Q4 2020 Arrowhead Pharmaceuticals Inc Earnings Call

Operator: And gentlemen, welcome to the Arrowhead Pharmaceuticals Conference Call. Throughout today's recorded presentation, all participants will be in a listen-only mode. After the presentation,

Operator: After the presentation, there will be an opportunity to ask questions.

Operator: Now hearing the conference call transferred over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. We'll go ahead and...

Operator: We'll go ahead, gents.

Vincent Anzalone: Chris Good afternoon everyone, and thank you for joining us today to discuss Arrowhead's results for its fiscal year and for September 30, 2020. With us today for management are President and CEO Dr. Christopher Anzalone, who will provide an overview of the quarter, Dr. Javier San Martin, Chief Medical Officer, who will discuss our clinical programs, and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, James Hazard, our Chief Commercial Officer, and Dr. James Hamilton, who was recently promoted to Senior Vice President and Head of Discovery and Translational Medicine, will both be available during the Q&A session of today's call.

Vincent Anzalone: Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Therefore, all statements other than statements of historical fact, including, without limitation, those with respect to Arrowhead's goals, plans, and strategies, are forward-looking statements. These include statements regarding our expectations regarding the development, safety, and efficacy of our drug candidates, projected cash runway, and expected future development and commercialization activities. These statements represent management's current expectations and are inherently uncertain. Thus, actual results may differ materially. Arrowhead disclaims any intent and undertakes no duty to update any of the forward-looking statements discussed on today's call.

Ladies and gentlemen, and welcome to the Arrowhead Pharmaceuticals conference call for <unk>.

Today's recorded presentation, all participants will be and the listen only mode.

After the presentation, there will be an opportunity to ask the question.

I'll now hand, the conference call over the rest of the loan Vice President of Investor Relations for Eric Please.

Please go ahead of that.

Thank you Chris Good afternoon, everyone and thank you for joining us today to discuss Arrowhead. The results for the fiscal year ended September Thirtyth 2020, with us today for management, our president and CEO Dr., Christopher Anzalone, the who will provide an overview of the quarter dr. hobby or C and marching and Chief Medical Officer, who will discuss for clinical program.

And Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, the James Hazard, our Chief Commercial Officer Dr., James Hamilton, who was recently promoted to senior Vice President and head of discovery and translational medicine will both be available during the Q of day session of today's call.

Vincent Anzalone: You should refer to the discussions on the risk factors in Arrowhead's annual report on Form 10-K and the company's subsequent quarterly reports on Form 10-Q for additional matters to be considered in this regard, including risks and other considerations that could cause actual results to vary from the presently expected results expressed in today's call. With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company. Thanks Vince.

For we begin I would like to remind you. The comments made during today's call contain certain forward looking statements within the meaning of section 27 eight of the Securities Act of 933 and section 21 E of the Securities Exchange Act of 93 for all statements other than the statements of historical fact, including without limitation and those with risk.

Christopher R. Anzalone: Good afternoon, everyone, and thank you for joining us today. This is our final earnings call for 2020. So, in addition to discussing our progress for the quarter and plans for 2021, I would also like to speak a bit more broadly about our philosophy and model. We're building a different kind of biotech company. We are not focused on a single therapeutic area but rather on any disease with an unmet medical need that is addressable with our technology. We are not focused solely on rare diseases but rather on large and small populations. We do not rely solely on partners for late-stage clinical development and commercialization, but rather, we use partnering strategically and judiciously to enable us to build substantial value by commercializing our own drugs. We are fast, probably the fastest in the business from idea to clinic, and we intend to remain fast as we grow. That devotion to speed also applies to the pipeline expansion. I believe we have the fastest-growing pipeline in our field, and we do not intend to slow that input just because we...

The arrow and goals plans and strategies are forward looking statements. These include statements regarding our expectations around the development safety and efficacy of our drug candidates projected cash runway and expected future development and commercialization activities. These statements represent management's current expectations and are inherently and in here.

Currently uncertain. Thus the actual results may differ materially Arrowhead disclaims any intent and undertakes no duty to update any of the forward looking statements discussed on todays call you should refer to the discussions on the risk factors and Arrowhead. Its annual report on form 10-K, and the company's subsequent quarterly reports on form 10-Q for additional.

Matters to be considered in this regard, including risks and the other considerations that could cause actual results to vary from the president of the expected results expressed in todays call with that said I'd like to turn the call over the Chrissy and Maloney, President and CEO of the GAAP Chris.

Christopher R. Anzalone: We are not in the Me Too product business, where we only provide an incremental benefit to patients. Rather, we seek to be pioneers. We believe that everything in our clinical pipeline represents the first RNAi approach to each target in humans. We don't operate like a normal pharmaceutical company. We are not burdened by endless gating committees but rather empower our people to make decisions.

Thanks and good.

Good afternoon, everyone and thank you for joining us today.

This is our final earnings call 2020. So in addition to the Skus in our progress for the quarter and plans for 2021 and I would also like to speak a bit more broadly about our philosophy and model.

We're building a different kind of biotech company.

We're not focused on a single therapeutic area for rather and any disease with unmet medical need and its addressable the dart technology.

Christopher R. Anzalone: Operationally, think of us as a startup in $7 billion market cap clothing, and we intend to continue in this nimble and creative fashion, even as we become a substantially larger and more valuable company. We see this as the most effective way to build a business, and, most importantly, to serve our patients. Every day that we can shave off the development process puts our patients one day closer to a new treatment they need. This is a powerful motivator indeed for us because the value of our work depends on the number of lives we touch. I mention all of this now because we are at a moment of transition for our company.

We're not focused solely on the rare diseases for rather address large and small populations. We do not rely solely on partners for late stage clinical development and commercialization of rather we use partnering strategically and judiciously to enable us to build substantial value by commercialize and our own drugs.

We're fast probably the fastest and the business for idea to the clinic and we intend to remain fast as we grow.

That devotion to speed also applies to the pipeline expansion I believe we have the fastest growing pipeline and our field and we do not intend the slow that input just because we are entering later stage clinical studies.

Christopher R. Anzalone: We have created a lot of value to this point by building what we believe will soon be the largest RNAi-based clinical pipeline in biopharma. As we move into later stage clinical studies, our focus needs to expand to include commercial planning. Ultimately, this is the reason we're in this business, and we need to do that well.

We're not in the me too product business, where we only provide incremental benefit to patients rather we seek to be pioneers.

We believe that everything and our clinical pipeline represents the first arnie I approach to each targeted and humans.

Christopher R. Anzalone: However, we also need to continue to do the things in discovery and early development that have made us successful while we build our commercial presence. On average, we expect to introduce three new drug candidates into clinical studies every year, and we expect to be able to address a new cell type every 18-24 months. Think of the potential value embedded in those statements.

We don't operate like and normal pharmaceutical company, we're not burdened by and less gain and committees, rather and power people to make decisions.

Operationally think of us at the start up and 7 billion dollar market cap and clothing, and we intend to continue and as nimble and creative fashion, even as we become the substantially larger and more valuable company.

We see this and the most effective way to build the business and most importantly to serve our patients every.

Christopher R. Anzalone: I expect that we will have 10 clinical programs by summer, spanning four different cell types. That could grow to 20 clinical programs spanning five or six cell types just four years from now. We expect this to drive substantial value because we expect some of those to become products that we will commercialize ourselves, and some can be partnered to fund development and commercial endeavors. Our ability to rapidly grow our pipeline enables this hybrid model of establishing a limited number of partnerships in order to fund wholly owned programs. We see this as a powerful model because it allows for the rapid value creation associated with commercializing wholly owned drugs while financing this expensive endeavor largely through non-dilutive capital from partnered programs. Thus, even as we approach and ultimately expand our commercial presence, our pipeline strategy should continue to be an important part of our value proposition. This is not only due to the brute force of the large numbers of potential drugs in our clinical studies but should also reflect our expectations of success. There are two components to this.

Every day and the we can shave off the development process puts our patients one day closer to a new treatment they need this.

This is the powerful motivator and d. for us because the value of our work depends on the number of lives we touch.

I mentioned all of US now because we are at the moment of transition for our company.

We have created a lot of value and at this point by building and what we believe will soon be the largest arnie I based clinical pipeline and bio pharma.

As we move into later stage clinical studies, our focus needs for expand to include commercial planning and ultimately this is the reason for in this business and we need to do that well. However, we also need to continue to do the things and discovery and early development and of made US successful, while we build our commercial presence.

On average we expect to continue to introduce three new drug candidates into the clinical studies every year and we expect to be able to address the new cell type every 18 to 24 months.

Think of the potential value embedded in those statements.

Christopher R. Anzalone: First, we seek to choose only well-validated targets. These are gene targets where a consensus of experts agree that reducing expression will likely have positive therapeutic benefits. By focusing on this, we believe we enter clinical studies with reduced biology and target risk relative to other candidates. Second, the RNAI mechanism and experience with the TRMM platform can provide additional wind at our backs. As we continue to treat more patients with drug candidates built on the TRMM platform and see consistent activity and a positive safety profile, our confidence increases that other candidates targeting different genes will also be successful. RNAi doesn't care what gene is being silenced.

I expect the we'll have 10 clinical programs by summer spanning for different cell types of that could grow to 20 clinical programs and five or six cell types of just four years from now weeks.

We expect this to drive substantial value because we expect some of those to become products that we will commercialize ourselves and some can be partner just the been development and commercial endeavors.

Our ability to rapidly grow our pipeline enables this hybrid model of establishing a limited number of partnerships in order to fund wholly owned programs. We see this as a powerful model because it allows for the rapid value creation associated with commercializing the wholly owned drugs well financing this expensive endeavor largely through non dilutive capital for part and pro.

Christopher R. Anzalone: Once we validate our ability to reduce the expression of a given gene in a given cell type, we have confidence that we can replicate that in other gene targets. We believe this is a powerful and scalable concept that gives us confidence that a larger percentage of our candidates entering the clinic will ultimately become drugs compared to traditional small molecules. We hope that as we approach and become a commercial company, the market will properly value our growing pipeline. As I mentioned, it will continue to be an important part of our value proposition, and we expect it to remain a substantial differentiator versus our competitors. With that, let's move into an overview of the last quarter. During the last few months, our accomplishments included the following. One, we hosted a KOL seminar on Arrow-ENAC, our first lung-targeted candidate to treat cystic fibrosis, and we initiated dosing in a Phase I-II clinical study.

Yes.

So even as we approach and ultimately expand our commercial presence our pipeline strategy should continue to be an important part of our value proposition.

This is not only do and the brute force the large numbers of potential drugs and our clinical studies, but should also affect reflect our expectations of success. There are two components to this for.

First we seek to choose only well validated targets. These are gene targets, where consensus of experts agreed the reducing the expression will likely have positive therapeutic benefits.

By focusing on this we believe we enter clinical studies with reduced biology and target of risk relative to other candidates sales.

And the Arnie and mechanism and experience with the trim platform and provided additional wind at our back.

As we continue to treat more patients with drug candidates built on the train platform and see consistent activity and and the safety profile our confidence increases the other candidates targeting different genes will also be successful.

Our and <unk> doesn't care, what gene has been silenced once we validate our ability to reduce the expression of the given gene in a given cell type we have confidence that we can replicate that and other gene targets.

Christopher R. Anzalone: We earned a $20 million milestone payment from Amgen following the start of a Phase II study of AMG-890, now called El Pasaran, which is a partner program targeting LP-a to treat cardiovascular disease. 3. We initiated a Phase 1B study for Arrowhead 2, our first tumor-targeted candidate to treat renal cell carcinoma. 4.

We believe this is a powerful and scalable concept the gives us confidence that a larger percentage of our candidates entering the clinic will ultimately become drugs compared to traditional and compared to traditional small molecules.

We hope that as we approach and become a commercial company the market will properly value our growing pipeline as I mentioned it will continue to be an important part of our value proposition and we expect it to remain a substantial differentiator versus our competitors.

Christopher R. Anzalone: We presented new data on Phase 1-2 studies of both of our wholly-owned cardiometabolic candidates, Arrow ApoC-3 and Arrow AMG-3, at multiple medical meetings, including the European Society of Cardiology and the American Heart Association meetings, and subsequently hosted KOL webinars to discuss the data and our plans for their future development. Five, we presented phase two data at ASLD on Arrow AAT, our candidate against liver disease associated with alpha-1 antitrypsin deficiency, showing that Arrow AAT strongly reduced the production of mutant Z-AAT protein and led to improvements in multiple biomarkers of alpha-1 liver disease. Six, we signed an agreement with Takeda to co-develop and co-commercialize Arrow AAT, which includes $300 million upfront, $740 million in milestone payments, a 50-50 profit sharing agreement in the U.S., and 20-25% royalties on sales outside the U.S. This is a lot of progress in a short period of time and even more impressive with the backdrop of disruptions caused by COVID-19. Let's take a look at the indicators.

With that let's move into an overview of the last quarter.

During the last few months our accomplishments include the following.

One we hosted the Cantwell seminar on Aero Enac, our first lot of targeted candidate to treat cystic fibrosis, and we initiated dosing in the phase one two clinical study.

Two we earned a $20 million milestone payment from Amgen following the start of the phase two study and the AMG 90, now called ill pass around which is for which is a partner program targeting LP little a to treat cardiovascular disease. Three we initiated a phase one b study for arrowhead to our first tumor targeting the candidates to treat renal cell carcinoma.

