Q1 2021 Arrowhead Pharmaceuticals Inc Earnings Call

Ladies 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. There will be an opportunity to ask questions. I will now hand, the conference call over to Vince and Selene, Oh, Vice President of Investor Relations for Arrowhead.

Unknown Executive: Hello everyone. Welcome to the Arrowhead Pharmaceuticals conference call. Throughout today's recorded presentation, all participants will be in a listen-only mode.

Unknown Executive: After the presentation, there will be an opportunity to ask questions. I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

Go ahead Vince.

Vincent Anzalone: Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2021. The first quarter ended December 31st, 2020. With us today from management are President and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter. Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, who has graciously agreed to sub in for Dr. Javier San Martin while he is out ill

Okay.

Good afternoon, everyone and thank you for joining us today to discuss arrowheads results for its fiscal 2021 first quarter ended December 31, 2020 with US today from management from President and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter Dr. James Hamilton, Our senior Vice President discovery and translational matter.

Who has graciously agreed to some in per Doctor Javier Martinez, while he was out yesterday.

Vincent Anzalone: And Ken Myszkowski, our Chief Financial Officer, will give a review of the financials. In addition, James Hazard, our Chief Commercial Officer, will be available during the Q&A portion of today's call. 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 subject to numerous risks and uncertainties.

Ken Moskovsky, our Chief Financial Officer, who will give a review of the financials.

James Hazard, our Chief commercial officer will be available during the Q&A portion of today's call.

Before we begin I would like to remind you that comments made during today's call contains certain forward looking statements within the meaning of section 27 day from the Securities Act of 1933 and section 21 of the Securities Exchange Act from 1934, all statements other than statements of historical fact, including without limitation those with.

Respect to arrowheads 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 subject to numerous risks.

And uncertainties.

Vincent Anzalone: It could cause actual results to differ materially from those expressed in any forward-looking statement. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and subsequent quarterly reports on Form 10-Q. Arrowhead disclaims any intent and undertakes no duty to update any of the forward-looking statements discussed on today's call. With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company.

Could cause actual results to differ materially from those expressed in any forward looking statements for further details concerning these risks and uncertainties. Please refer to our SEC filings, including our most recent annual report on form 10-K, and subsequent quarterly reports on form 10-Q.

<unk> disclaims any intent and undertakes no duty to update any of the forward looking statements discussed on today's call.

With that said I'd like to turn the call over to Christine's Aloni, President and CEO of the company Chris. Thanks.

Christopher R. Anzalone: Thanks, fans. Good afternoon, everyone, and thank you for joining us today.

Thanks Vince.

Afternoon, everyone and thank you for joining us today.

Christopher R. Anzalone: The last quarter was an important period for us and our shareholders because we demonstrated clear advances in multiple development programs that we believe represent key value drivers for the respective product candidates and our proprietary trim platform. We see this as positioning us well to build substantial value throughout 2021. We seek to create value in two primary ways. First, we push RNAi and our platform forward to address new diseases, therapeutic areas, and organs. This is fundamentally difficult and uncertain because it relies on innovation. Second, we drive our existing pipeline into later stage clinical studies toward eventual commercialization. This can be more straightforward and, we believe, increasingly predictable as we generate large amounts of data regarding how well the TRMM platform works. We would expect progress in either of these areas would drive value for us, but our goal is to show measurable progress in both.

The last quarter was an important period for us and our shareholders because we demonstrated clear advances in multiple development programs that we believe represent key value drivers for the respective product candidates and our proprietary trim platform we.

We see this is positioning us well to build substantial value throughout 2021.

We seek to create value in two primary ways first we push Arnie I and our platform forward to address new diseases therapeutic areas in Oregon systems. This is fundamentally difficult and uncertain because it relies on innovation.

We drive our existing pipeline into later stage clinical studies toward eventual commercialization.

This can be more straightforward and we believe increasingly predictable as we generate large amounts of data regarding how well the trim platform works.

We would expect the progress in either of these areas will drive value for us, but our goal is to show measurable progress in bulk.

Christopher R. Anzalone: As we look at 2021, we expect substantial progress on both fronts, with several opportunities in the first half of the calendar year alone. By the middle of the year, we could have clinical proof of concept for our ability to bring RNAi outside the liver, opening a whole new range of addressable diseases without adequate treatment. We also expect to begin three large phase 2B studies and a phase 3 study during this time frame. And we may also have a better idea about how we at Takeda may be able to streamline the Arrow AAT clinical program to accelerate that drug candidate to market. Let's begin by looking at our earlier stage program. The power of Arrowhead's TRMM platform is our ability to rapidly discover and develop multiple new drugs targeting diverse disease areas in a way that is predictable, reproducible, and with an attractive safety profile. Each new program builds upon prior programs, which could make them progressively lower risk.

As we look at 'twenty 'twenty, one we expect substantial progress on both fronts with several opportunities in the first half of the calendar year alone.

For instance by the middle of the year, we could have clinical proof of concept for our ability to bring arnie I outside the liver opening a whole new range of addressable diseases without adequate treatments.

We also expect to begin three large phase <unk> studies and the phase III study during this timeframe and we May also have a better idea about how we indicate that may be able to streamline the arrow AEP clinical program to accelerate that drug candidates to market.

Let's begin by looking at our earlier stage programs the power of their own heads trim platform is our ability to rapidly discover and develop multiple new drugs targeting diverse disease areas in a way that has been predictable reproducible and with an attractive safety profile each.

Each new program builds upon prior programs.

Which could make some progressively lower risk we've seen this in our liver targeted programs and are applying this concept to our extra hepatic initiatives.

Christopher R. Anzalone: We've seen this in our liver-targeted programs and are applying this concept to our extra-hepatic initiatives. We hope to do in many other tissues what we have done in the liver. Given our clinical experience in hepatocyte-targeted programs, specifically in HPV, AAT, ApoC3, ANG3, and LPa, we generally expect future hepatocyte-directed candidates, such as Arrow HSD and others, to also be highly potent and well-tolerated. Creating this type of expectation in a new cell type could represent a substantial value creation event.

We hope to do in many other tissue is what we have done in the liver.

Given our clinical experience in hepatocytes targeted programs, specifically in HBV, a T apoc, III and three and L. P. Little a we generally expect future hepatocytes directed candidates such as Arrow HST and others to also be highly potent and well tolerated creating.

Creating this type of expectation and a new cell type could represent a substantial value creation event now imagine leveraging that not not only in a single new cell type, but with many new cell types.

Christopher R. Anzalone: Now imagine leveraging that not only in a single new cell type, but with many new cell types. As we have said in the past, we expect to be able to target a new cell type every 18 to 24 months. If we can pull this off, we would expect it to provide a huge amount of leverage in value creation.

As we've said in the past, we expect to be able to target a new cell type every 18 to 24 months. If we can pull this off we would expect it to provide a huge amount of leverage and value creation.

Christopher R. Anzalone: This is exciting, and it's one reason I believe that the progress we've made over the recent time periods could be just a prelude to something bigger. We think we are now on the cusp of having clinical data to assess the ability of TRMM to knock down target genes in the lung and in solid tumors, and we are working toward bringing our first muscle-targeted program into the clinic late this summer. What will success look like for these new programs, and what have we seen so far? First and foremost, we need to have an acceptable safety profile.

This is exciting and it's one reason I believe that the progress we've made over the recent time periods could be just a prelude to something bigger we.

We think we are now on the cusp of having clinical data to assess the ability of trim to knockdown target genes in Milan and in solid tumors and are working towards bringing our first muscle targeted program into the clinic late this summer.

What will success look like from these new programs and what have we seen so far first and foremost we need to have an acceptable safety profile. The trim platform for liver delivery has been administered and literally thousands of patients.

Christopher R. Anzalone: The Trim Platform for Liver Delivery has been administered to literally thousands of patients, so we have a good idea about how it works. While the new tissue types are built on the same idea and the same fundamental platform, they are structurally distinct. Therefore, first we need to establish that these new molecules are well tolerated before we can take a breath and exhale and then focus on assessing efficacy in humans. We think we are almost at that exhale stage now.

So we have a good idea about how that performs while the new tissue types are built on the same idea and same fundamental platform. They are structurally distinct. So so first we need to establish that these new molecules are well tolerated before we can take a breath and exhale and then focus on assessing efficacy in humans. We think we are almost at that ex hail.

Stage now.

Christopher R. Anzalone: The studies are still ongoing, and data collection continues, but so far, we have not seen anything concerning on the safety and tolerability front for Arrow-ENAC, which is our first lung targeted program, or for Arrow-HIF-2, our first tumor targeted program. We still have not seen activity data from either program, but expect to start to see data in the coming months. We hope to share some early data by the middle of the year for both programs. Regarding Arrow ENAC, we hope to have preliminary FEV1 data in patients from the first one or two dose levels and also have some ENAC knockdown data in healthy volunteers via bronchial brushing and lavage. Well, longer term, we are, of course, focused on functional improvements in patients. However, the healthy volunteer data at this point may be more informative.

Studies are still ongoing and data collection continues but so far we have not seen anything concerning on the safety and Tolerability and Tolerability front or <unk>, which is our first lung targeted program or for arrowhead queue. Our first tumor targeted program.

We still have not seen activity data from either program, but expect to start to see data in coming months, we hope to share. Some early data by the middle of the year for both programs regarding <unk>, we hope to have preliminary <unk> data in patients from the first one or two dose levels and also have some enact knockdown data in healthy volunteers.

<unk> be a bronchial brushing and lavage.

While longer term, we are of course focused on functional improvements in patients the healthy volunteer data at this point may be more informative given the small number of patients we will be treating in the current study only four per cohort on active drug it may be difficult to discern F&B. One changes however, enact knockdown in healthy volunteers should be much easier to interpret.

Christopher R. Anzalone: Given the small number of patients we will be treating in the current study, only four per cohort on active drug, it may be difficult to discern FEV1. However, ENAC knockdown and healthy volunteers should be much easier to interpret, therefore this is our primary focus right now. Should this be positive, it would represent a huge leap forward for our company and for the entire R&AI field. We believe it would suggest we may not only have a drug in Arrow-ENAC but we may also have a lung franchise that could be leveraged against many gene targets for many different diseases. This would indeed be a big event.

Therefore, this is our primary focus right now.

Should this be positive you would represent a huge leap forward for our company and for the entire Arnie I field. We believe it would suggest we may not only have the drug in narrowing.

But when they also have a long franchise that could be leveraged against many gene targets from many different diseases. This would indeed be a big event.

Regarding arrowhead two we hope to have some preliminary knockdown data to share by the middle of the calendar year.

We're taking biopsies from metastases pretreatment and during treatment and we will be assessing hip two alpha knockdown.

This is too small a study in two short an observation period to be focused on progression free survival, but we think if we are able to show good reduction in hip two alpha expression in these metastases, we will have demonstrated something truly important.

Christopher R. Anzalone: Regarding Arrowhead 2, we hope to have some preliminary knockdown data to share by the middle of the calendar year. We're taking biopsies from metastases pre-treatment and during treatment, and we'll be assessing HIF-2-alpha-noctin. This is too small a study and too short an observation period to be focused on progression-free survival, but we think if we are able to show good reduction in hip-to-alpha expression in these metastases, we will have demonstrated something truly important. HIF-2-alpha is a well-validated target, particularly for the clear cell form of renal cell carcinoma.

<unk> is a well validated target, particularly for the clear cell form of renal cell carcinoma, so demonstrating a consistent reduction in expression could be strong evidence that we have a drug further and potentially more importantly, we believe it could have also suggest that we have a solid tumor franchise.

Our targeting strategy is not designed to be RCC specific but rather to enable delivery to a variety of solid tumor types.

If we can share reduction of any gene product inside of solid tumors. In this case two alpha it would suggest to us that we can address a wide variety of cancer targets across different solid tumors as a clinical proof of concept in Milan. This would be a giant leap forward and could represent a substantial value inflection point.

Christopher R. Anzalone: So demonstrating the consistent reduction in expression could be strong evidence that we have a drug. Further, and potentially more importantly, we believe it could also suggest that we have a solid tumor franchise. Our targeting strategy is not designed to be RCC specific but rather to enable delivery to a variety of solid tumors. If we can show reduction of any gene product inside of solid tumors, in this case HIF-2 alpha, it would suggest to us that we can address a wide variety of cancer targets across different solid tumors.

