commercial stage biopharmaceutical company. Thank you again for joining us Tonight and have a wonderful day.

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

Okay.

[music].