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For the presented new data on phase one two studies of both of our wholly own Cardiometabolic candidates Aero able to see three narrow and sthree and multiple medical meetings, including the European Society of Cardiology, and the American Heart Association meetings, and subsequently hosted Calwell Webinars and discuss the data and our plans for their future.

The development.

Five we presented phase two data at a sell the on Aero 18, our candidate against liver disease associated with the Alpha one Antitrypsin deficiency show in the Aero 80 strongly reduce the production of the mute the A.T. protein and lead to improvements and multiple biomarkers of Alphaville and liver disease.

Christopher R. Anzalone: It's a good example of our Selective Partnering Strategy. We expect Arrow AAT to benefit from Decatur's global footprint, existing infrastructure, expertise, and 18-year history in the AAT market to enable a rapid launch. If approved, Arrow AAT will join Takeda's global commercially available products, including Glastia, Arrow Lass, Intivio, and a growing GI pipeline. Decatur is clearly invested in and committed to these areas and has a proven track record of success. The deal is also important in terms of capital. In addition to the 300,

And the six we signed an agreement with the cater to co develop and co commercialize Arrow 18, which includes $300 million upfront $740 million and milestone payments. It 50, 50 profit sharing agreement and the U.S. and 20% to 25% royalties on sales outside the U.S.

There's a lot of progress and a short period of time and even more impressive with the backdrop of disruptions caused by COVID-19.

Let's take a look at the Kid of deal.

It's a good example of our select and partnering strategy.

We expect arrow 80 to benefit from T.K. This global footprint existing infrastructure expertise and 18 year history, and the 18 markets to enable a rapid launch.

Christopher R. Anzalone: Up front, we have potential access to substantial capital in the near, mid, and long term with a possible stream of milestone payments, profit sharing, and royalty. When this is added to the potential milestone payments and royalties from our partnerships with Amgen and Janssen, we feel our balance sheet is in a very strong position. This allows us to confidently move our wholly owned programs into later stage development and ultimately commercialization. This deal is also a step in an ongoing process toward rationalizing our growing pipeline, where we look to build commercial infrastructure in areas where we expect multiple drugs, such as cardiometabolic and pulmonary. We will look for synergy and leverage when deciding where to focus commercial buildings.

If approved Arrow 80 will join Takedas global commercially available products, including Glassia or last into.

And TBL and the growing G.I. pipeline.

The current is clearly invested and committed to these areas and has a proven track record of success.

The deal is also important in terms of capital.

In addition to the 300 me in addition to the $300 million upfront we of potential access to substantial capital and the near mid and long term for the with the possible stream of milestone payments profit sharing royalties when.

When the is added to the potential milestone payments and royalties from our partnerships with Amgen and Janssen, we feel our balance sheet is and very strong position.

This allows us to confidently move our wholly owned programs into later stage development and ultimately commercialization.

Christopher R. Anzalone: So let's take a look at the cardiometabolic pipeline. We presented data recently at AHA and also held two KOL webinars to discuss these programs. Javier will discuss these specifically in a moment, but I want to talk about where we are with these programs at a high level.

The steel is also step in and ongoing process toward rationalize and our growing the pipeline.

Where we look to build the commercial infrastructure in areas, where we expect the multiple drugs such as cardio metabolic and pulmonary.

We will look for synergy and leverage when deciding where to focus commercial build out.

So, let's take a look at the cardio metabolic pipeline.

Christopher R. Anzalone: The data across single and multiple doses and in healthy volunteers as well as various patient populations has been very strong and highly, In addition, ArrowApoC3 and ArrowAnz3 are showing unique profiles. What I mean by that is that we believe each drug may ultimately give cardiologists more tools to tailor their treatments to the specific lipid profiles of their patients. We also think they will fill holes in the current treatment paradigm and may potentially address lipid targets that have not been adequately addressed. For instance, there are more than 4 million patients in the U.S. with severe hypertriglyceridemia, and given published data, we would expect the overwhelming majority of them would not reach normal triglyceride levels with currently available treatments. There are also approximately 30 to 40 million addressable patients in the US with mixed dyslipidemia, which is elevated triglycerides and elevated LDL cholesterol. We have become increasingly confident that these programs in, uh,

We presented data recently and AJ and also held to Kayla Webinars to discuss these programs.

The air will discuss the most of these specifically in a moment, but I want to talk about about where we are with this programs at a high level.

The data across single and multiple doses and in healthy volunteers as well as various patient populations has been very strong and highly consistent.

In addition, Aero able see three and arrow and three are showing unique profiles. When the mean by that is that we believe each drug may ultimately give cardiologist more tools and tailor their treatments to the specific lip and profiles of their patients we.

We also think they will fill holes and the current treatment paradigm and may potentially address lip and targets the.

That have not been adequately addressed for instance, there are more than 4 million patients and the U.S. the severe hypertriglyceridemia hypertriglyceridemia and given published data we would expect the overwhelming majority of them would not reach the normal triglyceride levels with currently available treatments.

There are also approximately 30 to 40 million addressable patients and the U.S. with mixed Dyslipidemia, which is elevated triglycerides, and Alabama and elevated LDL cholesterol.

We have become increasingly confident that these programs.

And we have become increasingly confident and these programs and in our ability to move them to commercialization.

Christopher R. Anzalone: We've become increasingly competent in these programs and in our ability to move them to commercialization. We've also been able to move forward in our other clinical programs. Arrow HSB, our drug candidate against NASH and alcoholic hepatitis, is now in the patient portion of the Phase 1-2 study. Arrowhead 2, our candidate against renal cell carcinoma, and Arrowhead 3.

We've also been able to move forward and our other clinical programs Aero HST, our drug candidate the against Nash and alcoholic hepatitis is now and the patient portion of the phase one two study.

Arrowhead to our candidate against renal cell carcinoma, and the arrow in and our candidate and against cystic fibrosis are both being dosed and patients as well.

Progress and Arrowhead too and Arrow Enac is particularly important because it has been our goal of the gain clinical proof of concept and then move into a rapid pipeline expansion phase for tumor and pulmonary tissue types. We think we're just and the customer that phase now.

Christopher R. Anzalone: Fibrosis and fibrosis are both being dosed in patients as well. Progress in Arrowhead 2 and Arrow ENAC is particularly important because it has been our goal to gain clinical proof of concept and then move into a rapid pipeline expansion phase for tumor and pulmonary tissue types. We think we are just on the cusp of that phase now.

To that and we continue to work in parallel on multiple additional targets and tumor and pulmonary and also to expand our reach into new tissue types. The army's.

Christopher R. Anzalone: To that end, we continue to work in parallel on multiple additional targets in tumor and pulmonary and also to expand our reach into new tissue types beyond these. Before I move on to 2021, I'd like to say a few words about the novel coronavirus. As with the rest of the world, we were excited to see the interim results from some of the COVID-19 vaccine studies. Multiple safe and effective vaccines will be a humanitarian triumph, and we applaud the impressive work done by several companies. From an Arrowhead standpoint, some may ask if progress on the vaccines affects our internal programs. The answer is, not really.

Before I move onto the 2021 I'd like to see it the words about the novel current of virus.

As with the rest of the World. We were excited to see the interim results from some of the COVID-19 vaccines dice.

Multiple safe and effective vaccines will be a humanitarian triumph and we applaud the impressive work done by several companies.

From an arrowhead standpoint, somebody ask and progress on the vaccines affects our internal program of.

The answer is not really we continue to make progress on an anti viral approach. The is designed to work across different Corona viruses.

The history of Sars, Mers and how the current front of buyers suggest of the world should expect some type of current virus outbreak approximately every seven years.

As such we are study and conservative regions and known Corona viruses with the goal of creating and inhalable antiviral the could be applied to future outbreaks as well as the current virus should there be blind spots with the vaccines.

Christopher R. Anzalone: We continue to make progress on an antiviral approach that is designed to work across different coronaviruses. The history of SARS, MERS, and now the current coronavirus suggests that the world should expect some type of coronavirus outbreak approximately every seven years. As such, we are studying conserved regions in known coronaviruses with the goal of creating an inhalable antiviral that could be applied to future outbreaks, as well as the current virus, should there be blind spots with the vaccine.

We are still and early animal studies, but I hope that we will have an idea about the feasibility of this approach in 2021.

Moving to the future. There is a lot you should expect from us during the final month of the year and into 2021.

Our expectations include the following day.

One we are on track to file of CTG for Aero loan to at the end of this year the.

Second program.

As of the second program and our pulmonary franchise and is designed to treat C.O. PD by inhibiting and undisclosed targets and pulmonary EPS Celia.

Christopher R. Anzalone: We are still in early animal studies, but I hope that we will have an idea about the feasibility of this approach in 2021. Moving to the future, there's a lot you should expect from us during the final month of the year and into 2021. Our expectations include the following.

Two we are on pace to potentially have preliminary data read outs, but in the middle of 2021 for Aero HST Aerohive too and Arrow Enoch.

Three during the first half the 2021, we also intend to engage with the FDA and other regulators the skus pivotal trial, the study design and endpoints for Aero 80 base.

Christopher R. Anzalone: One, we are on track to file a CPA for Arrow Lung 2 at the end of this year. This is the second program in our pulmonary franchise and is designed to treat COPD by inhibiting an undisclosed target in pulmonary epithelia. Two, we are on pace to potentially have preliminary data readouts by the middle of 2021 for Arrow HSD, Arrow HIF-2, and Arrow ENAC. 3 During the first half of 2021, we also intend to engage with the FDA and other regulators to discuss pivotal trial study design and endpoints for Arrow AAT. Based on the impressive data that came out of our 2002 open-label study, it appeared that patients had large reductions in ZA-T monomer, which we expected, but they also had improvements in other downstream markers, such as polymer, globules, LFTs, and others.

Based on the impressive data of the came out of our 2002 open label study. It appeared the patients had large reductions and the 18 monomer, which we expected. The also had improvements and other downstream markers such as Palmer Colonials lefties and others.

These discussions may allow us to find the more streamlined and accelerated path to potential approval.

There also maybe additional open label data in 2021 for patients with 12 month and 18 month repeat biopsies.

For we also intend to initiate and multiple studies and the first half of 2021 for both of our Cardiometabolic programs for.

The arrow and Sthree and mixed Dyslipidemia patients, we're working on a phase to be dose finding study for Aero able to see three we are working to start three studies.

The phase Twob study.

And to be dose finding study in patients with triglycerides, ranging from 150 499 of.

The phase to be dose finding study in patients with triglycerides over 500, and the phase three study in patients with familial kind of them I couldn't give you the syndrome or EPS, yes.

Christopher R. Anzalone: These discussions may allow us to find a more streamlined and accelerated path to a potential approval. Additionally, there may be additional open-label data in 2021 for patients with 12-month and 18-month repeat biopsies. 4. We also intend to initiate multiple studies in the first half of 2021 for both of our cardiometabolic programs. For Arrowhands 3 and mixed dysthylipidemia patients, we are working on a Phase 2B dose finding study. For ArrowAbleC3, we are working to start three studies. Phase IIb Dose Binding Study in Patients with Triglycerides Ranging from 150 to 499, a Phase 2b dose binding study in patients with triglycerides over 500, and a Phase 3 study in patients with familial chylomicronemia syndrome or FCS. 5.

Five and the second half 2021, we intend to file of DTA for first and muscle targeted R&D therapeutic.

That program of hasn't moved forward very nicely and we are eager to talk more about that.

Of about that and what the data looks like.

Six for our partnered programs with Amgen and Janssen and we can't provide specific guidance on timing, but we continue to be pleased with their progress and look for two additional future progress.

Seven lastly, we are working on several other undisclosed programs and we'll likely have another ceta file for another program in 2021.

With that overview I'd now like to turn the call over to Javier and Martine Javier Thank.

Thank you, Chris and without the Moon globe anybody on the call.

I want to highlight the the from the 80, Italy for CP and aged FICO and since we have the import them readout for each of getting the last quarter.

And finally do the I would keep the very quickly view of the status of the El Nio States can you got for what.

Christopher R. Anzalone: In the second half of 2021, we intend to file a CTA for our first muscle-targeted RNAi therapeutic. That program has moved forward very nicely, and we are eager to talk more about that and what the data look like. Six, for our partnered programs with Amgen and Janssen, we can't provide specific guidance on timing, but we continue to be pleased with their progress and look forward to additional future progress. Lastly, we are working on several other undisclosed programs and will likely have another CTA.

HST utility investigation of the candidate for the purpose of treatment of alcohol and non alcohol related even of the.

The genetic Bunny this and so for inhibiting the target. It's just the 17 beat that the team the net securities alcoholic hepatitis and seasonal.

And we'll see space.

Conducting and face when seasonal and what the doses collect the study to evaluate the safety put it the ability of pharmacokinetics and Pharmacodynamic effect of Italy interest the normal healthy volunteers as well as the pace of non us well suspect goodness, we have complete single dose escalation income people in the us and the currently enrolling and what the.

Javier San Martin: for another program in 2021. With that overview, I'd now like to turn the call over to Dr. Javier San Martn.

Of those basin portion of the study and not all suspect in the us patients the.

Studying boots, neither the biopsy plus the so that the TV.

Javier San Martin: Thank you, Chris, and good afternoon to everybody on the call. I want to highlight data from the Arrow AAT, Arrow ApoC3, and Arrow H3 programs since we had important readouts for each during the last quarter. Before I do that, I will give a very quick review of the status of the earlier stage clinical trials. [inaudible] is our investigational candidate for the potential treatment of alcohol and non-alcohol related liver disease. The genetic validation is strong for inhibiting the target HSD-17-beta-13 in NASH cirrhosis, alcoholic hepatitis, and cirrhosis patients.