By the end of the second calendar quarter, we could have proof of concept that we can silence gene expression with RNA eye in three different cell types across eight different clinical programs I don't believe there is another company on the planet that can say that.

Later in the summer, we expect to increase our reach to a fourth cell type when we expect to file a cta for our first skeletal muscle targeted program.

While we're conducting these clinical studies, we continue to work in parallel on multiple additional targets in tumor and pulmonary.

Christopher R. Anzalone: As with clinical proof of concept in the lung, this would be a giant leap forward and could represent a substantial value in flexion. By the end of the second calendar quarter, we could have proof of concept that we can silence gene expression with RNAi in three different cell types across eight different clinical programs. I don't believe there is another company on the planet that can say that.

For the latter we have a number of early programs in development and I expect us to file at least two pulmonary cta's in calendar 2021.

We also continue work on our COVID-19 program. We are focused on developing an antiviral approach and are interrogating a number of different arnie I triggers targeting different positions within the current virus and potentially other corona viruses as well.

Christopher R. Anzalone: Later in the summer, we expect to increase our reach to a fourth cell type when we expect to file a CTA for our first skeletal muscle-targeted program. Meanwhile, while we're conducting these clinical studies, we continue to work in parallel on multiple additional targets in tumor and pulmonary. For the latter, we have a number of early programs in development, and I expect us to file at least two pulmonary CTAs in calendar 2021. We also continue work on our COVID-19 program. We are focused on developing an antiviral approach and are interrogating a number of different RNAi triggers, targeting different positions within the current virus and potentially other coronaviruses as well.

While we are excited about the the various vaccines mutations in the current virus and preparation for the next Corona virus suggest to us that our work continues to be important.

In addition, we are now starting to see promising early results on pulmonary formulation work that may open up some important new possibilities specifically, we've been evaluating the possibility of using an inhaler device as opposed to a nebulizer formulation for some indications.

That would improve convenience and could make for a more viable commercial product for higher prevalence diseases large patient populations.

Our plan for Errol lung, two which is in development to treat COPD was to begin the clinical program with the Nebulize formulation and then toward necessary and then to work out the necessary.

Ali to switch over to an inhaler, we have decided to hold off on the Cta for now since we are increasingly encouraged by our new possibilities. We don't think this slows the program's time to market and in the end may actually shapes from time off overall development. If the inhaler formulation work enables a more direct path.

Christopher R. Anzalone: While we are excited about the various vaccines, mutations in the current virus and preparation for the next coronavirus suggest to us that our work continues to be important. In addition, we are now starting to see promising early results on pulmonary formulation work that may open up some important new possibilities. Specifically, we have been evaluating the possibility of using an inhaler device as opposed to a nebulized formulation for some indications. That would improve convenience and could make for a more viable commercial product for higher prevalence diseases with a large patient population. Our plan for Arrow Lung 2, which is in development to treat COPD, was to begin the clinical program with a nebulized formulation and then to work out the necessary technology to switch over to an inhaler. However, we have decided to hold off on the CTA for now, since we are increasingly encouraged by our new possibilities.

The ultimate goal is to take forward, a therapeutic with optimal efficacy safety and convenience in a form that is useful to physicians and their patients. We will provide an update over the next quarter pending completion of a few ongoing studies.

Let's now shift to our later stage programs and discuss our progress toward commercialization.

Last quarter, we presented positive data from our Arrow, a T Aero Apoc, III and Arrow and three programs. We were very encouraged by the results and believe they support rapid advancement of these programs.

Typically we presented phase two data at a S. L D on arrow, a T showing strong reductions in the production of the mutant Z <unk> protein and improvements in multiple biomarkers of Alpha one liver disease.

Christopher R. Anzalone: We don't think this slows the program's time to market and, in the end, may actually shave some time off overall development if the inhaler formulation work enables a more direct path. The ultimate goal is to take forward a therapy with optimal efficacy, safety, and convenience in a form that is useful to physicians and their patients. We will provide an update over the next quarter, pending the completion of a few ongoing studies. Now, let's shift to our later stage programs and discuss our progress toward commercialization. Last quarter, we presented positive data from our Arrow AAT, Arrow ApoC3, and Arrow ANG3 programs. We were very encouraged by the results and believe they support the rapid advancement of these programs. Specifically, we presented Phase II data at AASLD on Arrow AAT, showing strong reductions in the production of the mutant Z-AAT protein and improvements in multiple biomarkers of Alpha-1 liver disease. This was exciting for us, for the Alpha One field, and for our partner, Decatur.

This is exciting for us for the Alpha one field for our partner Takeda.

These data were from biopsies after only six months of treatment. We also expect to have 12 month biopsy data over the next month or two.

Plan on discussing those data with the FDA and proposing some changes to the study design and endpoints with the goal of shortening the time to a potential NDA.

For Aero Apoc, III and Arrow and three we presented new data on phase one two studies and multiple medical meetings, including the European Society of Cardiology, and the American Heart Association meetings, and subsequently hosted K, well webinars to discuss the data and our plans for their future development.

These plants have continued to progress and we are now preparing to begin the next stages of development. In fact, we have already filed an IND for Arrow and story and intend to proceed with a phase <unk> study pending FDA review.

Arrow, a T Aero Apoc, III and Arrow and three are all getting to points, where the regulatory and development path and potential timelines become clearer.

I believe is a key event.

For all three programs the data generated to date have suggested that the drugs are doing what they are designed to do.

There is also a clear need in each disease for new therapeutics.

Christopher R. Anzalone: These data were from biopsies after only six months. We also expect to have 12-month biopsy data over the next month or two. We plan on discussing those data with the FDA and proposing some changes to the study design and endpoints with a goal of shortening the time to a potential NDA. For Arrow ApoC3 and Arrow ANG3, we presented new data on Phase 1-2 studies 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. These plants have continued to progress, and we are now preparing to begin the next stages of development.

With increased regulatory clarity, we may soon have a direct line of sight from the timelines required to have multiple potential commercial products as long as the day to continue to support advancement and we continued to execute efficiently.

We have a high level of confidence about both.

In the first half of the year, we expect the following one pending FDA review, we intend to begin a phase <unk> dose finding clinical study of <unk> III.

To file an IND for Aero Apoc III and then later following FDA review begin two phase <unk> studies and potentially a phase III study in patients with familial Chylomicron EMEA syndrome.

Three engage with FDA on design endpoints size and duration of treatment for potentially streamlined arrow a T study in.

Christopher R. Anzalone: In fact, we have already filed an IND for Arrow Ang3 and intend to proceed with a Phase 2B study pending FDA review. Arrow AAT, Arrow ApoC3, and Arrow ANZ3 are all getting to points where the regulatory and development path and potential timelines become clearer. This, I believe, is a key event. For all three programs, the data generated to date have suggested that the drugs are doing what they are designed to do. There is also a clear need in each disease for new therapeutics. With increased regulatory clarity, we may soon have a direct line of sight for the timelines required to have multiple potential commercial products as long as the data continue to support advancements and we continue to execute efficiently. We have a high level of confidence about both.

And for potentially report on 12 month biopsy results from the 2002 open label study of Arrow a T.

By the middle of the year, we plan to be on track to share preliminary data for Aero HST in healthy volunteers and in patients with Nash and suspected Nash.

We expect it to be the first company to have clinical data using any modality against the target HST 17 beta 13.

The genetic validation is strong for inhibiting the target and there's clearly substantial unmet need in Nash. So we're eager to see these data and evaluate the next steps for this program.

Silencing HST is thought to confer a possible protective effect against liver disease, but given the biology of this target we would not expect a decrease in liver fat there from what we are looking for is simply depth and duration of knockdown, we expect aero HST to be a potent drug candidate as has been the case for our four for our other site.

Christopher R. Anzalone: In the first half of the year, we expect the following one pending FDA review: We intend to begin a phase two B dose finding clinical study of Arrow Ange 3. 2, file an IND for Arrow ApoC 3, and then later, following FDA review, begin two phase 2B studies and potentially a phase 3 study in patients with familial chylomicronemia. 3, engage with FDA on design, endpoints, size, and duration of treatment for a potentially streamlined Arrow AAT study, and 4. possibly report on 12-month biopsy results from the 2002 Open Label Study of Arrow AAT. By the middle of the year, we plan to be on track to share preliminary data for Arrow HSD in healthy volunteers and in patients with NASH and suspected NASH.

Targeted drug candidates.

In the second half of the year, we expect the following one collective potentially report on 18 month biopsies from the 2002 open label study of <unk>.

To potentially begin phase <unk> studies for arrow in at Arrowhead, II and Aero HST and.

And three began a number of smaller phase <unk> studies for <unk> three in Aero Apoc III that will run in parallel with the studies I've already described there.

There are a number of questions that we would like to answer in both programs that we could address in short and open label studies. So so so we expect a regular data readouts for these programs while the lager blinded studies are ongoing.

With that overview I'd now like to turn the call over to Dr. James Hamilton James.

Christopher R. Anzalone: We expect to be the first company to have clinical data using any modality against the target HSD 17 beta 13. The genetic validation is strong for inhibiting the target, and there's clearly a substantial unmet need in NASH. So we are eager to see these data and evaluate the next steps for this program. Silencing HSD is thought to confer a possible protective effect against liver disease, but given the biology of this target, we would not expect a decrease in liver fat. Therefore, what we are looking for is simply the depth and duration of the knockdown.

Thank you, Chris and good afternoon, everyone.

We plan to have preliminary data this year for arrow enact arrowhead to an arrow HST I would like to go through the general designs for those clinical studies and provide an update on their status.

First I will discuss <unk> index, our inhaled <unk> therapeutic candidate designed to target the epithelium sodium channel to treat cystic fibrosis or CF.

CF is a rare disease caused by a genetic mutation that leads to mucus buildup in the lungs.

It is characterized by airway dehydration and reduced Mucociliary transport.

Patients with CF can have difficulty breathing and experienced frequent and persistent lung infections.

Christopher R. Anzalone: We expect Arrow HSD to be a potent drug candidate, as has been the case for our four other hepatocyte targeted drugs. In the second half of the year, we expect the following. 1.

<unk> is in a phase one two dose escalating study to evaluate the safety tolerability and pharmacokinetic effects of Aero <unk> in up to 24 normal healthy volunteers.

Christopher R. Anzalone: Collect and potentially report on 18-month biopsies from a 2002 open-label study of Arrow AAT, to potentially begin Phase 2B studies for Arrow Enoch, Arrow HIF-2, and Arrow HSD. 3 Begin a number of smaller Phase 2b studies for Arrow Ang3 and Arrow ApoC3 that will run in parallel with the studies I have already described. There are a number of questions that we would like to answer in both programs that could address in short and open-label studies. So we expect regular data readouts for these programs while the longer blinded studies are ongoing. With that overview, I'd now like to turn the call over to Dr. James Hamilton.

And to evaluate the safety tolerability and efficacy in up to 24 patients with CF.

The patient portion of the study includes three cohorts two of six patients each and one with 12 patients. This was the initially planned design.

We intend to make protocol changes shortly that will add an additional 12 healthy volunteers, who will undergo a bronchoscopy with bronchial brushing and bronchial alveolar lavage or P. A L to evaluate enact knocked down into one.

We are also considering expanding the CF patient cohorts as well.

We've completed dosing in all initially planned single dose healthy volunteer cohorts.

James C. Hamilton: Thank you, Chris, and good afternoon, everyone. Since we plan to have preliminary data this year for Arrow-ENAC, Arrow-HIF-2, and Arrow-HSD, I would like to go through the general designs for those clinical studies and provide an update on their status. First, I will discuss Arrow-ENAC, our inhaled RNAi therapeutic candidate designed to target the epithelial sodium channel to treat cystic fibrosis, or CF. CF is a rare disease caused by a genetic mutation that leads to mucus buildup in the lungs. It is characterized by airway dehydration and reduced mucociliary transport. Patients with CF can have difficulty breathing and experience frequent and persistent lung infections. Arrow-ENAC is in a Phase 1-2 dose escalating study to evaluate the safety, tolerability, and pharmacokinetic effects of Arrow-ENAC in up to 24 normal healthy volunteers and to evaluate the safety, tolerability, and efficacy in up to 24 patients with CF.

And we've been pleased with the safety and Tolerability results to date.

We believe this is an important finding for <unk> and for the pulmonary trim platform as we begin to expand our pipeline into additional diseases in the lung.

This is particularly relevant to drugs inhibiting enoch as many of the small molecule <unk> inhibitors have been dose limited by toxicity.

We are now dosing CF patients in the first cohort, which we expect to be fully enrolled before the end of next month at which time, we plan to begin enrolling the second patient cohort.

So what data do we expect from this study.

First and most importantly, we are assessing safety and tolerability in all cohorts.

And the expanded healthy volunteer cohort as I mentioned, we will be conducting bronchial brushing M. P. A L.

This method may give us a signal on target engagement and a better understanding of pharmacologic activity.

James C. Hamilton: The patient portion of the study includes three cohorts, two with six patients each and one with 12 patients. This was the originally planned design. We intend to make protocol changes shortly that will add an additional 12 healthy volunteers who will undergo bronchoscopy with bronchial brushings and bronchial alveolar lavage, or BAL, to evaluate ENAC knockdown in the lungs. We are also considering expanding the CF patient cohorts as well. We've completed dosing and all initially planned single dose healthy volunteer cohorts, and we have been pleased with the safety and tolerability results to date. We believe this is an important finding for Arrow ENAC and for the pulmonary trim platform as we begin to expand our pipeline into additional diseases in the lungs.

Remember that <unk> is not secreted. So we are not able to measure target engagement in the blood as we are typically able to do for our liver targeted programs.

In addition in CF patients, we will be measuring changes in F&B, one and in lung clearance index or LCI.

These would be indications of functional improvements and yuka ciliary clearance in lung function.

There is clearly a lot of data coming out of this first in human studies. So we are eager to see the arrow Enoch results.

The next program I'd like to highlight is arrowhead too.

Aero hip two is designed to treat clear cell renal cell carcinoma, or RCC and we are currently dosing RCC patients in a phase <unk> dose finding clinical study in three cohorts of at least six patients each for a total of 18 patients with advanced clear cell RCC.

James C. Hamilton: This is particularly relevant to drugs inhibiting ENAC, as many of the small molecule ENAC inhibitors have been dose limited by toxicity. We are now dosing CF patients in the first cohort, which we expect to be fully enrolled before the end of next month, at which time we plan to begin enrolling the second patient cohort. So what data do we expect from this study? First and most importantly, we are assessing safety and tolerability in all cohorts. In the Expanded Healthy Volunteer Cohort, as I mentioned, we will be conducting bronchial brushings and BAL.

The study is designed to evaluate the safety of arrowhead too and to determine the recommended phase II dose. We are also assessing pharmacokinetics and preliminary efficacy based on resist.

As well as post dose tumor expression of <unk>, two alpha and if associated genes.

We were dosing the second cohort at this time, which we expect to be fully enrolled this month.

James C. Hamilton: This method may give us a signal on target engagement and a better understanding of pharmacologic activity. However, remember that ENAC is not secreted, so we are not able to measure target engagement in the blood, as we are typically able to do for our liver-targeted program. In addition, in CF patients, we will be measuring changes in FEV1 and in the Lung Clearance Index, or LCI. These would be indications of functional improvements in mucociliary clearance and lung function. There's clearly a lot of data coming out of this first in human studies, so we are eager to see the Arrow ENAC results. The next program I'd like to highlight is Arrow HIF-2.

The patients in this study are heavily pretreated and have failed multiple lines of therapies. So a positive result for this first in human study would include data, suggesting delivery to tumors as well as measurable levels of hip to knockdown.

Similar to <unk>, we're also looking to characterize safety and Tolerability and to select the dose for further face further studies in phase two.

The last program I'd like to describe as Arrow HST, our investigational candidate for the potential treatment of alcohol and non alcohol related liver disease.

There was strong genetic data supporting HST 17 to be 13, as a target for Nash and alcoholic liver disease.

James C. Hamilton: Arrowhip2 is designed to treat clear cell renal cell carcinoma, or RCC, and we are currently dosing RCC patients in a phase 1b dose finding clinical study in three cohorts of at least six patients each for a total of 18 patients with advanced clear cell RCC. The study is designed to evaluate the safety of Arrow HIF-2 and to determine the recommended phase two dose. We were also assessing pharmacokinetics and preliminary efficacy based on RASIST, as well as post-dose tumoral expression of HIF2-alpha and HIF-associated genes. We are dosing the second cohort at this time, which we expect to be fully enrolled this month. The patients in this study are heavily pre-treated and have failed multiple lines of therapies, so a positive result for this first-in-human study would include data suggesting delivery to tumors as well as measurable levels of HIF-2 knockdown.

We are conducting a phase <unk> single and multiple dose escalating study to evaluate the safety Tolerability pharmacokinetics and pharmacodynamic effects of Aero HST in normal healthy volunteers as well as in patients with Nash or suspected Nash.

We've completed the single dose portion of the study in healthy volunteers.

We're currently enrolling and dosing the multiple dose patient portion of the study in Nash or suspected Nash patients.

We have completed the first patient cohort and expect to complete enrollment of the second patient cohort this month.

After that is complete there are two more patient cohorts to enroll sequentially.

This target is also not secreted so in order to assess target engagement, we utilized liver biopsies.

It is important to mention that this study only involves two doses, which relative to other later stage Nash studies is only a short duration of exposure. So we don't expect to see substantial signs of disease improvement, but rather we are focused on selecting the dose level in a regimen achieving optimal gene targets silencing.

James C. Hamilton: Similar to Arrow ENAC, we are also looking to characterize safety and tolerability and to select a dose for further studies in phase 2. The last program I'd like to describe is Arrow HSD, our investigational candidate for the potential treatment of alcohol and non-alcohol related liver disease. There is strong genetic data supporting HSD17B13 as a target for NASH and alcoholic liver disease.

However, we know the platform is highly effective at silencing Hepatocytes Express genes. So we would expect a high level of target engagement.

James C. Hamilton: We are conducting a phase 1-2 single and multiple dose escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of Arrow HSD in normal healthy volunteers, as well as in patients with NASH or suspected NASH. We've completed the single-dose portion of the study in healthy volunteers. We are currently enrolling and dosing the multiple-dose patient portion of the study in NASH or suspected NASH patients. We have completed the first patient cohort and expect to complete enrollment of the second patient cohort this month. After that is complete, there are two more patient cohorts to enroll sequentially. This target is also not secreted.

In addition, we were the first to study inhibition of this target in humans. So we will see if there are any early encouraging signs of efficacy, even though this would be unexpected.

As mentioned earlier, we expect all three of these programs to have preliminary data readouts around the middle of the year.

It's too early to know in which order they will come but we expect this to be an exciting period with all these potential data reports coalescing roughly around the same time.

Our intention would be to report topline data highlights in a press release and then further present, a fuller data set at an appropriate medical meeting.

I will now turn the call over to Ken Moskovsky Arrowheads, Chief Financial Officer, Ken.

Thank you James and good afternoon, everyone.

As we reported today, our net loss for the quarter ended December 31, 2020 was $20 7 million or <unk> 20 per share based on $102 8 million fully diluted weighted average shares outstanding.

James C. Hamilton: So in order to assess target engagement, we utilize liver biopsy. It's important to mention that this study only involves two doses, which relative to other later stage NASH studies is only a short duration of exposure. So we don't expect to see substantial signs of disease improvement, but rather we are focused on selecting the dose level and regimen achieving optimal gene target silencing. However, we know the platform is highly effective at silencing hepatocyte-expressed genes.

This compares with a net loss of $2 7 million or <unk> <unk> per share based on $97 1 million fully diluted weighted average shares outstanding the quarter ended December 31 2019.

Revenue for the quarter ended December 31, 2020 was $21 3 million compared to $29 5 million for the quarter ended December 31 2019.

Revenue in both periods relates to the recognition of a portion of the upfront payments and milestones received from our license and collaboration agreements with Janssen.

James C. Hamilton: So we would expect a high level of target engagement. In addition, we are the first to study inhibition of this target in humans, so we will see if there are any early encouraging signs of efficacy, even though this would be unexpected. As mentioned earlier, we expect all three of these programs to have preliminary data readouts around the middle of the year. It's too early to know in which order they will come, but we expect this to be an exciting period with all these potential data reports coalescing roughly around the same time. Our intention would be to report top-line data highlights in a press release and then further present a fuller data set at an appropriate medical meeting. I will now turn the call over to Ken Myszkowski, Arrowhead's Chief Financial Officer. Ken?

Revenue in the current period also includes the recognition of a portion of the $300 million upfront payment.

Upon the signing of the collaboration agreement with Takeda.

This payment was received in January.

Revenue for the Janssen at Takeda agreements will be recognized because we continue to work toward completing our performance obligations of managing clinical trials.

The clinical trials and process and certain manufacturing related services we.

We anticipate the remaining deferred revenue of $6 $7 million associated with the Janssen collaboration will be recognized in the next fiscal quarter.

The remaining 292 point million of revenue associated with the Takeda collaboration is anticipated to be recognized over approximately two years.

Kenneth A. Myszkowski: Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended December 31, 2020 was $20.7 million, or 20 cents per share, based on $102.8 million fully diluted weighted average shares outstanding. This compares with a net loss of $2.7 million, or $0.03 per share, based on $97.1 million fully diluted weighted average share is outstanding for the quarter ended December 31, 2019.

Any additional milestones achieved with our collaboration partners would be additive to this projection.

Total operating expenses for the quarter ended December 31, 2020, or $45 4 million compared to $34 3 million per the quarter ended December 31 2019.

This increase was primarily due to increased personnel costs and noncash stock compensation and R&D as our headcount continues to grow.

The increase was also due to increased candidate specific and discovery R&D costs.

Net cash used in operating activities. During the quarter ended December 31, 2020 was $38 9 million compared with net cash used in operating activities of $23 5 million during the quarter ended December 31 2019.

Kenneth A. Myszkowski: Revenue for the quarter ended December 31st, 2020 was $21.3 million compared to $29.5 million for the quarter ended December 31st, 2019. Revenue in both periods relates to the recognition of a portion of the upfront payments and milestones received from our license and collaboration agreements with Janssen. And revenue in the current period also includes the recognition of a portion of the $300 million upfront payment due upon the signing of the collaboration agreement with Takeda. This payment was received in January. Revenue for the Janssen and Decatur agreements will be recognized as we continue to work toward completing our performance obligations of managing clinical trials, the clinical trials in process, and certain manufacturing-related services.

The key driver of this change was the increased R&D costs.

Just.

We continue to estimate our full year cash burn to be between $200 million from 250 minutes.

Turning to our balance sheet, our cash and investments totaled $416 2 million at December 31, 2020, compared with 453 million at September 32020, a.

A decrease in our cash and investments was primarily due to cash used for operating activities.

With the collection of the $300 million upfront payment in January 2021 per cash.

Our current cash and investments total approximately $700 million.

Our common shares outstanding at December 31, 2020 were $103 2 million.

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

Thanks, Ken.

We have a lot in front of us this year.

We expect waves of clinical data readouts throughout the year from Arrow HST Aero ANAC Arrowhead to Arrow Apoc III.

Kenneth A. Myszkowski: We anticipate the remaining deferred revenue of $6.7 million associated with the Janssen collaboration will be recognized in the next fiscal quarter. The remaining $292 million of revenue associated with the Takeda collaboration is anticipated to be recognized over approximately two years. Any additional milestones achieved with our collaboration partners would be additive to this projection.

Barrow and three an arrow a T.

We expect to gain clarity on potentially streamlining and accelerating the arrowhead <unk> development program.

We expect to initiate multiple phase <unk> studies for Aero, HST Aero, Apoc, III, and arrow, and three and possibly for Aero ANAC and Arrowhead too.

We also expect to initiate a phase III study for <unk> three in Fcs patients.

We expect to file at least three new Cta this year, including our first <unk> candidate targeting skeletal muscle.

Kenneth A. Myszkowski: Total operating expenses for the quarter ended December 31, 2020 were $45.4 million, compared to $34.3 million for the quarter ended December 31, 2019. This increase is primarily due to increased personnel costs and non-cash stock compensation in R&D as our headcount continues to grow. The increase is also due to increased candidate-specific and discovery R&D costs. Net cash used in operating activities during the quarter ended December 31, 2020, was $38.9 million, compared with net cash used in operating activities of $23.5 million during the quarter ended December 31, 2019. The key driver of this change was the increased R&D cost discussed.

And by the end of the year I expect arrowhead to have at least 11 clinical programs targeting four different cell types and eight of those clinical programs could be wholly owned.

This is indeed, a substantial amount of potential value creation we.