It is.

It's the sign to see PS and renal cell carcinoma, and what it couldn't be both in patients in the phase one b those the findings and the study in up to 18 patients with advanced renal cell carcinoma.

The study for the same deliberately the safety of and over here.

And for that I mean, the if they come in the face to those but also assisting pharmacokinetics and preliminary efficacy based on the this is and for those two metrics space and the two other.

And the hit us to see the genes.

Our left and we basically that go and it's not.

And that the thing to keep cystic fibrosis and you know.

Javier San Martin: We are conducting a Phase I-II single and multiple dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of Aero-HSD in normal healthy volunteers, as well as in patients with NASH or suspected NASH. We have completed single-dose escalation in healthy volunteers and are currently enrolling the multiple dose patient portion of the study in NASH or suspected NASH patients. This study includes liver biopsies to assess drug activity. Arrowhead II is designed to treat clear-celled renal cell carcinoma, and we're currently dosing patients in the Phase 1b dose finding clinical study in up to 18 patients with advanced renal cell carcinoma. The study is designed to evaluate the safety of Arrow HIF-2 and to determine the recommended phase 2 dose, while also assessing pharmacokinetics and preliminary efficacy based on resistance and post-tumoral expression of HIF-2-alpha and HIF-associated genes.

And that is in the phase one to dose escalate. The study for the latest safety put it out of the up and I'm looking at the can pick up you know he Nike net to 20 for Norma automotive was the Tias and pool and they didn't have any of the an efficacy in up to 30 patient with expenses we.

We have dose escalate and looked at the time as plan and hope it will MPS and so far we're pleased with the safety and Tolerability of the site. It's always an important and find new for the new investigation by the drill and even more so for the new platform.

Well, no and rolling see because of the patient and the move and what the for both personal the study.

No and we move on to the recent the type of either for.

And ill 18, our investigation and and I could about the being developed at the pigment for the Reds and that the legal fees associated with the weather impacts of seemed the efficiency.

We presented data so the on our 2002 open label study.

To review the study is fully enrolled and 16 participant and three cohorts for patients in cohort one we see 200 milligrams of Italy tea and.

We'll have the repeat buy of CF to seek an 18 month.

For her one be the same but basically the Steve the 100 and many of those and eight patients in cohort two will receive 200, the meeting as of Italy, The and we have the biopsy the 12 and put the for months of the treatment.

Javier San Martin: Our last early stage clinical program is Arrow-ENAC designed to treat cystic fibrosis. It is in a phase 1, 2-dose escalating study to evaluate the safety, tolerability, and pharmacokinetic effect of Arrow-ENAC in up to 24 normal healthy volunteers and to evaluate safety, tolerability, and efficacy in up to 30 patients with cystic fibrosis. We have those escalated multiple times as planned in healthy volunteers This is always an important finding for a new investigational drug and even more so for a new platform. We are now enrolling 65 positive patients in the multiple dose portion of the study. Now I will move on to the recent data readout.

And so the way to the put the on six months and saw some color what we've seen the data strongly suggest the Italy East we would the designed to do which is free to use the production of the need for the mute and Z a P protein.

The results also indicate that the EBIT may have the ability to clear out accumulated CHP and begin to hit him itself. The.

And Mtc beta imports.

Importantly, we saw the for the.

Eight the seeks the 92% of dosing and assumes the 80 protein all patients demonstrate the greater than 80% of those and Nivo and see a the monomers.

Feel for pacing had the PC EBIT level volume and and seal for pace and demonstrate the the deduction and see a the pulling the with the range of 68 for 97%.

Oh patients showed a lot of people the though some green shoots and fairly safe to say, we see for the said so we've seen the beside of all positive indication of the strong Pharmacodynamic response, and income and too many leave and health for the we just see those and.

Javier San Martin: For Arrow AAT, our investigation on an RNAi therapeutic being developed as a treatment for the rare genetic liver disease associated with alpha-1 antidepressant deficiency. We presented data at ASLB on our 2002 Open Label Study. To review, the study is fully enrolled, with 16 participants in three cohorts. Four patients in Cohort 1 receive 200 milligrams of Arrow AAT and will have a repeat biopsy after six and 18 months. Cohort 1B is the same, but patients received the 100 mg dose.

Hey.

As Keith mentioned, we are currently preparing to engage with the FDA and other of the repartee agencies and the first half of 20.1 for the Skus Idiots, where the Italy, the pool and may potentially be streamline and accelerate a bit.

Let's now move to our kind of them at the Woody grow them, Italy for Sci Fi and Angel.

Javier San Martin: And eight patients in Cohort 2 received 200 mg of 808-T and will have repeat biopsy after 12 and 24 months. At HLD, we reported on six months' results from cohort 1. We think the data strongly suggest that Arrowhead is doing what it's designed to do, which is reduce the production of the misfolded mutant Z-AAP. The results also indicate that the liver may have the ability to clear out accumulated CAAT and begin to heal itself faster than anticipated. Importantly, we saw the following.

We held two key led the way of units last week to discuss the beta and before the some day.

We were fortunate to have built to create the Valentine's day from Baylor College of maybe seen and the height of Goldberg from Daimler use school of medicine, showing us and provided the perspective and valuable valuable insights.

The place of these events and available on the investors section of our website for the most could miss the live presentation.

The study anyway for CP I.

I would kind of you they targeting equally likely put the and see three being the below the potential treatment for the patient with type and for the city.

Javier San Martin: 86 to 93% reduction in serum CAAT protein. All patients demonstrated greater than 80% reduction in liver CAAT monomers, three or four patients had decreasing liver global involvement, and three or four patients demonstrated reduction in CAAT polymers with a range of 68 to 97%. All patients showed an ALT reduction ranging from 36 to, so we think that these are all positive indications of a strong pharmacodynamic response and improvement in liver health following just three doses of Arrowhead. As Chris mentioned, we are currently preparing to engage with FDA and other regulatory agencies in the first half of 2021 to discuss areas where the AOIAT program may potentially be streamlined and accelerated. Let's now move to our cardiometabolic programs, AeroApoc3 and AeroAmp. We held two KOL webinars last week to discuss the data and this program in more detail. We were fortunate to have Dr. Christy Valentine from Baylor College of Medicine and Dr. Ira Goldberg from NYU School of Medicine join us and provide their perspective on valuable insights. Replays of these events are available on the investor section of our website for those who missed Let's start with 8-0-8-pro-C3.

The current critic of heavy and is in phase one two single and multiple dose study blew by the way safety Tolerability pharmacokinetics and Pharmacodynamic effects of Italy.

That is the single dose and and Whats Bill goes for some of the study and Oh, how people and Pos and the multi bodes for personal for study and basically with type and so you see the dania, including equal and moving that to twin peaks and of weakening the pace.

The American Heart Association with the put the data from the multiple dose patients portion of the study.

So most of the subsequent beneath the sea and the highly encouraging to us as we prepare to the in the next page of the minimum for the program and the first half of next year.

And patient type of the through the city, Virginia, Italy proceeds between and resulted in the robust and that's the thing that's and thing. This is a non and SDN listed all leading female and put it.

Typically we have set of Masland and though some of the.

80% to 99% and they put some fee muscleman, England auction of some and before the 92 consenting Peachy Otay Mesa and.

So the night, the 62% that actually known HD and for this.

And that's my mean increase of 95% to 116% MH the unpleasant.

Javier San Martin: Our candidate targeting 8-0-8-lipoprotein C3 is being developed as a potential treatment for patients with hyperpigmentation. The current clinical study is in phase 1-2 single and multiple dose study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamic effects of Arrowhead. There is a single-dose and a multiple-dose portion of the study in adult healthy volunteers and a multi-dose proportion of the study in patients At the American Heart Association, we reported data from the multiple breast patients portion of the study.

Bisha would kind of them convenient fits into the us annually for CP achieve similar levels of for the that's and of equal CTG and changes in key lead the but and thus we have set of matrimony, the notion of 98% and Naples key messman, the and the notion of 88% and the GE of 59% a non HDL cholesterol.

And the messman piece of 120% DNA Steve.

Importantly, the effects of Italy for CP, what Im and theme for great. The them quickly both single and goes for regardless of the patient population within this indicates that was quoting the or less frequent dosing of maybe.

And what other wholly owned cut the amount that wasn't candidate is unchanged the study.

At the and entered for the at the life of protein, the or and TNT and.

Javier San Martin: The results were very impressive and highly encouraging to us as we prepared to begin the next stage of development for the program in the first half. In patients with hypertriglyceridemia, aeroApoC3 treatment resulted in robust and sustained reduction in triglycerides and non-HTL cholesterol with an increase in HDL. Specifically, we observed maximum mean reductions of 80% to 99% in ApoC3, maximum mean reductions of 74% to 92% in TG or triglycerides, and 39% to 62% reduction in non-HCG, and maximum mean increase of 95 to 116% in HDLB. In patients with chylomeconemia, 50 mg Arrow ApoC-3 achieved similar levels of reduction of ApoC-3 and changes in key lipid

He's been develop has the potential to net basically would make this meeting the current clinical studies the phase one single and multiple dose studies, we have other safety for the ability I don't look and at the pharmacodynamics effect of.

The American Heart Association and the reason the way we know we also present the data on the multiple dose patient portion of the Endo and the study as we do a plus the you'd see Lula field. The they think of the size of move forward with the program with the look of Campinas and the potential to help patients within the convenient the.

I think the showed the hit for the cycle of media hype and of course linear and pace, if we'd known and page and non if they'd space and.

We see this will be moving the though some of 78, the 90% of things feel free for those kind of 29, and 47% and timeliness of for the night, the 75% and LDL cholesterol and the other thats instead of the web and be five of the fight within a non HD and clinic.

Hi, Thank you today patients, Italy, and three the soap the introduction of 82% put HQ deal. The 75 per cent for the segment today of 56 puts and for non it's the and clinic.

Javier San Martin: We observed a maximum mean reduction of 98% in ApoC-3, a maximum mean reduction of 88% in TG and 59% in non-HDL cholesterol, and a maximum increase of 120% in HDL cholesterol. Importantly, the effect of Arrowhead Proceed 3 was maintained for greater than 12 weeks post-second dose, regardless of the patient population. We think this indicates that once quarterly or less frequent doses might be, Our other wholly-owned cardiometabolic candidate is Arrow H3, targeting angiopoietin-like protein 3 or HPTL, and is being developed as a potential treatment for patients with mixed dyslipidemia. The current clinical study is a Phase I-II single- and multiple-dose study to evaluate safety, tolerability, pharmacokinetics, and pharmaco At the American Heart Association and in the recent webinar, we also presented data on the multiple-dose patient portion of the ARO-AH3 study.

As we entered the plus you'd see the effect of arrow and see whats maintain for the greater than 12 weeks, both stick and both regardless of the patient population. We believe this indicates that once quarterly or less frequent dosing might be.

These results the life further supported the of the only and I make and engine and of and most specifically did up both the developed and seen that would keep the.

And to kind of phone very consistently regardless of the gene side. So far we have experienced very good for installation of the clinical data at the human clinical data with respect the safety, putting the ability and TV.

This gave us great confidence and each new program with the velo event of any of the stages. The next steps as the study and less and noted the can confide us where the nishan of for the state of the gene editing and meet the the desire and clinical benefit of specific patient population.

Javier San Martin: As with ARO-APO-C3, we were thrilled with the clinical results and moved forward with the program with a lot of confidence in its potential to help patients with mixed disease leukemia. The data shows that in heterozygous familial hypercholesterolemia and patients with non-FH and FH patients, AROH3 results in a mean reduction of 78 to 90% of NHPTL3, a reduction of 29 to 47% in triglycerides, 29 to 35% in LDL cholesterol, and a reduction of 31 to 35% in non-HDL. In high triglyceride patients, arrowh3 resulted in a mean reduction of 83% for HPTL3, 75% for triglycerides, and 56% for non-HDL cholesterol. As with Arrow ApoC-3, the effect of Arrow NH-3 was maintained for greater than 12 weeks post-second dose regardless of patient type. We believe this indicates that once quarterly or less frequent dosing might be needed. These results provide further support that the RNAi mechanism in general, and more specifically therapeutically developed using our CREAM platform, tends to perform very consistently regardless of the gene type.

As Keith mentioned earlier, we take the summit targets and the globally for basically generally will and this to the biology and strong support from the human genetic studies. These.

These provide us even more confidence that when the reducing waste to the extent both of them and less the Mason our two of the success.

I will now turn the call over at the Tim Gokey out of his chief.

Plain and simple Ken.

Thank you operator, and good afternoon, everyone as we reported today, our net loss for fiscal 2020 was 84.6 million or 84 cents per share based on 100.7 million weighted average diluted shares outstanding.

This compares with net income of 68 million or 69 cents per share based on 98.6 million weighted average diluted shares outstanding for fiscal 2000 range.

Revenue for fiscal 2020 with $88 million compared to 168.8 million for fiscal 2019.

Revenue for both periods, primarily relates to the recognition of a portion of the upfront payment milestones for our license and collaboration agreements with Janssen.

Revenue from the Janssen agreement is being recognized space and our estimate of the proportion of effort expended toward fulfilling our performance obligations, primarily overseeing the completion of the phase one too.

HPV clinical trial.