We feel great about where arrowhead is today and we're confident about what we can accomplish going forward. It seems like all the pieces are in place for scalable and sustainable growth.

We have a strong balance sheet and are disciplined in our use of cash which allows us to move forward rapidly in a capital efficient manner.

We also are eligible for substantial non dilutive capital in the form of milestone payments from Amgen Janssen indicator as our partnered programs continue to advance and ultimately if any other products are commercialized we will be eligible for royalties on sales.

We have an increasingly validated technology platform in true.

And we believe.

We believe treatments on the verge of potentially showing that arnie I can be a powerful therapeutic mechanism for diseases throughout the body.

A large and rapidly growing pipeline of differentiated product candidates addressing diseases without adequate treatment options. These are all innovative first in class molecules not fast follower incremental or me too products.

Kenneth A. Myszkowski: We continue to estimate our full-year cash burn to be between $200 million and $250 million. Turning to our balance sheet, our cash and investments totaled $416.2 million on December 31, 2020, compared with $453 million on September 30, 2020. The decrease in our cash and investments is primarily due to cash used for operating activities, plus the collection of 300 million upfront payment in January 2021 per cash. Our current cash and investments total approximately $700 million. Our common share is outstanding as of December 31st, 2020. We're 103.2 million. With that brief overview, I will now turn the call back to Chris.

And lastly, we have the right team in place and our unwavering culture of challenging the norms of drug development.

We had always finds a way to be better faster and more efficient than others in the field.

This is a powerful combination and it gives us the opportunity to make a difference from the way numerous diseases are treated.

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

Certainly ladies and gentlemen, if you have a question at this time. Please press Star then one on you touched on telephone. If your question has been answered and you'd like to remove yourself from the queue. Please press the pound key our first question comes from the line of <unk> Richter from Goldman Sachs. Your question. Please.

Good afternoon. Thanks for taking my questions. So just one on the <unk> program could you help us understand kind of the threshold knockdown that you want to see here and you know what you saw pre clinically that could translate and then on the.

Christopher R. Anzalone: Thanks Ken. We have a lot in front of us this year. We expect waves of clinical data readouts throughout the year from ArrowHSD, Arrow-ENAC, Arrow-HIF-2, Arrow-APOC-3, Arrow-ANG-3, and Arrow-AAT. We expect to gain clarity on potentially streamlining and accelerating the Arrow AAT development. We expect to initiate multiple Phase IIb studies for Arrow HSD, Arrow ApoC3, and Arrow ANG3, and possibly for Arrow Enoch and Arrow HIF2. We also expect to initiate a phase three study for Arrow ApoC3 and FCS patients.

On the.

His key program, what gives you confidence or optimism with regard to the transmission in man. Thank you.

I used to I mean, thanks very much. So so let me start with <unk>, that's a tricky question.

There is good.

There is there's good experimental evidence there's good genetic evidence.

On the possibility of knocking down <unk> and helping that mucociliary clearance in these patients, but the fact of matter is no one's been able to to create a therapeutic that can do that safely and so so we are true pioneers here.

Christopher R. Anzalone: We expect to file at least three new CPAs this year, including our first for a candidate targeting skeletal muscle, and by the end of the year, I expect Arrowhead to have at least 11 clinical programs targeting four different cell types, eight of those clinical programs could be wholly owned. This is indeed a substantial amount of potential value creation. We feel great about where Arrowhead is today, and we're confident about what we can accomplish going forward. It seems like all the pieces are in place for scalable and sustainable growth. We have a strong balance sheet and are disciplined in our use of cash, which allows us to move forward rapidly in a capital efficient way. We also are eligible for substantial non-dilutive capital in the form of milestone payments from Amgen, Janssen, and Takeda as our partner programs continue to advance, and ultimately, if any of the products are commercialized, we will be eligible for royalties on sales.

So it's hard to say what sort of knockdown could be it could be helpful. The best the best.

Idea, we've got I suppose if you look at the net the genetic analysis.

Ah heterozygous.

Essentially heterozygous Enoch knockouts in humans.

Do you see a clinical benefit we think and so so it feels like if we can reach 50 or so percent knockdown, we could see something helpful.

There is an awful lot of green between where we are in the end.

The pocket as they say and billiards and so we still have a lot to learn but that's sort of feels like the bogey to US right now is 50% knockdown could be helpful.

Back to <unk> two alpha.

That's also a hard one.

We have done as much as we have could as we've been able to do in animal models, but as you know.

Christopher R. Anzalone: We have an increasingly validated technology platform in TRIMM, and we believe TRIMM is on the verge of potentially showing that RNAi can be a powerful therapeutic mechanism for diseases throughout the body. We have a large and rapidly growing pipeline of differentiated product candidates addressing diseases without adequate treatment options. These are all innovative, first-in-class molecules, not fast follower, incremental, or meet-you products. And lastly, we have the right team in place and an unwavering culture of challenging the norms of drug development. Arrowhead always finds a way to be better, faster, and more efficient than others in the field.

Translation is always a trick with oncology. So we're just waiting to see.

We're looking forward to seeing the data over the next couple of months and we'll see where we are the annual day to have been good we feel we feel confident that we'll see knockdown.

Don't have a good idea about how much knock down you really need to see to see a clinical benefit but similar here I think I think we would call a win 50% or so knockdown, that's a bit arbitrary but that feels reasonable to us and so we'll see how we stack up against that over the next few months.

Yeah.

Thank you.

Sure.

Thank you. Our next question comes from the line of Maury Raycroft from Jefferies. Your question. Please.

Hi, everyone. Thanks for taking my question so.

Unknown Executive: This is a powerful combination, and it gives us the opportunity to make a difference in the way numerous diseases are treated. Thanks again for joining us today. I would now like to open the call to your questions. Operator?

I just wanted to do a quick check on timing for the three phase one readouts. It sounds like you can't predict the order of the Readouts, but Chris I think you mentioned by end of <unk> in your prepared remarks. So just checking if the guidance is for <unk> or is it softer and possible update could come in <unk>.

I know where we are.

For the end of.

Unknown Executive: Certainly, ladies and gentlemen, if you have a question at this time, please press star, then one on your touchtone telephone. If your question has been answered, and you'd like to remove yourself from the queue, please press the pound key.

The second quarter.

<unk>.

These are ongoing studies and so nothing is going to be finished by then and so we'll see what we have in hand, and we will see if we can make an interpretable.

See we have an interpretable data that's going to be really get a kicker for us I think that we can we can hit that by the end of the second quarter. That's the goal.

Unknown Executive: Our first question comes from the line of Salveon Richter from Goldman Sachs. Your question, please. Good afternoon, thanks for taking my questions. So just one on the ENAC program: could you help us understand the kind of threshold knockdown that you want to see here? And you know, what you saw pre-clinically that could translate? And then on the, on the HIF-2 program, you know, what gives you confidence or optimism with regard to translation in man? Thank you.

Got it okay. So your report the data by the end of the second quarter.

At school, Yes, yes, yes.

Again, it's gonna be a subset of data it'll be just top line.

As we as James mentioned in the prepared remarks. Our goal here is to is to show a fuller data set at appropriate medical meetings.

So.

Our goal here is to give you a taste.

To show, you whether or not.

It appears the drugs are working and then we'll then we'll we'll disclose more going forward.

Got it Okay, and then for the enact data can you clarify how many subjects you plan on reporting.

Christopher R. Anzalone: Hey, thanks very much. So, let me start with ENAC. That's a tricky question. There is good experimental evidence, and there is good genetic evidence on the possibility of knocking down ENAC and helping that mucosal area clearance in these types of patients. But the fact of the matter is, no one's been able to create a therapy that can do that safely, and so we are true pioneers here. So it's hard to say what sort of knockdown could be helpful. The best idea we've got, I suppose, is if you look at the genetic analysis, heterozygotes, essentially heterozygote knockouts in humans do see a clinical benefit, we think. And so it feels like if we can reach 50 or so percent knockdown, we could see something helpful. You know, there's an awful lot of green between where we are and the pocket, as they say in billiards.

There would be additional 12.

Subjects are that Youre planning on enrolling do you have an idea of what the the doses and dose range will be.

So let me, let's see if we can unpack that I don't I can't tell you how many patients we're going to we're going to be reporting on them because they just don't know as I said.

I think we'll be talking about this sort of midstream.

But my hope is that we'll have some data from the first.

And maybe the second dose cohort in the patient population, whether it's with respect to the healthy volunteers and bronchial brushing and lavage.

James you want to address what those doses are yes.

Sure.

At that dose is actually.

Up to us to select.

Based on what we see in.

In the previous cohorts from the Hell.

Volunteer cohorts.

It's likely that the safety profile has been favorable we will go with the highest dose.

Christopher R. Anzalone: And so we still have a lot to learn. But that sort of feels like the bogeyman to us right now is 50 percent knockdown. With respect to HIF2 alpha, you know, that's also a hard one.

The highest dose cohort and give us the best chance of.

Showing knockdown either in bronchial brushing.

Gail.

Okay. Okay fair enough and then last quick question just for the hip two patients can you say, how many biopsies you have already and maybe give a sense of what baseline of two expression levels look like.

Christopher R. Anzalone: We have done as much as we could, as we've been able to do in animal models. But, as you know, translation is always a trick with oncology. And so we're just waiting to see. We're looking forward to seeing the data over the next couple of months. We'll see where we are. The animal data has been good.

So we haven't seen the data yet.

Those are these are gonna be batched, and so we haven't seen any data yet although although James you want to talk about how many biopsies. We've had so far this year. So we have completed.

Christopher R. Anzalone: You know, we feel confident that we'll see knockdown. We don't have a good idea about how much knockdown you really need to see to see a clinical benefit, but similar here, I think I think we would call a win 50 percent or so knockdown. That's a bit arbitrary, but that feels reasonable to us. And so we'll see how we stack up against that over the next few months.

Sure.

Pre and post dose biopsies in.

All six of the cohort one patients and then.

Pre dose and five something towards two patients.

Now we won't know about viability of those until we start sustaining the slides so how many of those will be able to analyze.

Unknown Executive: Thank you. Our next question comes from the line of Maurice Raycroft from Jefferies. Your question, please. Hi, everyone.

We don't know that yet, but that's how many biopsies have been completed.

Got it okay. Thank you very much for taking my questions.

Youre welcome.

Thank you. Our next question comes from line of Sean <unk> from Citi. Your question. Please.

Christopher R. Anzalone: Thanks for taking my questions. So I just wanted to do a quick check on timing for the three phase one readouts. It sounds like you can't predict the order of the readouts, but Chris, I think you mentioned by end of 2Q in your prepared remarks. So just checking if the guidance is for end of 2Q or is it softer, and a possible update could come in 3Q.

Hi, guys. Thank you for the comprehensive update are you able to provide any more details on the safety update you provided today.

Just how many patients is it just.

Healthy volunteer or.

Are they actually see Ah patients in there as well and then I have one follow up on the skeletal muscle program.

Sorry, you broke up there a little bit. So you were asking how many patients have been treated so far with enact but between healthy volunteers and patients without a question.

Christopher R. Anzalone: I know we're shooting for the end of the second quarter. You know, these are ongoing studies, and so nothing's going to be finished by then. And so, you know, we'll see what we have in hand, and we'll see if we can make it interpretable. We see we have interpretable data that's going to really be the kicker for us. I think that we can hit that by the end of the second quarter. That's our goal.

Just the safety update your debt you gave today that everything looks good so far on how many patients does that include.

Sure that includes all the healthy volunteers and.

The first four patients in the study that's helpful true.

And you want to.

Go into how many how many other volunteers that is yeah sure. So that's a total of 24 healthy volunteers.

Christopher R. Anzalone: Got it. Okay, so you'll report the data by the end of the second quarter then. That's the goal.

Six per cohort and then we will add that additional 12 from the P. A L.

<unk>.

Great Great. Thank you and then for the skeletal muscle it seems like it's an area of <unk>.

Christopher R. Anzalone: Yeah, yeah, yeah, just, you know, again, it's going to be a subset of data, it'll be just a top line, you know. We, as we, as James mentioned, the prepared marks, our goal here is to show, you know, a fuller data set at appropriate medical meetings. So it'll, you know, our goal here is to give you a taste, to show you whether or not it appears the drugs are working, and then we'll, then we'll, we'll disclose more going forward.

Active area for RNA eye and antisense oligo are the gating steps for that program as a compound optimization at this point or is it more about being strategic for the indication that youre going after.

Yeah.

For the first one we're just we're just on the conveyor belt now once once you've got once you have nominations such Theres, just sort of the time it takes to get through GOP talks from alike, and we're just in that right now.

And so we feel comfortable that we've got drug candidate.

Christopher R. Anzalone: Got it. Okay. And then for the ENAC data, can you clarify how many subjects you plan on reporting there? And with the additional 12 subjects that you're planning on enrolling, do you have an idea of what the doses and dose range will be?

We just need to compete.

Complete the IND, enabling steps and we are in that process right now and we feel we feel comfortable that we're on track to file a cta sometime in the summer.

Okay. Thank you so much I appreciate it.

James C. Hamilton: So let me, let's see if we can unpack that. I don't, I can't tell you how many patients we're going to be reporting on because I just don't know. You know, as I said, I think we'll be talking about this sort of midstream, but my hope is that we'll have some data from the first and maybe the second dose cohort in the patient population. With respect to the healthy volunteers and the bronchial brushing and lavage, James, Yeah, sure that so that that

Youre welcome.

Thank you. Our next question comes from the line of Luke is he from RBC capital. Your question. Please.

Terrific. Thanks, so much for taking my question and congrats on all the progress maybe one on <unk>.

<unk>. Thank you mentioned optionality to streamline the Sequoia trial in the upcoming FDA meeting.

Give us a sense of Watson day, an agenda for debt meeting.

Some of the key goals that you're hoping to achieve during that meeting. So that's one and then the second on <unk> two alpha maybe bigger picture can you expand a little bit more on what the bogie for success here I understand that this is a trial primarily dose escalation and youre looking at PK, but wonder if somebody key biomarkers that you're really focused on two two to know whether this is a molecule that is worth.

James C. Hamilton: Yes, sure. So that dose is actually up to us to select based on what we see in the previous cohorts and the healthy volunteer cohorts. It's likely that we'll go with the highest dose, the highest dose cohort to give us the best chance of showing knockdown either in bronchial brushings or BAL.

Further pursuing thank you.

Sure. So first with a T I can't go into that too much because because we really haven't started discussions with the FDA. Yet. We are we are we're still collecting some data we want to collect the 12 month paired biopsy data and then go to the FDA and have an open discussion about how we.

James C. Hamilton: Okay, okay, fair enough. And last quick question just for the HIF-2 patients: can you say how many biopsies you have already and maybe give a sense of what baseline HIF-2 expression levels look like?

James C. Hamilton: So, we haven't seen the data yet, you know, those are going to be batch processed, and so we haven't seen any data yet, although, James, you want to talk about how many biopsies we've had so far? Yeah, sure.

May be able to change end points, certainly we will want to change the length of the study because what we what we think we've learned is that is that we see a pretty substantial effect much earlier than we expected as you may recall, we were first.

James C. Hamilton: So, we've completed pre- and post-dose biopsies in all six of the cohort one patients, and then pre-dosed in five of the cohort two patients, and now we won't know about the viability of those until we start staining the slides, so how many of those we'll be able to analyze, we don't know that yet, but that's how many biopsies have been completed.

Planning on treating patients for at least two years that does not appear to be to be required at this point and so we'll shorten study, but then we also want to see if we can if we can can agree on some maybe more appropriate endpoints. So let us have those discussions.

And then and then we'll get back to you on on what the FDA has advised.

With regard to hit two Alpha I tell you.

James C. Hamilton: Got it. Okay, thank you very much for taking my questions. Thank you, our next question comes from the line, Sean Egan from Citi. Your question, please. Hey guys, thank you for the comprehensive update. Are you able to provide any more details on the safety update you provided to the... How many patients? Is it just healthy volunteers, or are there actually CF patients in there as well? And then I have one follow-up on the skeletal muscle program.

Since this is our first solid tumor targeting program. We're really just focused our primary focus here is just two things safety and Tolerability of course, and so far that's been that's been.

<unk> and.

And second knockdown and as I mentioned, there, we just haven't seen data yet.

Ah biopsies are going to be are going to be batch and will have an idea over the next several months what cannot delegate, but we're really focused on knockdown not only for the drug for Arrowhead II, but also for the franchise. If we see that we are getting consistent and good knockdown and what does good mean, it's hard to say, but it sort of feels like it.

Unknown Executive: Sorry, you mixed up there a little bit, so you're asking how many patients have been treated so far with ENAC between healthy volunteers and patients, is that, was that the question?

If we are in the 50 or so percent knockdown range, we feel pretty good about that if we can hit that and we think we've got a drug and we think we've got a franchise.

Unknown Executive: Just the safety update you gave today that everything looks good so far. How many patients does that include?

Unknown Executive: And that includes all the healthy volunteers and the first four patients in the study. That's what we do.

Hip to offer as you know is well validated targets there have been other there is another drug right now in development that looks quite good.

Unknown Executive: Sure. And you want to want to go into how many health volunteers that is? Yeah, sure. So that's a

And so we think that as long as we can show reasonable knockdown, there's a place for us with this drug and then again.

James C. Hamilton: That's a total of 24 healthy volunteers, six per cohort, and then we'll add that additional 12 for the BAL studies.

We see a lot of upside.

If we can knockdown hip to alpha in solid tumors, we can knockdown we think.

James C. Hamilton: Great, great, thank you. And then for skeletal muscle, it seems like it's an area of, you know, active research for RNAi and antisense oligo. Are the gating steps for that program, is it compound optimization at this point, or is it more about being strategic for the indication that you're going after?

The host of other cancer targets and so filling the blank theres a number of of targets that we're going to want to go after maybe ourselves maybe maybe in partnership with others.

Against against various.

Tumors. So so we're in a really interesting and really exciting spot right now where we're just waiting for data and if those data look positive and I think we're off to the races.

Christopher R. Anzalone: You know, for this first one, we're just, we're just on the conveyor belt now. You know, once you've got nominations and such, there's just sort of a time it takes to get through GLP talks and the like, and we're just in that right now. And so we feel comfortable that we've got a drug candidate. We just, we just need to, you know, complete the IND enabling steps, and we're in that process right now. We feel, we feel comfortable that we're on track to file that CTA, you know, sometime in the summer.

Very helpful. Thank you.

Welcome.

Thank you. Our next question comes from the line of Esther <unk> from UBS. Your question. Please.

Hey, Thanks, Chris and team and I have a couple on a per day and then why don't <unk>.

In the past.

Talked about initiating a phase three registrational trial in STS and your comments today seem to suggest that that's a potential am I reading too much into it or are you still going strong with the STS.

And then with regards to the phase two trial. The two phase two trials that youre going to start in Nash patients with them I believe what you said in the past the severe type of Chegg listed and react and.

Unknown Executive: Okay, thank you so much. I appreciate it.

Unknown Executive: You're welcome.

Christopher R. Anzalone: Thank you. Our next question comes from the line of Luca Issi from RBC Capital. Your question, please? Oh, terrific. Thanks so much for taking the question, and congratulations on all the progress.

Greater than 115.

I noticed that the trial.

Christopher R. Anzalone: Maybe one on A118. I think you mentioned optionality to streamline the Sequoia trial and the upcoming FDA meeting. Can you just give us a sense of what's on the agenda for that meeting and what are some of the key goals that you're hoping to achieve during that meeting? So that's one. And then the second on HIF-2Alpha, maybe a bigger picture, can you explain a little bit more on what's the bogeyman for success here? I understand that this is a trial primarily dose escalation, and you're looking at PKs, but what are some of the key biomarkers that you're really focused on to know whether this is a molecule that is worth further pursuing? Thank you.

In phase two patients excluding patients who have.

What have you from pancreatitis. So why is that right two questions in there.

Oh sure.

So with respect to FCS, Yes, you are reading too much into that.

We are we are going full speed ahead on a pivotal study for <unk> in those patients.

They.

Our timing of this as we plan to file an <unk>.

For Apoc III.

First and then and then follow that up with.

With plans for that pivotal study, but it is it is still our intention to move forward as quickly as we can on that population. We think it's we think it's a strong unmet medical need we think that <unk> three is going to be a really important drug for those patients and so so we are full speed ahead, there with respect to apoc III I'll, just say a couple of things I'll hand, it over to <unk>.

Christopher R. Anzalone: Sure. So first, with AAT, I can't go into that too much because we really haven't started discussions with the FDA yet. We're still collecting some data. We want to collect the 12-month paired biopsy data and then go to the FDA and have an open discussion about how we may be able to change the endpoints. Certainly, we will want to change the length of the study because what we think we've learned is that we see a pretty substantial effect much earlier than we expected. You know, as you may recall, we were first planning on treating patients for at least two years. That does not appear to be required at this point.

James So so the two phase III studies as you know.

We're going to be in patients.

With severe hyper triglyceride EMEA, so those patients above 500.

We view that as kind of our fat market right.

We think it's a it's a grossly underserved markets.

And there are.

Christopher R. Anzalone: So we'll shorten the study, but we also want to see if we can agree on some maybe more appropriate endpoints. So let us have those discussions, and then we'll get back to you on what the FDA has advised. With regard to HIF-2-alpha, you know, I tell you, since this is our first solid tumor targeting program, we're really just focused on two things. Safety and tolerability, of course.

The regulatory pathway. There, we think is reasonably clear.

And we think it's a pretty large population. So it's one that we're really focused on now now.

We also want to look at in a phase <unk> study those patients.

Who have elevated triglycerides, so say between $1 50 and 499.

Think we think that that is also.

Unmet medical need.

That we think would require a more.

Christopher R. Anzalone: And so far, that's been acceptable. And second, knockdown. And as I mentioned there, we just haven't seen the data yet. You know, those biopsies are going to be batched, and we'll have an idea over the next several months what kind of knockdown we'll get. But we're really focused on knocking down the opposition. Not only for the drug, for ARHF-2, but also for the franchise. If we see that we are getting consistent and good knockdown, and what good means is hard to say, but it sort of feels like if we are in the 50 or so percent knockdown range, we feel pretty good about that. If we can hit that, then we think we've got a drug and we think we've got a franchise.

Comprehensive phase III study, probably a an outcome study I don't know that were going to do that but we want to retain the optionality. So we wanted to do that phase <unk> study right now just in case.

In the future, we're going to want to expand into that patient population.

Anyway.

Turn it over to James for sure. The question was about excluding pancreatic patients with pancreatitis in April <unk> three is that right yeah, that's right.

So we actually don't exclude patients with pancreatitis.

There are those phase III studies and either as a severe hyper triglyceride anemic or the kind of middle of the road greater than 150.

High Triglycerides study, we do have an exclusion for any patients with active pancreatitis within the last 12 weeks. So we just don't want anyone in the study who is <unk>.

Christopher R. Anzalone: HIF-2-alpha, as you know, is a well-validated target. There's another drug right now in development that looks quite good. And so we think that as long as we can show reasonable knockdown, there's a place for us with this drug. And then again, you know, we see a lot of upside. If we can knockdown HIF-2-alpha in solid tumors, we can knockdown, we think, you know, a whole host of other cancer targets. And so fill in the blank with a number of targets that we're going to want to go after, maybe ourselves, maybe in partnership with others against various tumors. So, you know, we're in a really interesting, really exciting spot right now where we're just waiting for data. And if those data look positive, then I think we're off to the races.

Recently had pancreatitis and may still be suffering from associated sequela. So we actually have some endpoints in the severe hypertrichosis frightening study looking at you know.

The rates of pancreatitis and things like that so we don't exclude those patients.

Got it so its only if they've had it within the last 12.

So that debt, but you're not guidance.

Hi, Dan.

Right prior to their first dose so we just don't.

Screening patients who have <unk>.

Very recently had pancreatitis.

Okay, Okay and then.

On the AP, you'll have a few readouts from 2021 and can you frame for us some of the scenarios for that 12 months made out and what the true could be for the phase III trial.

Unknown Executive: Very helpful. Thank you. Thank you. Our next question comes from Esther Agafino from UBS. Your question, please. Hey, thanks, Chris and team.

It sounds like in your response to a prior question you seem to have more confidence that that you may not meet that two point reduction in fibrosis for registration.

Christopher R. Anzalone: I have a couple on ApoC3 and then one on AAP. So, in the past, you've talked about initiating a Phase 3 registrational trial in FCS, and your comments today seem to suggest that that's a possibility. Am I reading too much into this, or, you know, are you still sort of going strong with the FCS? And then, with regard to the Phase 2 trials, the two Phase 2 trials that you're going to start in patients with, I believe what you said in the past with severe hypertriglycerdemia and those with levels greater than 150, but I noticed that in the trial in the severe Phase 2 patients, you're excluding patients who have recent So, why is that? There are two questions in there.