Javier San Martin: So far, we have experienced very good translation of preclinical data to human clinical data with respect to safety, tolerability, and activity. This gives us great confidence in each new program we develop, even at very early stages. The next steps are to study in larger and larger clinical trials whether inhibition of the respective genes targets leads to the desired clinical benefit in a specific patient population. As Chris mentioned earlier, we try to select targets at the discovery stage with generally well-understood biology and strong support from human genetic studies. This provides us with even more confidence that we're reducing risk to the extent possible and maximizing our probability. I will now turn the call over to Kenneth Myszkowski, Arrowhead's chief.

We expect the remaining 19 million of deferred revenue to be recognized in the first half of fiscal 2021.

And the additional milestones achieved with Janssen or Amgen will be additive to this projection.

In addition, the current period revenue also included 20 million of the 20 million dollar milestone payment we received from Amgen upon the initiation of the phase two clinical trial for AMG, eight and already which and I referred to as all passed for him.

Total operating expenses for the year ended September Thirtyth 2020 were 181.1 million compared to 107.6 million for the year ended September 32019.

This increase is primarily due to increased noncash stock compensation expense.

Stock stock compensation expenses increased because of the valuation of new stock.

Option and restricted stock Award Grant grants has increased with the growth of our stock price.

Kenneth A. Myszkowski: Financial.

Kenneth A. Myszkowski: Thank you, Javier, and good afternoon, everyone. As we reported today, our net loss for fiscal 2020 was $84.6 million, or $0.84 per share, based on 100.7 million weighted average diluted shares outstanding. This compares with net income of $68 million, or $0.69 per share based on 98.6 million weighted average diluted shares outstanding for fiscal 2019. Revenue for fiscal 2020 was $88 million compared to $168.8 million for fiscal 2019. Revenue in both periods primarily relates to the recognition of a portion of the upfront payments and milestones for our license and collaboration agreements with Janssen. Revenue from the Janssen Agreement is being recognized based on our estimate of the proportion of effort expended towards fulfilling our performance obligations, primarily overseeing the completion of the Phase 1-2 HPV Clinical Trial. We expect the remaining $19 million of deferred revenue to be recognized in the first half of fiscal 2021. Any additional milestones achieved with Janssen or Amgen would be additive to this projection.

Additionally, the stock compensation expense increased through the timing of the achievement of certain performance based awards and each period.

The increase in total operating expenses was also driven by the please increased clinical trial costs.

As our pipeline of clinical candidates has increased and increased personnel costs in both R&D and Gionee, who is our head count continues to grow.

Net cash used by operating activities in fiscal 2020 day was 95.4 million compared with net cash provided by operating activities of $173 million in fiscal 2019.

The operating cash generated in fiscal 2019.

Reflects the 175 million upfront payments payment for him to $25 million milestone payments received from Janssen.

Net by cash used for operations.

Turning to our balance sheet, our cash and investments.

Balances totaled 453 million at September Thirtyth, 2020, compared to 302.9 million at September 32019.

The increase for cash and investments was primarily due to the December 2019 equity financing, we completed which generated $250.5 million and net cash proceeds to the company.

Kenneth A. Myszkowski: In addition, current period revenue also included the $20 million milestone payment we received from Amgen upon the initiation of their Phase II clinical trial for AMG 890, which is now referred to as Olpasserin. Total operating expenses for the year ended September 30, 2020 were $181.1 million, compared to $107.6 million for the year ended September 30, 2019. This increase is primarily due to increased non-cash stock compensation expense. Stock compensation expense has increased because the valuation of new stock, Option, and Restricted Stock Award Grants has increased with the growth of our stock. Additionally, stock compensation expense has increased due to the timing of the achievement of certain performance-based awards in each period. The increase in total operating expenses was also driven by increased clinical trial costs, as our pipeline of clinical candidates has increased, and increased personnel costs in both R&D and G&A as our headcount continues to grow.

In addition to the cash and investments.

Assets discussed.

As of September Thirtyth 2020, we also anticipate receiving of 300 million.

From the upfront payment from Takeda for the end of this calendar year or shortly thereafter.

Similar to our agreement with Janssen, we anticipate recognizing this upfront payment as revenue over the course of.

Completing our performance obligations with and the deal.

Which primarily consist of.

The managing the ongoing arrow itchy clinical studies and providing certain manufacturing services.

Looking ahead. The 2021, we expect our full year cash burn to be in the range of 202 hundred 50 million.

This increase is due to growth throughout the company.

Our program costs are expected to increase as arrow and Sthree and air through April Cdthree begin larger phase two clinical trial.

Our newer programs continue to advance our headcount increased in 2020, and we expect continued increases in 2021, which drives increases and payroll related facility costs discovery, R&D and GE and expenses.

Kenneth A. Myszkowski: Net cash used by operating activities in fiscal 2020 was $95.4 million, compared with net cash provided by operating activities of $173 million in fiscal 2019. The operating cash generated in fiscal 2019, reflects the $175 million upfront payment and two $25 million milestone payments received from Janssen, offset by cash used for operations. Turning to our balance sheet, our cash and investments balances totaled $453 million at September 30, 2020, compared to $302.9 million at September 30, 2019. The increase in our cash and investments was primarily due to the December 2019 equity financing we completed, which generated $250.5 million in net cash proceeds to the company. In addition to the cash and investments discussed, Assets Discussed, we also anticipate receiving $300 million from the upfront payment from Takeda by the end of this calendar year or shortly thereafter. Similar to our agreement with Janssen, we anticipate recognizing this upfront payment as revenue over the course of, fulfilling our performance obligations within the deal, which primarily consists of Managing the Ongoing ARO-AHE Clinical Studies and Providing Certain Manufacturing Services.

Our common shares outstanding at September 32020, 102.4 million.

With that brief overview I will now turn the call back to Chris.

Thanks, Ken.

There's no question, we've had a productive recent period.

The more clinical experience, we gain for the trim system. The more confident we become that we're on the path to providing physicians with potentially transformational therapies. The may make a big difference and the lives of millions of patients that's important and gratifying.

We also feel confident and do we have the right strategy.

We believe the combination of focusing on the well validated targets our speed of Friday into the clinic.

Ability to address the new cell type every 18 to 24 months the.

The rapid nature of our pipeline expansion and our selected partner and model together provide our shareholders with the potential for wrap and value creation.

So what's the next for US we think our initial commercial focus on Cardiometabolic and pulmonary will allow us to build out the necessary infrastructure over the coming years and of focused and effective manner, but also in a way that is ever conscious of capital efficiency.

That has been and Arrowhead hallmark and we intend for that to continue.

And lastly, we are eager to gain clinical validation for our trim platforms for a term platform's ability to target tissues outside the liver. This includes lung tumor muscle and other tissue types and we have not yet disclosed.

Kenneth A. Myszkowski: Looking ahead to 2021, we expect our full-year cash burn to be in the range of $200 to $250 million. This increase is due to growth throughout the company. Our program costs are expected to increase as Arrow Ang3 and Arrow ApoC3 begin larger Phase 2 clinical trials, and our newer programs continue to advance. Our headcount increased in 2020, and we expect continued increases in 2021, which drives increases in payroll, related facility costs, discovery R&D, and G&A expenses. Our common shares outstanding at September 30, 2020 were 102.4 million. With that brief overview, I will now turn the call back to Chris.

Arnie works, well and the pad of sites, we know that but our goal has never been simply to address and never based disease. Rather we have always worked to bring our NII wherever it is needed and we are on the brink of demonstrating that right now.

We R&D building and different kind of biotech company and we look forward to continuing to share our progress.

And again for joining us today I would now like to open the call to your questions operator.

Thank you.

Ladies and gentlemen, the if you have a question at this time. Please press star Wonder telephone two of George Your question. Please press the pound key.

Please standby of what we compiled the Q and a roster.

And our first question comes from a lot of Sean Egan with Citi. Your line is now.

Hi, guys. Thank you for the update today and for taking my question as investors start to do work for 2021 can you maybe the set expectations for the net program the in regards to.

Christopher R. Anzalone: Thank you. There's no question we've had a productive recent period. The more clinical experience we gain with the TRMM system, the more confident we become that we are on the path to providing physicians with potentially transformational therapies that may make a big difference in the lives of millions of patients. That's important and gratifying.

What data and point, there will be a and b.

And is come up a few times and I guess what level of but at the there would give you confidence and and you guys also plan to test for ethnic knockdown or are there any other approaches you can use to validate group the concept.

Christopher R. Anzalone: We also feel confident that we have the right strategy. We believe the combination of focusing on well-validated targets... our speed from idea to the clinic. Our ability to address a new cell type every 18 to 24 months. The rapid nature of our pipeline expansion and our selective partnering model together provide our shareholders with the potential for rapid value creation. So, what's next for us? We think our initial commercial focus on cardiometabolic and pulmonary will allow us to build out the necessary infrastructure over the coming years in a focused and effective manner, but also in a way that is ever conscious of capital efficiency. That has been an Arrowhead Hallmark, and we intend for that to continue.

Sure sure and we'd like to address that yes. So.

Let me kind of with the the.

And about by when we're going to have data next year 2021 and.

It's like it to be EBIT at the end of the first half or maybe at the of the sequel.

The quote Q3 of 2021.

We got the what we think will the success was as you know one of the key efficacy and plenty said to the one and we have is that the the the slashing not the hopefully we'll be able to see a change from baseline in the range of.

Anywhere between I would say.

Life and 15% for the first so that was the approving the piece was.

Christopher R. Anzalone: And lastly, we are eager to gain clinical validation for our trim platform's ability to target tissues outside the liver. This includes lung, tumor, muscle, and other tissue types that we have not yet disclosed. RNAi works well in hepatocytes; we know that. But our goal has never been simply to address liver-based disease. Rather, we have always worked to bring RNAi wherever it is needed, and we are on the brink of demonstrating that right now. We are indeed building a different kind of biotech company, and we look forward to continuing to share our progress. Thanks again for joining us today. I would now like to open the call to your questions, operator.

An increase and if you went of approximately 5% the more coal and don't have pulled US you know more and the range of 10 of 13%. So we're looking for the up for that proof of concept scene and movement and if the one in the face went the other thing with the concealed success and I wouldn't mind and.

Let me let me also expand upon that so so when we look at and at our EPS of you on results, we're not comparing those.

To try CAFTA.

At least our initial the patient populations are going after will be those those patients who are not eligible for tuck EBITDA either they they are no no of patients and so they have no sea of target and we'll see.

Yes, you are correct.

Or they are refractory to to try to have to or the like so so.

Operator: Thank you.

Operator: Ladies and gentlemen, ladies and gentlemen.

So the bar here is really is really nothing right. The the these patients have very limited.

Operator: and if you have a question at this time, please press star 1 on your telephone. To submit your question, please press the pound key. Please stand by while we compile the Q&A roster. And our first question comes from Eliana Shawne-Egan with Citi. Eliana's now. Hi guys, thank you for the updates today and for taking my questions. As investors start to do work for 2021, can you maybe set expectations for the ENAC program in regards to what data endpoints there will be? I know FEV1 has come up a few times. I guess what level of benefit there would give you confidence? And do you guys also plan to test for ENAC knockdown? Or are there any other approaches you can use to validate proof of concept?

Therapeutic options and so and so I think the that if we can show a five.

5% of proven and I think the one that's a big thing for those patients and I think that's just the we've got a drug.

Great and then maybe one follow up question on the.

For the next program like when you consider the physical barrier of President and the page and I guess, what gives you confidence that the drug will get to the target up of the value of though.

Well so of course, we don't have anything because they thought and the small the so and we cannot answer the question definitively one other thing that were doing two per then that to happen. The is the post to dosing that we would both we have both the patients and three consecutive days.

For the three weeks of that allow us to hopefully see that the global reach of.

Javier San Martin: Sure. Javier, would you like to address that?

Javier San Martin: Yeah, so... Let me start with the comment about when we're going to have data next year 2021. And it's likely to be either at the end of the first half or maybe early, 3 Q3 of 2021.

To the anatomical areas and the non weather is necessary and so.

I think that is one of the thing the way we into two really tight the month you make of the Doe will reach the target PC and and when we first got into two pulmonary. Our first question are among our for his questions was whether or not we're able to get through the mucus and our Cana wells were non plus by that they said you know what given the size and charge of the mall.

Javier San Martin: With regard to what we think will be a success, well, as you know, one of the key efficacy endpoints is FED-1, and we have a study that is large enough that hopefully we'll be able to see a change from baseline in the range of... Anywhere between, I would say, 5% and 15%. You know, the first drug that was approved in this disease had an increase in FEV1 of approximately 5%. The more current drugs approved, as you know, are more in the range of 10% or 13%. So we're looking for that proof of concept. Seeing a movement in FEV1, in a phase one study, I think will be considered a success in our minds.

Well, we don't expect any problem to get the mucus and sure enough in animal models, whether it be the rodents or any other piece or sheep, we found out to be the case and so that was heartening. We've been asked what about CF mucus. We know that's dehydrated, we know that thats it thats a bit different unfortunately, as Javier said theres not a good and I'll model for that however, we have done and beauty.

Well the analysis using actual CF mucus and it does appear we are able to get through that so we're optimistic.

Never know until you know and so and so look the these this first study will tell us an awful lot about the of Translatability of.

Christopher R. Anzalone: And let me also expand upon that. So, you know, when we look at our FEV1 results, we are not comparing those to Trikafta. At least our initial patient populations that we're going after will be those patients who are not eligible for Trikafta. Either they, you know, they are null-null patients, and so they have no CFTR to correct, or they are refractory to Trikafta or the like. So the bar here is really nothing, right? You know, these patients have very limited therapeutic options. So I think that if we can show a 5% improvement in FEV1, that's a big thing for those patients, and I think that suggests that we have a drug.