So so how are you thinking about it I mean is it is it are you going for that Palomar reduction right and maybe tying that to other studies that have shown.

A link between polymer reduction and and fibrosis.

Yes.

I don't want to speak too much on this because I don't want to get out ahead of our of our discussions with the FDA, but but in a nutshell, yes, I think that debt I think that it's clear that debt. The accumulation of the zebra team is what causes alpha one liver disease I think it's clear as day and so so we think that we can make an argument that.

That that could be in <unk>.

We'll end point or at least part of a composite endpoint that we might that we shouldn't have to show a reduction in fibrosis.

Christopher R. Anzalone: Sure. So with respect to FCS, yes, you are reading too much into that.

If that's not an approval endpoint for Nash, we don't think that should be an approvable endpoint for for this kind of a rare disease.

Christopher R. Anzalone: We are going full speed ahead on a pivotal study in those patients. Our timing for this is we plan to file an IND for ApoC3 first and then follow that up with plans for that pivotal study. But it is still our intention to move forward as quickly as we can on that population because we think it's a strong unmet medical need. We think that Arrow ApoC3 is going to be a really important drug for those patients, and so we are going full speed ahead there. With respect to ApoC3, I'll just say a couple of things.

So it will be and frankly this quite study wasn't looking wasn't dependent upon resolution of fibrosis either it was it was it was improvement in a in the histologic rating scale without worsening of fibrosis.

Our hope is that we can we can move that a bit as well because because.

Again, we think that the biology is increasingly clear on these folks in the debt.

Debt that simply reducing the burden.

Christopher R. Anzalone: I'll hand it over to James. So the two phase 2B studies, as you know, are going to be in patients with severe hypertriglyceridemia, so those patients above 500. You know, we view that as kind of our fat market, right? You know, we think it's a grossly underserved market. And, you know, the regulatory pathway there is reasonably clear, and we think it's a pretty large population. So it's one that we're really focused on. We also want to look at, in a Phase IIb study, those patients who have elevated triglycerides, so say between 150 and 499. We think that that is also an unmet medical need that would require a more comprehensive Phase III study, probably an outcome study. I don't know that we're going to do that, but we want to retain the optionality, and we want to do that Phase IIb study right now, just in So with that, I'll hand it over to James.

B a good a good marker.

Okay. Thank you.

Youre welcome.

Thank you. Our next question comes from the line of Ted <unk> from Piper Sandler Your question. Please.

Great. Thanks, guys. Thanks for the update.

Could you talk a little bit I mean, so much going on here you talked about a lot of success with partnering.

Suppose hepatitis hepatitis B and obviously.

As we kind of look forward what are what are what is arrowhead gonna be when you grow up like how are you going to be a targeted cardiovascular company.

What's going on in oncology with respect to combos is that something that might be a partner of <unk> liver disease. Similarly give us kind of a broader sense for how you're looking at these different assets.

What do you think is going to be core in the future. Thanks.

Yeah, Thanks to Ed that's a great question and it's and it's a dynamic question because what we are capable of focusing on we will of course change as we grow and such.

Christopher R. Anzalone: Sure, the question was about excluding pancreatic patients with pancreatitis from the ApoC3, is that right?

We see broadly.

As you know Ted.

Followed us for quite some time, we've even when we were.

James C. Hamilton: Yeah, that's right.

A $40 million company.

James C. Hamilton: So, we actually don't exclude patients with pancreatitis in either of those Phase 2B studies and either the severe hypertriglyceridemic or the kind of middle of the road, greater than 150 high triglycerides study. But we do have an exclusion for any patients with active pancreatitis within the last 12 weeks, so we just don't want anyone in the study who has recently had pancreatitis and may So, we actually have some endpoints in the severe hypertriglyceridemic study.

We never saw ourselves in the future as they as as a company that is focused only on a specific therapeutic area. We just thought this technology was too powerful.

Thought there was too much value to create to focus that narrowly and so and so we've done an awful lot of work over the last decade, and again, you've seen most of that.

Looking to push this technology into other cell types and we're now just in the cusp of that so so so then it gets to the question. Okay. You know with with this embarrassment of riches that we've talked about a lot what day, what do we keep in house and what do we what do you mean.

James C. Hamilton: Looking at, you know, rates of pancreatitis and things like that, so we don't exclude those patients.

What do we look for partners on as I said in the past at least at least at least for right now cardiovascular and pulmonary and make a lot of sense to us we like the synergy of those two areas.

James C. Hamilton: So it's only if they've had it within the last 12 weeks or so that you're not going to include them.

James C. Hamilton: Right, prior to their first dose, so we just don't, excluding patients who have very recently had pancreatitis.

We've got we've got an awful lot to offer those types of physicians those will not be the last areas, we're going to focus on that I can virtually guarantee you.

James C. Hamilton: Okay. Thank you.

Christopher R. Anzalone: And then, on AAP, you have a few readouts in 2021, and can you frame for us some of the scenarios for that 12-month readout and what the read-throughs could be for the Phase 3 trial? It sounds like, in your response to a prior question, you seem to have more confidence, Chris, that you may not need that point reduction in fibrosis score for registration, so how are you thinking about it?

As we as we buildup other franchises.

I am quite certain that we will that we will build out.

Sales infrastructure and marketing infrastructure in other areas as well and would that be oncology it could be in the in the near term, though like oncology is hard.

My hope is that is that we see some good positive data in arrowhead too.

Would that would enable us to bring in a good partner to start to really blow out that franchise. It doesn't mean, we won't have our own our own wholly owned offerings, but but at some point it would be we'd be certainly open to working with with the with our broad based oncology company with deep expertise.

Christopher R. Anzalone: Yeah, yeah, I get it.

Christopher R. Anzalone: at the FDA. But, but

Christopher R. Anzalone: But in a nutshell, yes, I think that it's clear that the accumulation of this Z-protein is what causes alpha-1 liver disease. I think it's as clear as day.

Christopher R. Anzalone: And so we think that we can make an argument that that could be an approvable endpoint, or at least part of a composite endpoint, that we shouldn't have to show a reduction in fibrosis. I mean, if that's not an approvable endpoint for NASH, we don't think that should be an approvable endpoint for this kind of rare disease. So it will be, and frankly, the SCOIA study wasn't dependent upon resolution of fibrosis either. It was improvement on a histologic gradient scale without worsening of fibrosis. Our hope is that we can move that a bit as well. Again, we think that the biology is increasingly clear for these folks and that simply reducing the burden could be a good marker.

To help us prioritize targets and such we're not there yet we want to generate some data first but at some point is that that probably makes some sense for us.

Yeah, perfect. It makes a lot of sense.

Yep. Thanks, Thanks debt.

Thank you. Our next question comes from the line of Alicia Young from Cantor Your question. Please.

Hey, guys. This is lee on for Alethia, and thanks for taking our call. So just wondering at day two program.

Well, what other target might be asking for it to you.

Apologies and then.

Are you thinking about other companies with similar Nash.

Christopher R. Anzalone: Okay, thank you. Thank you. Our next question comes from the line of Ted Tenthoff from Piper Sandler.

Cash target. Thank you.

Yes.

Sorry. So the question was was other oncology targets and then how do we fit.

Christopher R. Anzalone: Your question, please? Great. Thanks, guys. Thanks for the update. Kind of changing tack a little bit. I mean, so much going on here.

And then and then the other one was that was how do we fit with other Nash strategies debt.

Oregon.

Yes.

Okay.

Yeah, I don't know if I would tell you on on the oncology targets. We are we are working with some other targets.

Christopher R. Anzalone: You guys have had a lot of success with partnering assets, both Hepatitis B and obviously AAT. As we kind of look forward, what is Arrowhead gonna be like when you grow up? Like, are you gonna be a targeted cardiovascular company? You know, with so much going on in oncology with respect to combos, is that something that might be a partnerable asset? Liver disease, similarly. Give us kind of a broader sense for how you're looking at these different assets and what you think is gonna be core in the future. Thanks.

Haven't disclosed any.

We haven't disclosed anything there but.

But we are we do have some internal programs as I as I mentioned.

You mentioned.

Just a second ago.

We would like to bring in a partner at some point I don't know when the right time is I don't know if its this year next year or some other time, but but to the extent that we have positive data.

We would like to do this to do at least part of oncology with with the partner and so I don't have much to much to offer on other targets. We're thinking about right now with respect to Nash or Nash is hard.

Christopher R. Anzalone: And we thought there was too much value to create to focus that narrowly. And so, we've done an awful lot of work over the last decade. And again, you've seen most of that, looking to push this technology into other cell types, and we're now just in the cusp of that. So, then it gets to the question, okay, you know, with this embarrassment of riches that we've talked about a lot, what do we keep in house? And what do we and what do we, what do we look for partners on, as we said in the past, at least at least, at least for right now, cardiovascular and pulmonary make a lot of sense to us, you know; we like the synergy of

We liked the genetic data for HST.

It is compelling that if you can knockdown HST. It does seem to have a bit of a protective effect against against Nash doesn't mean that debt that that should be a silver bullet in fact, I would expect that Nash is going to be more like HBV in that in that it's going to be a combination approach I have no idea what the right combination is and frankly, it's probably different combination.

For different patient populations I think we're learning debt that it is that it's probably.

A number of different diseases.

We think that that HST could be a really nice backbone.

And could help.

A variety of these patient populations and then you can layer on on top of a Aero HST.

Christopher R. Anzalone: That probably makes some sense to us.

Christopher R. Anzalone: Yep, perfect. It makes a lot of sense.

Some other compounds, it's too early for us to tell right now because again, we haven't even seen any data yet, but that's sort of how we see it. We've also said in the past that we've that we also know that we like the idea of HST for alcoholic hepatitis as well the genetic data there were at least as as.

Christopher R. Anzalone: Yep, thanks. Thanks, Ted. Thank you. Our next question comes from the line of Alephia Young from Cancer. Your question, please. Hi guys, this is Leon and Felicia. Thanks for taking our call. So, just wondering if the HIP2 program looks successful, what other targets might be of interest to you in oncology? And then, how are you thinking about other companies with similar MeSH targets? Thank you.

As exciting as they were for Nash and so while we're not doing anything right now in those patient populations I could foresee us getting into that at some point in the future. So sorry, that's kept us from a non answer answer.

Christopher R. Anzalone: Sorry, so the question was about other oncology targets, and then how do we fit in, okay, and then the other one was how do we fit with other NASH strategies. Is that where we're going?

But that's the way that's how we are thinking about Nash right now.

Okay. That's helpful. Thank you.

Christopher R. Anzalone: Okay. Yeah, I don't have much to tell you about the oncology targets. We are working with some other targets. We haven't disclosed anything there, but we do have some internal programs. As I mentioned just a second ago, we would like to bring in a partner at some point. I don't know when the right time is. I don't know if it's this year or next year, some other time.

Welcome.

Thank you. Our next question comes from the line of Patrick <unk> from H C. Wainwright Your question. Please.

Thanks, Good afternoon, I've got a follow up on the cardio metabolic programs. So I'm wondering what questions Youre looking to answer in the smaller open label studies with Aro <unk> <unk> three in Aero Ams three secondly, how many studies would you anticipate and how many patients would you anticipate enrolling in these studies and when would the data from these studies to be expected.

Christopher R. Anzalone: But, you know, to the extent that we have positive data, we would like to do this, to do at least part of oncology with, you know, with a partner. And so I don't have much to offer on other targets we're thinking about right now. With respect to NASH, boy, NASH is hard.

Yes, I'm glad you picked that up.

I think it's an important point, we've talked in the past about the two phase <unk> studies for <unk>, three and one phase <unk> study for.

Our ancillary and of course and of course, the phase III enable C. Three for FCS patients we've talked about those a lot.

Christopher R. Anzalone: We like the genetic data for HSD. You know, it is compelling that if you can knock down HSD, it does seem to have a bit of a protective effect against NASH. But that doesn't mean that that should be a silver bullet. In fact, I would expect that NASH is going to be more like HPV in that it's going to be a combination approach. I have no idea what the right combination is.

We are now just starting to explore.

Some other questions for the smaller studies, we haven't set on those yet.