This platform, but we go into this reasonably confident given.

Our our of our country.

And finally.

Great. Thank you so much.

You're welcome.

Thank you and the next question comes from the line of margin rig credit Raycroft with Jefferies. Your line is now open.

Hi, everyone.

That's on the progress and thanks for taking my questions. First one is also on E. snack and have two alpha also so for both programs can you provide more specifics on where the where you're at with dosing are you out of therapeutically relevant dose and is there anything else you can say and safety at this point.

Christopher R. Anzalone: Great. Maybe one follow-up question on the Arrow-ENAC program. When you consider the physical barriers present in CF patients, I guess what gives you confidence that the drug will get to the target epithelial cells?

Javier San Martin: Well, of course, we don't have preclinical data on this model, so we cannot answer the question definitively.

Yes. So there is not so much we and say that it's been our policy as you know Maury you're not to get blow by blow and we have we have given some interim data before but but you know in a more.

Javier San Martin: One of the things that we're doing to prevent that from happening is the approach to dosing that we will dose, or we are dosing patients with three consecutive days every three weeks. So that allows us to hopefully see that the drug reach out to the anatomical areas in the lung where it's necessary. So I think that is one of the things that we're doing to really try to maximize the chance that the drug will reach the target.

And different sort of environment.

So you. So we can tell you. The we are dosing patients in the in the area. The next study. We are we are at that portion of the study. So that's that is encouraging give drop of of course, we are dosing patients.

Christopher R. Anzalone: And when we first got into pulmonary, our first question, or among our first questions was whether or not we were able to get through the mucus. And our KOLs were nonplussed by that. They said, you know what? Given the size and charge of the molecule, we don't expect any problem getting it to the mucus. And sure enough, in animal models, whether it be rodents or NHPs or sheep, we found that to be the case. And so that was heartening.

Uh huh.

It's not much else like and I can tell you I I just went out and thank you with with the with Aerohive to we have not seen any day to get those data are batched and so at some point I hope and the near future. We will we will we will see some early data and will indicate whether or not we're seeing knockdown at these first doses, but this point, we just don't even know internally with arrow enac.

Christopher R. Anzalone: We then asked, what about CF mucus? We know that's dehydrated. We know that that's a bit different. Unfortunately, as Javier said, there's not a good animal model for that.

We have just begun the patient portion and so we don't have we don't have data. The are yet to know we are in a therapeutic range the.

Christopher R. Anzalone: However, we have done in vitro analysis using actual CF mucus, and it does appear that we are able to get through that. So we're optimistic. You never know until you know. And so this first study will tell us an awful lot about the translatability of this platform. But we go into this reasonably confident, given our good preclinical results.

That's the that's the big unknown for both of these we have a good idea about what the therapeutic range would be in our models, but we'll just see how this translates and this really is uncharted territory for US we have a good idea about how things translate from rodents to and HP to humans in the path of sites. This of course is our first our first foray into solid tumors.

And and and opponent of feel sales and so we'll learn a heck of a lot over the next few months.

Got it and that's helpful perspective, and then for the initial data updates midyear 21, and have you decided of if you're in the reported a conference or in the press release, and then any thoughts on the amount of patients either and included in those initial data updates.

Yeah, it's really too early to tell there. Unfortunately.

When you look of the calendar. We it appears that we will have some of these preliminary data by the middle of the year, but how much we're going to have is not clear and therefore, what sort of what sort of venue. The we can share of these data are not clear and so unfortunately I can't give you a good a good answer for that at this point.

Eliana Rachel Merle: Great! Thank you so much.

Christopher R. Anzalone: You're welcome.

Maurice Thomas Raycroft: Thank you. And our next question comes from the line of Mario Raycroft with Jeffries. Your line is now open.

Christopher R. Anzalone: Hi everyone, congrats on the progress and thanks for taking my questions. The first one is on ENAC and HIP2-alpha also. So for both programs, can you provide more specifics on where you're at with dosing? Are you at a therapeutically relevant dose? And is there anything else you can say on safety at this point?

Okay understood. Thanks for.

You're welcome.

[noise].

Christopher R. Anzalone: Yeah, so there's not so much we can say about that, you know, it's been our policy, as you know, Maury, not to give blow by blow. We have given some interim data before, but in a more different sort of environment. So, we can tell you that we are dosing patients. In the area next study, we are we are at that portion of the study. So that's encouraging.

Ladies and gentlemen, if you would like to ask a question goes star one of the telephone.

We appear to be having some technical difficulties and the the question queue has disappeared.

So we'll give everyone a few minutes to get back into that queue, because right now it seems to be to be gone.

Christopher R. Anzalone: I give to Alpha, of course; we're dosing patients. There's not much else I can tell you at this point, I don't think. With Arrowhead 2, we have not seen any data yet. Those data are being batched, and so at some point, I hope in the near future, we will see some early data that will indicate whether or not we're seeing knockdown at these first doses. But at this point, we just don't even know internally. With Arrow ENAC, we have just begun the patient phase, and so we don't have data there yet to know if we are in a therapeutic range. That's the big unknown for both of these. We have a good idea about what the therapeutic range would be in animal models, but we'll just see how this translates, and this really is uncharted territory for us. We have a good idea about how things translate from rodents to NHP to humans in hepatocytes. This, of course, is our first foray into solid tumors and pulmonary epithelial cells, so we'll learn a heck of a lot over the next few months. I got it.

Okay now reconstituting itself.

Go ahead, operator, you can move on for the next question.

The next question comes from the line of the lease young with Canaccord. Your line is now open.

Hey, guys. Thanks for taking my question and I thought the whole thing went dead for a second but I'm glad to see that we're all back up and running you know I just want to talk a little bit of out and it's a little bit Big picture, just and how you're kind of outside the extra hepatic liver approach differs from some of your competitors. The you don't want of way the whole secret sauce, but I guess.

The net worth of inherent like big picture of differences and things that you think about I mean, you know many companies say, there's something and pursuing you got the pursuing it went and a very robust way. So just why and the I've gotten the question before and I. Just went deposits you guys. And then also can you talk a little bit of out your confidence and going after him I mean, as the studies get going and I know.

Christopher R. Anzalone: Okay, that's a helpful perspective. And then for the initial data updates, mid-year 21, have you decided if you're gonna report at a conference or in a press release, and then any thoughts on the number of patients that you're gonna include in those initial data updates?

Sometimes below the trick and are in a and and kind of in that world of came up but just wanted to get kind of your perspective, but your technology.

Sure.

So the first so the first question once the.

Christopher R. Anzalone: Yeah, it's really too early to tell there, unfortunately. You know, when we look at the calendar, it appears that we will have some, at least, preliminary data by the middle of the year. But how much we're going to have is not clear. And therefore, what sort of venue we can share these data is not clear. And so, unfortunately, I can't give you a good answer for that at this point.

We have been thinking about as you know if the U.S. you of followed us for a bit we've been thinking about and working on bringing arnie I outside of the liver for probably a decade now you know the spans our even our our our prior.

Platform that we are developing and we always knew this was going to be.

And important value inflection points, we wanted to be there. So so a lot of this is just brute force we've been working on this for a decade now and so it's so we look like and overnight success and separates and been a 10 year overnight.

Christopher R. Anzalone: Okay, understood. Thanks for... Yeah, you're welcome.

Operator: Ladies and gentlemen, if you would like to ask a question, that is star 1 on your telephone.

Operator: We appear to be having some technical difficulties, and the question queue has disappeared. So we'll give everyone a few minutes to get back into that queue because right now, it seems to be gone. Okay, it's now reconstituting itself. Go ahead, operator. You can move on to the next question.

So that's more broadly more specifically of course and part of that is building a library of linker chemistries that we can use to optimize delivery and involves establishing the library of of targeting moieties are that we can use and maybe maybe most importantly, it it involves and.

Alicia Young: Our next question comes from the line of Alicia Young, with Cantor. Your line is now open. Hey guys, thanks for taking my question. I thought the whole thing went dead for a second, but I'm glad to see that we're all back up and running.

Our ability to to design. These very potent arnie I triggers again, and you know as you and you've heard us talk about in the past lead the Oh.

Christopher R. Anzalone: You know, I just wanted to talk a little bit about, and it's a little bit of a big picture, just, you know, how your kind of outside the extra hepatic liver approach differs from some of your competitors. I know you don't want to give away the whole secret sauce, but I guess, you know, what are some inherent big picture differences and things that you think about. You know, many companies say this is something they're pursuing. You guys are pursuing it in a very robust way, so I just wanted to, I've gotten this question before, so I just wanted to pose it to you guys. And then also, can you talk a little bit about your confidence in going after HIF, I mean, as those studies get going? I know, you know, it's sometimes been a little tricky in RNA and kind of in that world of PMOC, but just wanted to get kind of your perspective on your technology.

We have a set of algorithms and rules that are proprietary that enable us to you know to to design triggers that made the may not be potent in vitro, but we'll be potent in vivo and look that's important.

As it relates to getting to a pad sites because it does allow us to make to make more potent compound of site directed constructs and look at the LP Little a data that Amgen showed that was a very potent and.

Appeared to be a very potent sequence.

But it's absolutely critical when you're looking at going outside the liver because we know the there's no galnac analog if you will and other cell types. There's nothing there's no front door like that and other sales that we've ever found and so we need to squeeze all of the potency. We can out of these constructs and.

So so so that ability has been has been just critical and our in our ability to rapidly expand into law and solid tumor and and the next year and muscle cells. We hope to continue that as we talked about is the big part of our value proposition is the big part of a model.

Christopher R. Anzalone: Sure. So the first question: let's see.

Christopher R. Anzalone: We have been thinking about, as you know, you have, you know, you have followed us for a bit, we've been thinking about and working on bringing RNAi outside the liver for probably a decade now. You know, this spans, you know, our prior research of Targeting Moieties that we can use. And maybe most importantly, it involves our ability to design these very potent RNAi triggers. Again, as you've heard us talk about in the past, Olivia, we have a set of algorithms and rules that are proprietary that enable us to design triggers that may not be potent in vitro but will be potent in vivo. And look, that's important as it relates to getting to hepatocytes because it does allow us to make more potent hepatocyte-directed constructs.

Next question was around 52 Alpha so sorry, so are you asking about what we need to show vis-a-vis. The peloton Merck drug is that that would your what you're curious and well I love. It yeah kind of just to kind of flavor in context of that yes.

Sure So look so.

That.

That's been a great programming at the that the the data have looked pretty good.

And that has has helped the further validate the target. The we've been excited about also for gosh almost a decade.

And there is an opening however, they have seen some anemia. The we may see less of its too early to tell the we may see less of because were targeted.

Christopher R. Anzalone: You know, look at the LP little data that Amgen showed, you know, that was a very potent, appears to be a very potent sequence. But it's absolutely critical when you're looking at going outside the liver, because we know that there's no GalNac analog, if you will, in other cell types. There's nothing, there's no front door like that in other cells that we've ever found.

But at the end of the day, you know I think I think we just need to show a well tolerated and active drug that's a big enough market. The there's plenty of room for a couple of US I don't I'm not absolutely focused on on showing X percentage of better.

Responsiveness than that and then the competitor drug and I think we just need to be on the board and we're hopeful we can be there because as the again, we've as we talked about the past that program has value for us in two ways. One we think it's a good drug and we think it could be a helpful drug and renal cell carcinoma, we think it could play well of others, because we don't expect a lot of overlap.

Christopher R. Anzalone: And so we need to squeeze all the potency we can out of these constructs. So that ability has been critical in our ability to rapidly expand into the lung and solid tumors and, next year, muscle cells. We hope to continue that, as we talked about, this is a big part of the value proposition. This is a big part of our model. Now, the next question was about HIP2-alpha. So are you asking about what we need to show vis-a-vis the Peloton, Merck?

Lapping a ease some.

So that's that is.

Sorry interest, but second it's a good proof of concept.

If we can show that we can knock out the of two out the NVS metastasis. It will suggest to us the we have a platform and we have a franchise.

And then we can go after other gene targets and potentially other solid tumor types as we said in the past our targeting strategy here.

Is not specific to two RCC metastasis, but rather we believe it could be you could allow us to get into solid tumors more broadly.

Christopher R. Anzalone: Well, a little bit, yeah. Kind of just to get a flavor and context for that, yes.

Christopher R. Anzalone: Sure, sure. So, look, so, you know, that's been a great program. The data have looked pretty good, and that has helped to further validate a target that we've been excited about also for, gosh, almost a decade. There is an opening, however.

Great. Thanks.

Sure. Thank you.

Thank you and the next question comes with the amount of sovereign risk the with Goldman Sachs and long as no.

Christopher R. Anzalone: They have seen some anemia that we may see less of. It's too early to tell, but we may see less of it because we're targeted. But at the end of the day, I think we just need to show a well-tolerated and active drug. That's a big enough market that there's plenty of room for a couple of us.

Thank you and you know just.

And another question here on extra hepatic tissues, you plan and targeting could you walk us through your thoughts beyond lung and muscle with your strategy and on the skeletal muscle targeted asset which is entering the clinic and mid 21, when we might get the preclinical data here and and you know and he thought you could provide.

Christopher R. Anzalone: I don't, you know, I'm not absolutely focused on showing, you know, X percentage, you know, better responsiveness than the competitor drug. I think we just need to be on the board, and we're hopeful we can be there because, again, as we've talked about in the past, that program has value for us in two ways. One, we think it's a good drug, and we think it could be a helpful drug in renal cell carcinoma. We think it could play well with others because we don't expect a lot of overlapping AEs. So that is exciting to us. But second, it's a good proof of concept. You know, if we can show that we can knock down HIF-2 alpha in these metastases, it will suggest to us that we have a platform, that we have a franchise, and then we can go after other gene targets and potentially other solid tumor types. As we said in the past, our targeting strategy here is not specific to RCC metastases, but rather, we believe it could allow us to get into solid tumors more broadly.

And the initial indications that you may be targeting.

Boy I apologize you asked a lot of questions, there and I really can't answer it any of those.

We can't we taught we've talked about sell the tumor of course, and and skeletal muscle and lung. We are working on other cell types weve not disclosed any of those yet and so we're not prepared to disclose any of those at this point, but.

But but we clearly have others that we're working on as we talked about this is a big part of our growth strategy.

What we have done for the kind of sites, we want to do for long and solid tumor and muscle and for Phil and the blank a number of additional cell types with respect to.

Oh gosh since I was the other question.

The target for must start and muscle of sorry, yeah right sorry.

Again, we've we haven't we haven't talked about that yet.

Christopher R. Anzalone: Great, thanks. Thank you.

Salveen Richter: Thank you. And our next question comes from Salveen Richter.

Operator: Drifted with Goldman Sachs, Alanis Morissette and Alanis Morissette and Alanis Morissette

We gave some we have we have mentioned some early data and the get our at our R&D day last year, we haven't really shared any any non clinical data since then.

Christopher R. Anzalone: Thank you. Just another question here on the extrahepatic tissues you plan on targeting. Could you just walk us through your thoughts beyond lung and muscle with your strategy? And on the skeletal muscle-targeted asset, which is entering the clinic in mid-21, when might we get to see preclinical data here? And any thoughts you could provide us on the initial indications that you may be targeting?

I do expect the we will do it.

But we're just not prepared to do a quite yet and I'm not being coy I don't know when we're going to do it.

We feel confident that the sometime in the summer I believe.

We will will be fine its ceta for that for that that asset and so some similar upstream of that and we will talk about admitted in more depth. At this point, we're just not quite prepared to do that yet.

Christopher R. Anzalone: Boy, I apologize. You asked a lot of questions there, and I really can't answer any of those. You know, again, we've talked about solid tumors, of course, and skeletal muscle and lung. But we are working on other cell types. We've not disclosed any of those yet, and so we're not prepared to disclose any of those at this point. But we clearly have others that we're working on. You know, as we talked about, this is a big part of our growth strategy. You know, what we have done for hepatocytes, we want to do for lung and solid tumors and muscle and for, you know, fill in the blank number of additional cells with respect to gosh, I'm sorry, what was the other question?

Thank you.

Sure.

Thank you and.

The next question comes from the line of Ted Tenthoff with Piper send the your line is now.

Great. Thanks, guys and congrats on the progress really exciting since the see how part of the platforms come along and see the recognition.

Of course, what's really of to do with the cardiovascular programs most interested in and see it took the true.

Right.

Literally on the.

For the in the press release this morning.

Christopher R. Anzalone: target for muscle target muscles sorry yeah right again you know we've we haven't we haven't talked about that yet um um you know we gave some we we have we have mentioned some early data i think at our at our r&d day last year we haven't really shared any uh any non-clinical data since then um i do expect that we will do it um but we're just not prepared to do it quite yet and i'm not being coy i don't know when we're going to do it um you know we we feel confident that that sometime you know in the summer i believe um we will uh we'll be filing that cta um for that for that that asset and so some some more upstream of that um we'll talk about it in more depth but at this point we're just not quite prepared to do that yet

I'm kind of get a sense for what the cost of these sales.

These two the them stays true fees. The appreciating that you gave the guidance of 200 to two of those lets me.

Moving next year, you know when it comes on the outcome study.

What kind of what kind of cost should we be thinking.

Thank you very much.

Yes, and again I apologize Tad I these are important questions.

And I can't answer them.

We've not given guidance on what we think those costs are going to be you know at this point, we talked about how large we think the studies could be in the the phase Twob studies for the for the large outcome study.

Edward Andrew Tenthoff: Thank you. Our next question comes from the line of Ted Tenthoff with Piper Sandler. Your line is now open.

For for Arrow, and Sthree, it's not and clear what the number of those patients are going to be yet you know.

Operator: and there's now.

The probably range anywhere from 8000, if you look at Amarin studies.

Christopher R. Anzalone: Great Thanks, guys. And congrats on all the progress. It's really exciting just to see how far the platform has come and to see the recognition. My questions really had to do with the cardiovascular program, so it was interesting to see Amjad mention Lp8a in a... In a press release this morning, I'm trying to get a sense for what the costs of these phase three and phase two B's could be, appreciating that you gave the guidance of 200 to 250 million next year. You know, when it comes to an outcome study, what kind of what kind of cost should we be thinking about?

Or messes couple of studies all the way of to May of 15000, and so we need to see what our fees to be data look like for the Sherman how large that size and have to be and then and at that point, we might build the give you a bit of guidance on what we think thats been the costs for your model right now.

I think you can plug and.

What what those costs generally are for a company like us for it for the Amarin type study or the or the medicines company type study, but I can't give you better guidance and that unfortunately, I apologize none of that's okay. I think the make sense with the potency of the molecule.

Great. Thank you very much looking forward to excite and 2021.

You're welcome Thanks Ted.

Christopher R. Anzalone: Thanks for

Thank you and our next question comes from a lot of money, who are with SVB, Larry your lungs and open.

Christopher R. Anzalone: Again, I apologize, Ted. These are important questions, but I can't answer them. We've not given guidance on what we think those costs are going to be. At this point, we've talked about how large we think those studies could be, the Phase 2B studies. For the large outcome study for Arrowhands 3, it's not even clear what the number of those patients is going to be yet. They probably range anywhere from 8,000 if you look at Ameren studies or medicines company studies all the way up to maybe 15,000. We need to see what our Phase 2B data look like before we determine how large that study is going to have to be. Then, at that point, we might be able to give you a bit of guidance on what we think that's going to cost. For your model right now, I think you could plug in what those costs generally are for a company like us, for the Ameren type study or the pharmaceutical company type study, but I can't give you better guidance.

Hey, guys. Thanks, taking the question I guess building off of the what had asked earlier.

For the you can't give the guidance around the cost of some of the trial and some of which for a few years away for of course pretty tough the pick up and is that far out of.

But you've got a lot of trial going through early mid late stages and as you think about some of these asset moving forward given some of the what your metrics are in terms of the gating to move at the forward as opposed to the other.

The put the de prioritizing or shutting down program and how do you think about that at each stage of development.

Sure. So we so I think the real question there that is strategic right.

I don't think we that we have you know I don't think the were considering shutting down and the programs right. Now I think the question is do we partner these programs or do you hold on to them internally right now it feels like like we can't build out of commercial infrastructure for pulmonary and Cardiometabolic. We have good line of sight I think.

Christopher R. Anzalone: No, that's okay. I think that makes sense.

Christopher R. Anzalone: That's okay.

Christopher R. Anzalone: Great. Thank you very much. Looking forward to an exciting 2021.

Luca Issi: Thank you. And our next question comes from the line of,

On half a dozen potential pulmonary drugs that we can that we can develop.

Javier San Martin: Mani Foroohar with SVB Larynx and Ilana Znaupi. Hey guys, thanks for taking the question. I'm building off of what Ted asked earlier, so I know you can't give specific guidance around the cost of some of these trials, some of which are a few years away, so, of course, pretty tough to make estimates that far out. But you've got a lot of trials going through early, mid, and late stages. As you think about some of these assets moving forward, give us a sense of what your metrics are, in terms of accelerating to move assets forward, as opposed to deprioritizing or shutting down programs. And how do you think about that at each stage of development?

Their 60000, Pulmonologists and the U.S. and so we like that leverage.

Of of addressing of fell a fairly large market with only about 16000 touch points, where we can sell and any.

Any number of of drugs into it that makes sense to us cardiometabolic as well look we the arrow and three and Arrow FSC three or are are potentially big drugs.

And we and we could see ourselves build that sales force.

Addressing cardiologists and lip and clinics to sell those two drugs and makes sense to us as we go forward those will not be the last two areas that we're going to build commercial infrastructure around I think thats for sure, but right now given our current clinical pipeline, we can make that that.

That forecast as we as we bring and additional candidates into the clinic and as we address new cell types, we can expand that going forward, but right now that makes sense to us. So then when you look at our assets outside of that it doesn't mean that we're going to partner all those it just means that that the that we've got.

Christopher R. Anzalone: Sure. So I think the real question there is strategic, right? I don't think that we're considering shutting down any of the programs right now. I think the question is, do we partner with these programs, or do we hold on to them internally? Right now, it feels like we can build out a commercial infrastructure for pulmonary and cardiometabolic diseases. We have a good line of sight, I think, on half a dozen potential pulmonary drugs that we can develop. There are 16,000 pulmonologists in the U.S., and so we like that leverage of addressing a fairly large market with only about 16,000 touch points where we can sell any number of drugs to it. That makes sense to us. Cardiometabolic as well.

And we've got a little bit of the higher bar I suppose of when we're when we think about building another sales force there. So they take for instance of two alpha.

That's our only oncology drug and makes no sense for us to build all sales force to sell to sell one drug and that becomes a franchise like we think of it could that could make sense for us to add on the commercial franchise. There and it also makes sense to do a hybrid approach of of finding the right oncology partner to help us build that out and also established commercial.

Javier San Martin: Look, we think Arrow ANG3 and Arrow ApoC3 are potentially big drugs, and we could see ourselves building a sales force targeting cardiologists and lipid clinics, you know, to sell those two drugs. That makes sense to us. As we go forward, those will not be the last two areas that we're going to build commercial infrastructure around. I think that's for sure.

The chops, it's just it's a bit too early to tell at this point.

Thanks Scott.

You're welcome.

Thank you and the next question comes from the line of Lukas busy with RBC capital. Your line is now.

Christopher R. Anzalone: But right now, given our current clinical pipeline, we can make that forecast. As we bring additional candidates into the clinic, and as we address new cell types, we can expand that going forward. But right now, that makes sense to us. So, when you look at our assets outside of that, it doesn't mean that we're going to partner with all of them. It just means that we've got a little bit of a higher bar, I suppose, when we think about building another sales force there. So, say, take, for instance, HIF-2-alpha. If that's our only oncology drug, it makes no sense for us to build a whole sales force to sell one drug. But if that becomes a franchise, like we think it could, it could make sense for us to add on a commercial franchise there. It could also make sense, you know, to do a hybrid approach of finding the right oncology partner to help us build that out and also establish commercial chops. But it's a bit too early to tell at this point.

Oh the terrific. Thank for taking my question and not just a quick one and.

The first one I think I saw include the Freida golf and the size of the hit to I'll try and has been recent the reviews from 40 patients to 18 patients as the wondering if you have any color there and medium of more broadly thoughts and partnering I think you just articulated but that but any thoughts there big picture thoughts would be helpful. And then the second and.

It would seem some data for our young is the on the Nacco of course, the antisense oligonucleotides and again.

Again wondering if you have any thoughts and that did affect thank you.

Oh sure of how the air do you want to take the the controls as well as the of the Enac and I'll I'll circle back Sir So the two study correct, we changed and amended protocol and revenue this year the with the.

Multitude of April and the recent was to reassess really well we went up and then from that study and the two really think that we get about number one safety and them and to let able to get it for the cells and none of them to in order to the that we didn't need the 40 basis and he said he was saying I guess, the very ambitious and proto and.

Who really of and they different doses of sequences and then we made the the season the selling through the first thing for US which is proof of concept that we get for the tumor and we.

Christopher R. Anzalone: You're welcome.

Christopher R. Anzalone: Thank you. And our next question comes from the line of Luca Issi with RBC Capital. Your line is now open.

Christopher R. Anzalone: Oh, terrific. Thanks for taking my question. Just two quick ones.

We know of them the team as we dealt with all of the leave it at that and so that's the reason to do that get the proof of concept and safety the a set of if possible.

Luca Issi: The first one, I think I saw on clinicaltrial.gov that the size of the HIF-2 alpha trial has recently been reduced from 40 patients to 18 patients. So wondering if you have any color there, and maybe more broadly thoughts on partnering. I think you just articulated it, but any thoughts there or big picture thoughts would be helpful. And then the second is, I think we've seen some data for Ionis on the ENAC, of course, antisense oligonucleotides. Again, wondering if you have any thoughts on that data set? Thank you.

Okay, and so I think of it and I'll be back and that brand for the of two partnering.

So we.

Look we're excited about that about that franchise and about that platform, having said that oncology is hard.

And so and so and perfect World, we can achieve proof of concept for him to alpha to show. The we can do this and then bring in the right oncology partner to help us.

Christopher R. Anzalone: Sure. Javier, do you want to take the quintrials as well as the ENAC, and then I'll circle back?

The prioritize our next set of targets and then do some with that partner and the maybe some by ourselves.