I assume that by the by our next conference call, we'll have set those and probably step doesn't motion a bit. So I can talk about debt more than but at this point, we're exploring what those mean theres going to be a handful of these things. Our goal here was was twofold. One is to is to answer as many questions. As we can during this timeframe because look these phase III studies are going.

Christopher R. Anzalone: And frankly, it's probably a different combination for different patient populations. I think we're learning that it's probably a number of different diseases. We think that HSD could be a really nice backbone and could help, you know, a variety of these patient populations. And then you can layer on top of AeroHSD, you know, some other compounds.

I did and they're gonna be no long, but say a year of exposure and so theres going to be a time.

That we just do that.

Net debt, we can't the timeframe that we can't move into a pivotal study until those are finished and so we might as well take advantage of that time to answer. Some other questions. We're looking to do that I think these are going to be shorter studies.

Christopher R. Anzalone: It's too early for us to tell right now because, again, we haven't even seen any data yet. But that's sort of how we see it. We've also said in the past that we like the idea of HSD for alcoholic hepatitis as well. The genetic data there were at least as exciting as they were for NASH. And so while we're not doing anything right now in those patient populations, I could foresee us getting into that at some point in the future. So, sorry, that's sort of a non-answer answer.

Many of them are some of them can be open label and so it gives us a chance to get to.

To report on these on on some of these these studies while the longer ones are still are still in process and so it allows us to continue to talk about these and tell you about what we're seeing but I really can't give you specifics yet because we're still we're still sort of in the trenches on that I expect it will have those debt over the next couple of them.

Months or so.

Got it and then just a few on the lung programs follow ups first on Arrow what's.

Christopher R. Anzalone: But that's how we're thinking about NASH right now.

Christopher R. Anzalone: Okay, that's helpful. Thank you.

Drove the decision from the protocol changes, that's something FDA asked for or what specifically is the driver of those changes and then on Aero could be a competing arnie I program had been delayed because of the need to conduct more work and a hamster model. So I'm wondering how things are progressing for Aero Kobe and if this program could begin human trials in 2021 and then.

Christopher R. Anzalone: You're welcome.

Christopher R. Anzalone: Thank you. Our next question comes from the line of Patrick Trucchio from H.C. Wainwright. Your question, please. Thanks, good afternoon.

Christopher R. Anzalone: I have a follow-up question on the cardiometabolic programs. So I'm wondering what questions you're looking to answer in the smaller open-label studies with Arrow ApoC3 and Arrow Ang3. Secondly, how many studies would you anticipate and how many patients would you anticipate enrolling in these studies? And when would the data from these studies be expected?

Secondly to what extent are the new emerging variance impacting this program should we expect your more R&M triggers to avoid resistance and how do you view <unk> antiviral positioning as compared to the monoclonal antibodies several of which have the EUA authorization emergency use authorization from the U S. But they appear to have some resistance issues.

Christopher R. Anzalone: I'll probably set those in motion a bit so I can talk about that more then, but at this point, we're exploring what those mean. There are going to be a handful of these things.

Christopher R. Anzalone: Our goal here was twofold. One was to answer as many questions as we could during this time frame because, look, these Phase 2B studies are going to be blinded and they're going to be not long, but say a year of exposure. And so there's going to be a time that we can't, the time frame that we can't move into a pivotal study until those are finished. And so we might as well take advantage of that time to answer some other questions. We're looking to do that, but I think these are going to be shorter studies. Many of them, or some of them, can be open label. And so it gives us a chance to, you know, report on some of these studies while the longer ones are still in process. And so it allows us, you know, to continue to talk about this and tell you about what we're seeing. But I really can't give you specifics yet because we're still sort of in the trenches on that. I expect that we'll have those set in the next couple of months or so.

With these new variants.

Okay. There's a lot of questions. There so let's start with <unk>. The changes in the protocol were driven entirely by our desire to see.

You can look at knockdown health volunteers wasn't required by anybody.

It wasn't included in the first protocol, because because frankly, we didn't have an assay yet we weren't really sure we get it we can measure it.

Since then we have developed this assay and we're ready to go and so now we know we.

We want to look at bronchial brushing and and bronchial lavage.

In order to see knockdown in healthy volunteers.

That's going to be a really important measure.

For us because as I mentioned in the prepared remarks.

This is a small study in patients and so it is it is likely that that it is.

Can be difficult to see F&B, one changes in four patients in a given cohort just because it's too small.

Christopher R. Anzalone: Got it. And then just a few on the lung programs, follow-ups first on Arrow-Enac. What drove the decision for the protocol changes? Is that something FDA asked for, or what specifically is the driver of those changes? And then on Arrow-CoV, a competing RNAi program had been delayed because of the need to conduct more work in a hamster model. So I'm wondering how things are progressing for Arrow-CoV and if this program could begin human trials in 2021. And secondly, to what extent are the new emerging variants impacting this program? Should we expect more RNAi triggers to avoid resistance? And how do you view RNAi antiviral positioning as compared to monoclonal antibodies, several of which have EUA authorizations, emergency use authorizations in the US, but they appear to have some resistance issues with these new variants?

And so this gives us.

A better measure on how well this drug is working and how well it's delivering to pulmonary epithelium cells. So that was the rationale for that for a change in the protocol and including those those folks now with respect to Covid.

You know Covid is as we've not been able to move as fast as we wanted to on Covid.

In large part because the animal models are just we don't control the animal models and its been hard to to get slots to do these these animal studies.

We have not been as fast as we have been in other areas, where we can and do our own studies or we are we've got a larger variety of of <unk>.

We can work with so its so its lag a bit because of that.

Christopher R. Anzalone: Okay, there are a lot of questions there. So let's start with ENAC. The changes in the protocol were driven entirely by our desire to see and look at knockdown health volunteers. It wasn't required by anybody. It wasn't included in the first protocol because, frankly, we didn't have an assay yet and weren't really sure we could measure it. Since then, we have developed this assay, and we're ready to go. And so now we want to look at bronchial brushing and bronchial lavage in order to see knockdown in healthy volunteers. That's gonna be really important.

We're still excited about it of course.

You mentioned the new variants that people are talking about that does not has not affected our program, but it has just reinforced R. R.

Our belief that there is a real role here for four for RTI mediated.

Antivirals alright.

It is certainly possible that debt that at some point this virus is going to mutate around.

The feedback scenes.

And so our goal here was to was to make a broad based anti viral that not only could work against this current coronavirus, but also potentially future coronaviruses and so and so this is sort of playing out the way we thought it might play out and again it just underlines the need for per hour kind of therapeutic.

Christopher R. Anzalone: Now, with respect to COVID, you know, COVID has not been able to move as fast as we wanted to on COVID in large part because the animal models are just, you know, we don't control the animal models, and it's been hard to get slots to do these animal studies. So, you know, we have not been as fast as we have been in other areas where we can do our own studies or we've got, you know, a larger variety of CROs we can work with. The way we view this is probably that multiple triggers is going to be better than a single trigger for the same reason that it was for HPV. As you may remember, our HPV compound has two different triggers. You know, one reason is to guard against mutation, but the other reason is to give you broader coverage across genotypes. That would be the case here as well because of the wide variety of coronaviruses that are out there.

As we've shown with with HBV, we know what were pretty good at playing in Antivirals.

And your point is a good one about multiple triggers the way we view this as probably multiple triggers there's going to be better than it was a single trigger from the same reason that it was for HBV as you may remember from our HPV compound as two different triggers.

One reason is to guard against a mutation, but the other reason is to give you broader coverage across genotypes that'll be the case here as well for for a wide variety of Corona Corona viruses that are out there.

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

Got it that's helpful. Thank you very much.

Christopher R. Anzalone: Thank you. Our next question comes in line, from Riley Securities, on your question. Hi, congrats on a productive 2020 and seems like even a busier 2021 ahead for you. Thanks for taking my question. So a quick follow-up on EMAC. Is there anything you've learned from the PD standpoint or anything, you know, from an alternative approach and the sense that that gives you confidence at this point about, you know, target engagement and anything you can comment on that?

Welcome.

Thank you. Our next question comes from line of Mike maintain from B Riley Securities. Your question. Please.

Hi, congrats on a productive and Randy and seems like even a busier duane to anyone else. Thanks for taking my questions. So a quick follow up on <unk> is there anything you've learned on the beat from a BD standpoint anything.

From an all day native a blow down defense that that gives you confidence at this point on target engagement any anything you can comment on debt.

Christopher R. Anzalone: Yeah, that's a good question. You know, it's hard for us to interpret the antisense data that we've seen. So, so...

Yes.

Yeah. That's a good question you know.

It's hard for us to interpret the antisense data that we've seen.

So so.

Christopher R. Anzalone: There's been no bad news there for us, but there's been no good news either, the way we look at it. And so, unfortunately, you know, we'll have to wait to see what those data look like. And we're, of course, anxious to see what our data look like. We're gonna know a heck of a lot more over the next couple of months, that's for sure.

There has been no bad news there for us, but theres been no. Good news either the way we look at it.

And so so no. Unfortunately.

We will have to wait to see what those data look like and where of course anxious to see what our day to look like what we have.

We're going to know a heck of a lot more over the next couple of months that's for sure.

Christopher R. Anzalone: Okay, and then just a quick follow-up on the biopsy duration for the HSD program and anything if at all we learned from, you know, the surprise six-month biopsy we got from the AAT program. Is there any read-through to, again, I understand it's different proteins we are talking about, different types of knockdown, complicated diseases. Any read-through you guys think internally about as you think about the NASH program?

Okay, and then just a quick follow up on the biopsy duration for the Disney program and anything if at all we learned from this is Brian Essex bone biopsy.

We got from the day program is there any read through too.

Again I understand.

Different proteins, we are talking about different types of non doesn't complicated disease any anything to you guys thinking broadly about as you think.

About the Nash program.

Christopher R. Anzalone: I don't know if there's read-through. You know, what we've learned from all these programs is that, is that, is that, you know, all these proteins are different. And so, so, you know, all the triggers are different, you know, depending on the trigger and the protein knockdown, depth and duration are going to be different. And so, and so, so, we are confident that we will see good, deep, and durable knockdown in Arrow HSD because of our experience with HPV and AAT and ApoC3 and ANZ3 and LpA and others. But, but I don't know that we learned anything in particular with AAT that we can apply to Arrow HSD. You know, we are, I think success here is pretty narrow.

I don't know that there's read through what we've learned.

What we've learned in all of these programs is that as debt.

Uh huh.

Is it is it all of these proteins are different and so so.

And all the triggers are different depending upon the trigger in the protein knockdown a day.

Depth and duration are going to be different and so and so so.

We are confident that we will see good deep and durable knockdown in Aero HST because of our experience with HBV and <unk> and <unk>, three and <unk> III and L P little a and others.

But but I don't I don't know that we learned anything in particular with <unk> that we can apply to HST.

We are I think success here is pretty narrow, we're just really looking at at depth and duration of knockdown as we mentioned, we're not really looking for alleviation of disease in this very short study.

Christopher R. Anzalone: We're just really looking at the depth and duration of knockdown. As we mentioned, we're not really looking for alleviation of disease, you know, in this very short study. We don't expect it. And so, you know, we're just looking at it, we're trying to pick a dose. And unfortunately, since we don't know of a circulating biomarker, the only way to choose a dose is to get in there and take a biopsy and see how deep and durable the knockdown is. And then, and then we'll take that into a larger Phase 2b study that may give us some idea about disease progression. But, But we don't expect to learn anything about that at this time.

We don't expect it.

We're just looking at we're trying to pick a dose and unfortunately since then.

Since we don't know of a circulating biomarker the only way to choose a dose is to get in there and take a biopsy them and see how deep and durable knockdown is and then and then we'll take that into a larger phase <unk> study that would that may give us some idea about about disease progression, but but we don't expect to learn anything about that at this point.

Christopher R. Anzalone: And to clarify, 6 month duration biopsy, right? Or 12 months?

And if that is a six month duration biopsy at 12 months.

James C. Hamilton: So we do two different post-dose biopsy time points. One is at day 71, after the last dose; these patients get two doses. And the other is at day 169. So we staggered them to get a better idea of duration.

So we do two different post dose biopsy time points. One is at day 71 post dose and the others.

After the last dose these patients get to doses and the other day 169, so we staggered them to get a better idea of duration.

James C. Hamilton: Okay, great. And my final question as you think about cash flows, and you obviously have some. We might have lost you. You're very quiet. Can you hear me now? Can you hear me now?