Javier San Martin: So the HIF-2 study. We changed and amended the protocol early this year, I think it was March or April, and the reason was to reassess what we really wanted to learn from that study. And there are really two things that we care about. Number one, safety, and number two, if we're able to get into the cells and knock down HIFs. In order to do that, we didn't really need 40 pages. Initially, it was, I guess, a very ambitious program to really evaluate different doses and those sequences. And then we made the decision to say, let's do the first thing first, which is prove the concept that we get to the tumor. And we knock down the gene, as we've done with all the liver targets. So that's the reason to do that, get to proof of concept and safety rate as early as possible.

That's where we are right now you are do we have to partner hip to the Canada itself, not necessarily but I, but I, but I do hope that that the that the data will be compelling enough to enable us to blow out that that platform. If you will and the best way to do that would be at least the lease in part with the partner and so how the or you want to talk about the enac with the Ioannis.

Yes, so when we look at that date the carefully when the the schools the and month of so ago and you know.

My opinion of the they thought it's not currency and that initially I think we filled because of the for those groups and only one so the and movement within the about 50% and though down and that wasn't the highest dose was the second highest though so I think first glance it seems the theme.

Our pension and we're working on and we decided to the work on C., we can replicate the and so our data so wedding that doses to think about of work on the development of the scope of US day and were thinking about how to do this in the clinical trial, whether it's with good heavy none of my healthy volunteers.

Javier San Martin: Okay, and so I'll piggyback on that for the HIF-2 partnership. So, look, we're excited about that franchise and about that platform. Having said that, oncology is hard. And so, in a perfect world, we can achieve a proven concept for HIF-2 alpha to show that we can do this, and then bring in the right oncology partner to help us prioritize our next set of targets, and then do some with that partner, and then maybe some by ourselves. That's where we are right now. Do we have to partner with HIF-2, the candidate itself? Not necessarily, but I do hope that the data will be compelling enough to enable us to blow up that platform, if you will. And the best way to do that would be, at least in part, with a partner. And so, Javier, you want to talk about Enoch with Ionis?

And or patients. So we're working on it was interesting.

I think and I I said I am.

And my question Mark about the day going.

Terrific. Thank you.

Welcome.

Thank you and our next question comes from the lot of the Madhu Kumar with Baird. Your line is now.

Hey, everyone. Thanks for taking our questions I guess my first one of the tenant the elephant in the room, which is the reef one trial with gay and Jay and the tide is be so kind of by our back of the envelope calculations near the end of last year as what we might expect kind of the 48 weeks of treatment from that trial to kind of income.

Javier San Martin: Yeah so we look at that data carefully when they disclosed a month or so ago and you know my opinion on the data is that it's not as consistent as initially I think we thought because it is four dose groups and only one show a movement within about 50% note down and that wasn't the highest dose it was the second highest dose so I think first glance it's interesting it got our attention and we're working on it we decided to really work on see if we can replicate that and show our data so we're in that process to think about or work on the development of the proper assay and we're thinking about how to do this in the clinical trial whether it's going to be normal healthy volunteers and or patients so we're working on it it was interesting but again I said I had my question mark about the data.

The plus some degree of number crunching do we expecting and visibility of from Jane Jay about the kind of timing for the release of at least the 48 week treatment data from week, one like how do you think about any kind of data cadence from that hepatitis B trial.

Thanks, Mike and so Thats funny. So you asked about the you mentioned the open the room, I was thinking which help and of that and and the and the reef one was not a true bidding the kind of line. Okay. So so I can't give any guidance on that.

You have to look of JNJ for that as I recall, it was 48 weeks of treatment and and six months of follow up.

And so so that that's the best I can I can give you at this point of I.

Luca Issi: Terrific. Thank you. Welcome.

Madhu Sudhan Kumar: Thank you. Our next question comes from the line of Madhu Kumar with Baird. Your line is now open.

I can tell you and we've talked about it and the past we're really excited about about that drug candidate. We're really excited about JJ, we think that they have been extraordinarily fast and thoughtful about all of these trials and that theyre, starting its multinational and so the all of that makes us really excited to be their partner and but I can't give you any guidance on when those data might.

Christopher R. Anzalone: Hey everyone, thanks for taking our questions. I guess our first one is kind of the elephant in the room, which is the REEF-1 trial with J&J and hepatitis B. So, kind of by our back-of-the-envelope calculations, near the end of last year is when we might expect kind of the 48 weeks of treatment from that trial to kind of conclude, plus some degree of number crunching. Do we expect to get visibility from J&J about the timing for the release of at least the 48-week treatment data from REEF-1? Like, how do you think about any kind of data cadence from that hepatitis B trial?

Come out.

Okay, and then moving on the 18. So you mentioned here you mentioned before this idea of streamlining kind of clinical development of 80 basis on the effects, you've seen and the open label extension. So I mean, how are you thinking about that and there's some kind of like nominal price bids we should be looking at for kind of endpoint comparison.

Christopher R. Anzalone: And the reef one was not, didn't even come to my mind. Okay, so I can't give you any guidance on that. You know, you'll have to look to J&J for that. As I recall, it was 48 weeks of treatment and then six months of follow-up.

And he's ore and of composite endpoint of that might come into play and the trial and alpha one antitrypsin liver disease.

Christopher R. Anzalone: And so, that's the best I can give you at this point. I can tell you, and we've talked about it in the past, we're really excited about that drug candidate. We're really excited about J&J. We think that they have been extraordinarily fast and thoughtful about all these trials that they're starting. It's multinational, and so all that makes us really excited to be their partner. But I can't give you any guidance on when those data might come out.

So Javier has probably dying to answer that question of I can't let him answer it at this point [laughter], here's here's the deal.

We were we had we were so excited about those data for a lot of reasons and I believe the which is and is that.

The suggested this drug is doing what we wanted to do and back doing a bit faster than we expected and so we are going with those data and probably some additional data to the FDA to talk about change and endpoints and and and changing size and maybe changing the duration of the study until we have those those discussions it's probably not appropriate for us to the.

Christopher R. Anzalone: Okay, and then moving on to AAT, so you mentioned here, you mentioned before this idea of stress.

Christopher R. Anzalone: Clinical Development of AAT Based on the Effects You've Seen in the Ultralabel Extension

Christopher R. Anzalone: So Javier is probably dying to answer that question, but I can't let him answer it at this point.

Speculate on and on the specifics of what those changes could be I don't want to get out in front of this conversation and we've had a very good collaborative relationship with the FDA as it relates to the program. We expect this to continue to be collaborative and.

Christopher R. Anzalone: The deal, you know, we were, we have been so excited about the data for a lot of reasons, not the least of which is that, you know, they suggested this drug is doing what we wanted it to do, in fact, doing it a bit faster than we expected. And so we are going with those data and probably some additional data to the FDA to talk about, you know, changing endpoints and, and, and changing size and maybe changing the duration of the study. Until we have those discussions, it's probably not appropriate for us to speculate on the specifics of what those changes could be.

And I, just don't want to jeopardize that I want to have that discussion and open discussion with them and then come back to you and tell you what we have.

What the what we've decided together.

Okay, and and stepping back on the macro so you mentioned the the dean of the call. The idea of going after the targets, where there is kind of validation from the outside side to the community. So.

What does that exactly me and like are we talking and of genetic validation are we talking like earlier kind of integrations of therapy and like anything of that moving forward kind of what you need for and given target to get you all excited about it.

Christopher R. Anzalone: I don't want to get ahead of this conversation, but you know, we've had a very good collaborative relationship with the FDA as it relates to this program, and we expect this to continue to be collaborative. And I just don't want to jeopardize that. I want to have that discussion, you know, an open discussion with them, and then come back to you and tell you what we have decided together.

Yeah, I think it's all those things right you know I think it's I think it is it is it is early data for.

From some other drugs that looks good but because of safety reasons off target safety reasons. They couldn't go forward I think its gwas analysis, you know with all with all of the increasing the amount of GE lost data that are coming out there is an awful lot of important genetic data.

Christopher R. Anzalone: Okay, then stepping back on the macro, so you mentioned at the beginning of the call the idea of going after targets where there is kind of validation from the outside community. What exactly does that mean? Like, are we talking about some kind of genetic validation? Are we talking about earlier, kind of iterations of therapy? And like, how do you think about that moving forward kind of what you need for a given target to get?

That that can that can validate the targets and so think HST I think the lesser extent, but still enac and also experimental data. There there are a number of targets the that that have been the.

Studied in animal models, but for one reason or the or another you couldn't be druggable in humans. So look we're just looking and this is a very as you know.

This is this is a business full of risk and we're just looking where we can lop off risk and we think we can if we can if we can remove or lease limit target risk. That's a good thing for us and so and so we don't you for me say of before we should not be and the in the target validation business. When we are.

Christopher R. Anzalone: Target to get y'all excited. Yeah, I think it's all those things, right? You know, I think it's I think it is, it is, early data from some other drugs that look good, but because of safety reasons, you know, off-target safety reasons, they couldn't go forward. I think a GWAS analysis, you know, with all of the increasing amount of GWAS data that are coming out, there's an awful lot of important genetic data that can, you know, validate a target, think HSD And also experimental data, you know, there are a number of targets that have been studied, you know, in animal models, but for one reason or another, they couldn't be druggable in humans. So, look, we're just looking at this is very, as you know, you know, this

You need to shaking the vital of pals and remind me of that because because I think this is an important thing is this is this is an important luxury and we have at least at this point.

Especially given the we can go outside the liver, we've got all the new tissues now and so and so we can we can go through and an awful lot of of validated targets before we have to start taking charge of risk I think.

Okay, and one last one how are you thinking about multi organ targeting and what the opportunities pieces, where you could go after targets that are expressed for more than one tissue.

Multi organ targeting so so so with the one construct a dressing adjusted different cell types of the question.

Maybe not one maybe would be the existing target, but targeting the going after document of that gene across multiple different tissue types and once.

Christopher R. Anzalone: This is a business full of risk, and we're just looking where we can lop off risk. And we think if we can remove or at least limit the target risk, that's a good thing for us. And so we don't – you've heard me say this before. We should not be in the target validation business. When we are, you need to shake me by the lapels and remind me of that, because I think this is an important thing – this is an important luxury that we have, at least at this point, especially given that we can go outside the liver. We've got all these new tissues now, and so we can go through an awful lot of validated targets before we have to start taking target risks, I think.

Sure you know, we're not doing that right now.

But yes, you know for us for some disease and certainly that would be of interest that that's why we try that we try to the to limit complexity, what you're talking about as elegant.

The complex and so and so.

I don't think that again I think that there are enough good targets out there right now that we don't have to introduce that level of complexity that may change at some point for right now that's not a real focus of ours.

Christopher R. Anzalone: Okay, and one last one. What how do you think about multi-organ systems?

Gotcha.

Christopher R. Anzalone: multi-organ targeting so so so with one construct addressing and adjusting different cell types that question

Okay. Thanks for my Hugh.

And our next question comes from the line of May day mom tightly with B. Riley Securities. Your line is the health.

Christopher R. Anzalone: Maybe not one, maybe it would be the same target, but going after the knockdown of that gene across multiple different tissue types at once.

Hey, good afternoon, and thanks for taking my question and then can you add some and productive quarter day. So if I may ask another the other thing in the room type of question, So, Dave which will go and you'd think is going to be the flow of first to market and your view of the high then how did you think about building and commercial.

Christopher R. Anzalone: Uh, sure. You know, we're not doing that. Not right now.

Christopher R. Anzalone: But yes, you know, for some diseases, certainly that would be of interest. That's, that's, we try to, we try to limit complexity. What you talk about is elegant, but complex. And so and so I don't think that, again, I think that there are enough good targets out there right now that we don't have to introduce that level of complexity. That may change at some point. But right now, that's not a real focus Gotcha.

And I wish them on a you know a gloss cardiometabolic and bumble and but that May one day, which program are you thinking.

I would get would cross the finish line flow given all the between GAAP and cash to all the looking at.

Yeah, that's a good question.

So the so able to see three against FCS could be.

Christopher R. Anzalone: Okay, thanks very much. Thank you.

Christopher R. Anzalone: And our next question comes from the line of Mayank Mamtani with B. Reilly Securities. Hey, good afternoon, Dean.

So could be a relatively near a relatively speaking near term market opportunity as we as we talked about on the on the K well women are we're thinking that could be you know a 60 or so patient pivotal study.

Mayank Mamtani: So if I may ask another elephant in the room type of question. So Chris, which program do you think is going to be the first to market, in your view? And how does Zain think about, you know, building a commercial organization, you know, across cardiometabolic and pulmonary franchises, like, which program are you thinking would cross the finish line first, given all the different gantt charts you guys are looking at?

You know, we're a bit of head of ourselves now because we haven't started that study yet, but but that feels to me like like that could mean nearest term.

A wildcard here could be Arrow and act.

You know I don't again, I don't want to get out over my skis, because we haven't seen a day to yet, but but should those day to be.

The exciting should they should they should the data in the phase one two study.

Christopher R. Anzalone: Yeah, that's a good question. So, ApoC3 against FCS could be, you know, could be a relatively near, or relatively speaking, near-term market opportunity. You know, as we talked about on the KOL webinar, we think that could be, you know, a 60 or so patient pivotal study. But we're a bit ahead of ourselves now because we haven't even started that study yet. But, but that feels to me like, like that could be a nearish term. A wild card here could be Arrow-ENAC.

Suggest of that that we have something here it could be the that that we could you move directly into a phase two three study.

The earliest that could be would be the end of next year, because we don't have talks coverage until then but that's a possibility.

And and and so.

All right and the other wildcard here would be will be partnered programs of course 80.

A big a big possibility here is is we'll see how good it has good hobby areas.

You know what the once we have those discussions with the FDA and other regulators, while the good idea about whether or not we can shorten up that that.

That a time to watch the market I think we can I think that we can make a very compelling arguments as to why we can do that and so that's one of the possible. One I don't know if youre talking only about wholly owned or more broadly speaking, but I guess that runs the gamut of partnered and wholly owned.

Christopher R. Anzalone: Again, I don't want to get out over my skis because we haven't seen any data yet, but should the data be exciting, should the data in this Phase 1-2 study suggest that we have something here, it could be that we could move directly into a Phase 2-3 study. The earliest that could be would be the end of next year because we don't have tox coverage yet. And sorry, the other wildcard here would be partnered programs. Of course, AAT, you know, a big possibility here is, you know, we'll see how good Javier is. But, you know, once we have those discussions with the FDA and other regulators, we'll have a good idea about whether or not we can shorten that time to market. I think that we can make a very compelling argument as to why we should do that. And so that's another possible one. I don't know if you're talking only about wholly owned or more broadly speaking, but I guess that runs the gamut of partnered and wholly owned.

Well on the and also how you build the commercial organization I guess the data.

Some of these and.

Some guy and will drive a lot of that.

All of 'em.

Well done at the.

It's a question about when we start to build the the commercial organization.

Yeah, it's and.

Absolutely.

The.

I'm thinking what about the strong how do other think about lately.

On the in the house.

How should we think about that.

Yeah, I can't give any guidance on that at this point, let's let us get into the phase three study with FCS, let's see how fast that kind of role and then we kind of a better idea about what we are looking at of course AG, we're not going bill.

Christopher R. Anzalone: I guess the data and some of the other...

Christopher R. Anzalone: Interaction points will drive a lot of that. Is that kind of fair?

Christopher R. Anzalone: Is the question about when we start to build the commercial organization?

Commercial organization, there won't be working with with the cadence of worked commercial organization and then Enac again that it's just the just a bit too early let's give us and give us a bit of time hopefully next year.

Christopher R. Anzalone: Yeah, essentially, like. I'm thinking more about the span, right, how to think about where you want Wagner and you.

Christopher R. Anzalone: and how should we think about that?

And what we can have a better idea about timeframe and then have a better idea about about spend for the commercial build out.

Christopher R. Anzalone: Yeah, I can't give any guidance on that at this point. Let's, you know, get into the phase three study with FCS, let's see how fast that can enroll, and then we can have a better idea about what we're looking at. Of course, AAT, we're not gonna build a commercial organization there. We'll be working with the cadence to build the commercial organization. And then ENAC again, it's just a bit too early. Let's, you know, give us a bit of time. You know, hopefully next year, we can have a better idea about the timeframe and then have a better idea about the spend for the commercial build out.

Understood and then just two quick follow ups of good could you address the new add to it as the true.

Ill draw of guys and you envision go hard but.

But I'm, assuming you're seeing some liver enzyme data of the minimum of what is the data Kid and disclosure on the and then 12 of the only massive doses patients out in the business for Alcoholics and audits and and my final question.

Christopher R. Anzalone: And then just two quick follow-ups. Could you address the ARO-HSD trial progress and you are in the patient cohort, but I'm assuming you're seeing some liver enzyme data at the minimum. What is the data cadence disclosure and confirm if only NASH cirrhosis patients are in there, there's no alcoholic cirrhotics? And my final question.

If you've not heard down your.

So you blog.

India flow and.

And gold and who just the net down due out a lot of you doing the are you doing other approaches odds and gold and thanks for taking my questions.

Christopher R. Anzalone: Question. If you've narrowed down your, you know, three-pronged R&D effort in COVID to just direct antivirals, or are you doing something else?

Sure. Thanks for the questions. Let me go let me start with the Kobe and go backwards.

Christopher R. Anzalone: Blender

Christopher R. Anzalone: Are you doing other approaches also in COVID? Thanks for taking the time to answer my questions.

So so we are and we are still.

Christopher R. Anzalone: Sure, thanks for those questions. So let me start with COVID and go backwards. So we are still investigating some anti-inflammatory strategies, in large part because that coincides with developing these anti-inflammatory medicines for other disease areas. And so that just works well, and so we're still pursuing that, you know, as we pursue the antiviral approach, you know, for hopefully broader coronaviruses.

Interrogating some anti inflammatory.

And strategies.

In large part because that coincides with with developing the anti inflammatory.

Medicines for other disease areas and so the so that just works well and so we're still pursuing that.

You know as as we pursue the of the anti viral approach for hopefully for us for the for broader current of ours is now.

Christopher R. Anzalone: Now, what was the first question?

Christopher R. Anzalone: As you may know, there's no known circulating biomarker, and so we have to rely on biopsies, and we're just looking for gene knockdown. In most of our, as you know, most of our Phase 1 and 2 studies, we're looking for not just safety and finding a dose, but we're looking for other activity measures. Here, we're just looking to find a dose, so we'll be taking biopsies and looking at knockdown. And then, based on that, we will take a dose or two forward into the next phase.

Some of the gun host first question HST exiting the are you write that okay. So he just the.

That is helpful and as Ed.

As you May know, there's there's no known circulating biomarkers and so we are really so we have to rely on biopsies and we're just looking for for gene knockdown of this.

And most of our as you know the most of our phase one two studies were looking for.

Not for non 50, and finding and dose and we're looking we're looking for for other actually the measures here. We're just looking to find a dose the and so so we'll be taking biopsies and looking and knockdown and then based on that we can we will take a dose or two forward into the study.

Christopher R. Anzalone: And for enrollment, that's just NASH, suspected NASH, and no alcoholic beverages.

Christopher R. Anzalone: Thank you.

Christopher R. Anzalone: Great, thank you.

Christopher R. Anzalone: Thank you. And we have time for one more question. So our last question comes from Eliana Patrick Trucchio with H.C. Wainwright.

Christopher R. Anzalone: Thanks. Good afternoon.

Christopher R. Anzalone: I have a few follow-ups. The first one is on NASH. So just regarding the Phase 1-2 trial in NASH, can you remind us if participants in this study are expected to be confirmed NAFLD or NASH patients, and if that is to be confirmed by FibroScan or biopsy or some other methodology?

Study.

And for enrollment, that's just Nash expected national alcohol and Scott. Thank.

Thank you.

Great. Thank you.

You're welcome.

Thank you and we have time for one more question. So last question comes from the amount of how true crucial with and C. Wainwright and has no.

Javier San Martin: Javier

Javier San Martin: That should be the first of the three questions.

Javier San Martin: Yeah, the first one is just a phase 1-2 trial in NASH. Can you remind us if the participants in the study are expected to be confirmed NAFLD or confirmed NASH patients?

Thanks, Good afternoon, and I have a few follow ups first one is on that so just regarding the phase one two trial and math.

Javier San Martin: I got it so

Javier San Martin: Thank you. We are enrolling patients that we have suspected of NASH, and that's a broad definition that includes the MRIs of the...

And your mind active participants in the study are expected to be income from not for the or Nash patients and.

Javier San Martin: AgroScan, the MRI data in terms of liver fat and metabolic syndrome and baseline LSD. So it's a combination of those three things, but we do not require to have confirmed an FLD of NASH, but most people who have those clinical features are likely to have an FLD. If someone has a biopsy prior to the study that's defined as NASH, then that patient will be enrolled in the study. Well, the broader question about clinical development in NASH, of course, it's a very complex situation. And as you know, many, many large pharma companies or midsize pharma companies are working on this. The development of the guidance took easily a year, 10 years or so to get to where they are right now.

And can be confirmed by the fiber scan or for biopsy or some other methodology and then second.

Secondly, can you can you tell us how you think about the regulatory bar and not specifically of the regard the 2018 guide and food safety would be and three trials against the backdrop on some of these recent challenges and drug development and the space and.

And and then finally can you talk about what mechanisms. The you believe if any could be of synergistic with arrow each of the and potential comet the combination treatment of Nash.

Okay. That's it for the first one of the three of the two question yes.

Yeah. The first one is just on the phase one two trial and Nash if you can remind us of the it's the participants in the study are expected to be confirmed map of the year or confirmed mass, but each of them.

Javier San Martin: And it is complex. The whole endpoint that they are asking for to be approved is complex because of the way people read this biopsy, the category of fibrosis level, and all those complexities. So we're at the very beginning of our journey. We're looking for proof of concept that, you know, HST is doing what it's supposed to. And at that point, we need to think carefully about how to develop a drug for NASH. And as we understand better, perhaps the mechanism of function, we may be able to select the patient population in a more, you know, smart fashion. But with regard to the overall development plan, phase two, phase three biopsies, and what is necessary to be approved, you know, for now, we may need to follow what the team proposes as a sky lab.

Got it so thank you well, we and building patient the we have suspect the Nash and thus the brought the finishing that include the Emory I. So the others cash they MRI data and most of liver fat and metabolic syndrome and baseline LSD. So it's a combination of both the thief of Weve not required.

And have come from.

And it of the of net but most of the people who we had those clinique of features are likely to have net for the if someone of how the biopsy prior to the study that the fine now less than the patient will be will be it would be enrolled in the study.

Well the other question about Clinique and the minimum in us of course, it's a very complex situation and as you know many many large pharma companies for me say pharma company and working them. These the development of the Guy the Twoq.

Javier San Martin: The last question was on synergy with other mechanisms or agents.

Javier San Martin: Well, you know... Um, you know, NASH seems to be a disease that can start at different points and evolve via different mechanisms. And when you look at all the drugs in development, you can try to target different aspects of the disease, those who are more metabolically oriented, more inflammation oriented, or more fibrotic oriented.

We see a 10 year sort of so to get the where the out right now and the these companies the whole endpoint the data.

Asking for too to be approved.

It's complex because the way people read these payoffs the the theory of fibrosis level and.

All of those complexities. So one of the very beginning of of our journey, we're looking out of the proof of onto the the.

Javier San Martin: Where are we in that mix? We don't know. We don't think that maybe we're on the metabolic side. So that could be an interesting and clinically, like, in my opinion, like a scenario how to go about it. But, you know, I think we need to wait. We need to learn more about our own role and how the field of Nash evolves in the next couple of years.

The HST is doing what it's supposed to and at that point, we need to think carefully how to that of the go for much and that's we understand that the but has the the.

Making the for fashion, we may be able to select the patient population and the more smart of fashion, but we think that the the overall development plan face to face the biopsies and for the instead of the be approved for now we may need to follow what is.

Javier San Martin: Yeah, if I may, just one follow-up question on the imaging and biopsy and evaluation of patients for NASH. Can you talk about the advances in the evaluation of non-invasive imaging or biomarkers that can enable potentially quicker enrollment of mid and later stage NASH studies as compared to what we've been accustomed to historically and where we are in that process? Chase, would you like to shortlist that question? Sure, sure, I can take a stab at that. Certainly, if there's another option, an alternative to liver biopsy. Something like MRI, PDF, or MRE would be preferable.

In the both the of Sky, though.

And last question.

The synergy with other mechanisms range well you know.

And that seems to be of the see the kind of and defend the starting point and they've all of the beef and make anything and when you look of broadly all the broken development and you can cite the Doug and the filling up the of the DC built quite a moment that would equal the intermodal inflammation of the until my more fibrosis liquidity and.

Well, we and the and me we.

We don't know, we don't think that maybe what in the mid Atlantic side, so that could be and interesting and clinically.

Javier San Martin: And that'd be something that's quite ready for prime Time as an approvable endpoint.

Right.

My opinion like a scenario of how to go about these the.

But you know I think we need the way we need to learn more about our ongoing how the feel of Nash and for the next couple of years.

Javier San Martin: But looking down the road, I mean, MRI, and PDF are already used a lot in clinical studies, phase two clinical studies, and I would suspect that MRE will become

Yes, if I may just one one follow up on the and the imaging and and biopsy and the valuation on patients for match here.

Javier San Martin: More commonly,

Can you talk about the advances and evaluation of non invasive imaging or biomarkers I'm not commit enabled potentially quicker enrollment of mid and later stage NAV studies as compared to what weve been accustomed to historic weighted and where we are and that process.

Javier San Martin: you know, a key endpoint in Nash studies or other studies of liver disease down the road.

Javier San Martin: Produced Broadly Down The Road

Christopher R. Anzalone: That's helpful. Thank you very much.

Operator: And this does conclude today's question-and-answer session. We'll now let the term...

Hi.

Christopher R. Anzalone: Turn the call back to Chris Anzalone for any closing remarks.

And would you like to assertiveness, not quite sure sure check and I can take a stab at the.

Christopher R. Anzalone: Well, thanks everyone for participating today and listening to the call. I hope that you all have a happy and safe Thanksgiving weekend.

Yes, certainly if there is another option and alternative to liver biopsy.

Something like MRI pdfs for Emory that would be preferable.

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

Those at least in the setting Emery that may not be something that's quite ready for prime time, as an approvable endpoint, but.

But looking down the road I mean, the MRI PFS is already use a lot.

Operator: ???

And and clinical studies phase two clinical studies and I would suspect that Mari will become more commonly looked at as.

The key endpoints and Nash.

Nash studies for other studies of liver disease broadly of down the road.

That's helpful. Thank you very much.

Thank you and.

This does conclude today's question and answer session well now that the turn the call back the Chris and his alone for any closing remarks.

Well, thanks, everyone for participating today and listening to the call.

Hope for you all have a happy and safe Thanksgiving weekend.

Ladies and gentlemen. This concludes today's conference call you may now disconnect and participate.

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