Okay, Great and my final question as you think about cash flows and you obviously have some.

Yeah.

Okay.

Thank you.

Okay.

Yes.

Yeah.

Thanks, so much.

I think we.

It might have last few years very quiet Mike.

Can you hear me now can you hear me now yeah you're back.

Christopher R. Anzalone: Yeah, so the final question was on cash flows. You think about 2021 and think about the different partner milestones from J&J, Amgen, and Takeda. How should we think about your burn rate? Again, in context of some of the commercial stage programs might be getting pushed out a little bit, like ApoC3 and AAT, obviously being partnered out. How should we think about the expense for 2021?

Yes. So final question was on on cash flows.

Do I need to anyone and think about the different partner milestone from J&J Amgen and again, how should we think about your burn rate again in context of some of the the commercial stage programs might be getting pushed out a little bit like apoc, III and EBITDA, obviously being button. It out obviously, we think about the expense for Duane.

Anyone.

Well, so we reiterated today that we expect to burn between 202 hundred $50 million.

Christopher R. Anzalone: Well, we reiterated today that we expect to burn between $200 and $250 million in fiscal 2021. We've got plenty of cash to afford that, and I do think that we have a chance of triggering some milestone payments during that time. We can't give you any guidance on any of that because A, it's uncertain, and B, even if it was certain, I can't tell you until we get it. But I think it's possible. But again, the worst case is we don't trigger any of those this year. That's okay. We have plenty of cash right now to absorb that kind of burn. And then, again, I feel quite comfortable that we can have access to additional milestone payments. And so, look, I feel good about our balance sheet right now. I feel good about our access to additional capital between all three partnerships.

In fiscal 2021.

We've got plenty of cash to afford that and Thats, an end and I do think that we have a chance of of triggering some milestone payments during that time.

Can't give you any guidance on any of that because they it's uncertain and be even if it was certainly can't tell you until we get it.

But I think it's possible.

But again worst cases, we don't we don't we don't trigger any of those this year. That's okay. We have plenty of cash right now to absorb that that kind of burn and then next year again I feel quite comfortable that that we that we can have access to additional milestone payments and so look I feel good about our balance sheet right now I feel good about our access to additional cash.

<unk>.

Between all three partnerships.

Christopher R. Anzalone: Excellent. Thanks for taking my question.

Excellent. Thanks for taking my question.

Youre welcome.

Thank you. Our next question comes from the line of Keith <unk> from Chardan. Your question. Please.

Christopher R. Anzalone: You're welcome.

Christopher R. Anzalone: Thank you. Our next question comes from Keay Menke from Chartie. Your question, please. Yeah, thanks, Chris. With respect to HIF, if your working thesis right now is that 50% knockdown could have an effect on the disease, should that prove to be too low, based on your current dose levels and dose intervals? Do you believe you could go higher than that to achieve a higher knockdown if needed?

Yeah, Thanks, Chris with respect to <unk>.

If youre working thesis right now is at 50% knockdown could have an effect on us.

Disease.

Should that proved to be too low based on your current dose levels and dose intervals.

Can you believe it could go higher than that to achieve a higher knockdown if needed.

Christopher R. Anzalone: Yeah, we'll see, you know, it'll be really helpful to see what the dose response looks like. If, in fact, we see 50% knockdown at the highest dose we're giving, at least what we've seen so far, we see no signs that we can't escalate more. You know, this is not, it's not, it's not a traditional cancer trial, right? You know, where we dose as high as we can until we get people sick, and then we knock the dose down. You know, we don't expect those living toxicities. And so to your point, sure, you know, it is certainly possible that we get 50% knockdown, and we still think that there's more knockdown to be had, as long as we're not seeing DLTs. We're happy to escalate. And like I said, you know, neither in HIF-2 alpha nor in ENAC so far have we seen evidence that we've got a safety issue.

Yes, we will see.

It'll be really helpful to see what the dose response looks like.

If in fact, we see 50% knockdown at the highest dose we are giving.

At least what we've seen so far we see no signs that we can't escalate more this is not it's not it's not a traditional cancer trial, where we dose as high as we can so we get people sick and then we knock those down.

We don't expect dose limiting toxicity and so to your point.

Sure It is.

Certainly possible that debt that we get hit you were sent Knockdowns and we still think that theres more knockdown to be had as long as we're not seeing a DLT is we're happy to have to escalate and like I said.

Neither in hip two alpha nor in <unk>, so far and we've seen.

Evidenced.

Christopher R. Anzalone: Great, thank you.

Christopher R. Anzalone: You're welcome.

Debt, we've got a safety issue.

Christopher R. Anzalone: Thank you. Our next question comes from the line of Mani Foroohar from SVB LeRink.

Great. Thank you.

Welcome.

Thank you. Our next question comes from the line of Manny Farooq from SBB Leerink. Your question. Please.

Christopher R. Anzalone: Your question, please. Thanks for the question, guys. I want to quickly follow up on something.

Thanks for taking the question guys I want to quickly follow up on somebody I think it was more actually touched base on this around the Enoch weed out you mentioned in your prepared comments it <unk>.

Christopher R. Anzalone: I think Maury actually touched on this around the ENAC readout. As you mentioned in your prepared comments, it's reasonably possible to see an uninterpretable or unclear FEB benefit while seeing a very substantial knockdown benefit in healthy normal volunteers. Should you see that data set, which is one that's a profile that we'll see in the early data sets from Vertex, TranslateBio, etc., many others, how do you interpret that as either A, the target isn't effective, or B, you need to dose higher? How do you choose to move forward from a data set that doesn't necessarily give you a relationship between knockdown and dose and efficacy?

Reasonably possible to see an uninterrupted able are unclear F&B benefit while seeing a very substantial knockdown benefit and the healthy normal volunteers should you see that dataset, which is one that's a profile of what we'll see in the early datasets from vertex translate bio et cetera, and many others.

How do you interpret that as either I E the targeted and effective.

Or be you're going to dose higher.

How do you choose to move forward from a data set that doesn't necessarily give you a relationship between knockdown in dose and efficacy.

Christopher R. Anzalone: Yep. So look. There's a lot of, it's hard to play that game until we see the data. But I guess the broad answer would be, look, if we saw a good knockdown, but in those four patients we can't discern, you know, FEV1 changes, I don't think that we're so worried at this point. You know, we say to ourselves, this is good news, you know, we've got a drug that is working the way we want it to, we've got a franchise, certainly, you know, that we can, we think that we can go into other disease areas. And so now with CF, look, let's treat some more patients, because four is not a very large number in a cohort. Let's see if we can start to see an FEV1 change after we get to 10 or so patients.

Yeah, So Phil.

There's a lot there's a lot of it's hard to play that game until we see the data.

But I guess the broad answer would be look if we saw good knockdown book, but in those four patients we can't discern F&B one changes I don't think that we're I don't think that we're still worried at this point, we say to ourselves. This is good news we've got a drug that is working the way wanted to we've got a franchise.

But we can we think that we can go into other other disease areas and so now with CF look, let's let's treat some more patients because for us.

A very large number and a cohort, let's let's see if we can start to see what to see in F&B. One change if we get to 10 or so patients. That's one second is is look this is it's a pretty short study as well so we'd be happy to.

Christopher R. Anzalone: That's one. Second, look, you know, this is, it's a pretty short study as well, and so we'd be happy to, you know, assume that we're getting good knockdown, maybe we just need a bit more, a bit more in the way of dosing to start to see those manifest in FEV1 changes. So all is not lost, you know, if we cannot register an FEV1 change but we see good knockdown. On the contrary, I think that suggests that we have something that's really powerful. And we've got plenty of time this year to treat some more patients, as well as treat them for a bit longer, or at least monitor them longer to see if we can see some FEV1 changes.

Say to assume we're getting good knockdown, maybe we just need a bit more.

A bit more in the way of dosing to start to see those those manifest in F&B one changes so.

So all is not lost.

We cannot registering F&B won't change, but we see good knockdown to the contrary I think that I think that that suggests that we have something that's really powerful and we've got plenty of time this year to treat some more patients as well as street from a bit longer or at least monitor them longer to see if we can see some efficacy one changes.

Christopher R. Anzalone: Great

Great that's really helpful.

James C. Hamilton: The cohorts we'll have in the middle of the year will be the two lower dose cohorts, so we still have the top dose in CF patients to go.

Thank you.

The cohorts, we'll have middle of the year will be the two lower dose cohort. So we still have the top dose.

CF patients to go.

James C. Hamilton: It would be the baseline characteristics of the patients. When you're talking about small ends like this, that may make a difference. It shouldn't matter theoretically what the genotype is or background therapy, but this is a small end. So I think the main point here is that we get knocked down, we get functional delivery, and we're safe. And then that's a win.

It also it would be the baseline characteristics of the patients. When you are talking about small ends like this that that may make a difference it shouldnt shouldnt matter theoretically with the genotype is or background therapy, but we this is a small end.

So I think the main point here is that we get knocked down we get functional delivery and we're safe and then that's a win rate that's what we.

Christopher R. Anzalone: Right, yeah, that's what we want people to focus on. You know, let's look at that if you want, of course, because that is ultimately going to be important. But when we're looking at this drug over the next couple of quarters, what we're really focused on, you know, are the knockdown data and, of course, the safety and tolerability of the drug. If both those are positive, we are off to the races. And, you know, we'll continue to look at it.

Don't be able to focus on let's look at that maybe one of course, because because that ultimately is going to be important but when we're looking at this drug over the next couple of quarters. What we're really focused on are those the knockdown data and of course.

Safety and Tolerability of the drug if both of those are positive we are off to the races.

And we'll continue to look at patients going forward.

Christopher R. Anzalone: That's really helpful. And then hopping over to

That's really helpful and then.

Hopping over to Nash there've been a couple of other companies that don't feel comments, but off of a genetic data. Obviously, there's some pub. There is some evidence possible unclear if it's correlate over cognitive and from the potential benefit.

Christopher R. Anzalone: Ash. There have been a couple of other companies that have also commented on the genetic data. Obviously, there's some evidence, unclear if it's correlative or causative in terms of potential benefit in both alcoholic and non-alcoholic steatohepatitis. What kind of data sets would you need to see, maybe in later stage studies from you guys, to parse that out and say, okay, this is really causative, and a knockdown of HSD is going to be reasonably expected to show benefits Are there biomarkers you're tracking? Are there early clinical data sets that we might see as early as 2022 to sort of parse out that causation correlation issue?

And both alcoholic and non alcoholic hepatitis.

What kind of datasets would you need to see maybe in later stage studies from you guys to parse that out and say Okay. This is really positive and you know.

A knockdown of HST is going to be reasonably expected to show a benefit.

And our longer term pivotal trial, either other biomarkers, you're tracking of their early clinical datasets that we might see as early as 2022, just sort of parse out that causation correlation issue.

James C. Hamilton: Yeah, sure. I'll take that one.

Yeah sure I'll take that one I mean the debt.

James C. Hamilton: I mean, the easy one for this target is ALT, correlative to the loss of function mutation, meaning those individuals tend to have lower ALTs. So that's, you know, an easy biomarker for us to read out in early stage studies and beyond. Beyond that, there's not a whole lot else from a biomarker standpoint, in terms of imaging or other blood tests. I think then you're looking at phase 2b biopsy studies to show, you know, proof of pharmacologic effect and benefit.

Easy one for this target as a L T.

And that's been.

Correlate to the loss of function mutation that those individuals tend to have lower ltvs and so that's.

An easy biomarker for us to read out.

Early stage studies and beyond.

Beyond that theres, not a whole lot else from a biomarker standpoint in terms of imaging or other blood tests. I think then youre looking at phase two be a biopsy studies to show.

Proof of pharmacologic effect.

And benefit.

James C. Hamilton: Great! That's really helpful.

Yeah.

Great. That's really helpful. Thank you thanks for taking my questions.

Christopher R. Anzalone: Thank you. Thank you for taking my questions. Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Chris Anzalone for any further remarks.

Youre welcome.

Thank you. This does conclude the question and answer session of today's program I'd like to hand, the program back to Chris Anzalone for any further remarks.

Christopher R. Anzalone: Thank you everyone for joining us today. It's been a pleasure to speak with you, and we'll talk to you next quarter.

Thanks, everyone for joining us today, it's been a pleasure to speak with you and we'll talk to you next quarter.

Unknown Executive: Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

Thank you, ladies and gentlemen for your participation in todays conference. This does conclude the program you may now disconnect good day.

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