Q3 2021 Arrowhead Pharmaceuticals Inc Earnings Call

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Operator: 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 Vincent Anzalone, Vice President

Ladies and gentlemen, and 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 and opportunity to ask question.

I will now hand, the conference call over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead Sir.

Vincent Anzalone: & Company, Vice President of Investor Relations for Arrowhead.

Vincent Anzalone: Thank you. Good afternoon, everyone.

Thank you good afternoon, everyone. Thank you for joining us today to discuss arrowheads results for its fiscal 2021 third quarter ended June 30th 2020.1.

Vincent Anzalone: Thank you for joining us today to discuss Arrowhead's results for its Fiscal 2000.

Vincent Anzalone: 21, third quarter, ended June 30th, 2021. With us today from management, our president.

With us today from management are president and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter Dr. Javier San Martin, Our Chief Medical Officer, who will provide an update on our pipeline and Ken Moskovsky, Our Chief Financial Officer, who will give her a review of the financials and addition, James Hazard, our Chief commercial officer and Dr. James Ham.

Vincent Anzalone: CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter, Dr. Javier San Martin, our Chief Medical Officer, who will provide an update on our pipeline, and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, James Hazard, our Chief Commercial Officer, and Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, will be available during the Q&A session on 10-11.

And our senior Vice President of discovery, and translational medicine will be available during the Q&A session of today's call.

Vincent Anzalone: are in the Q&A session 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.

Before we began and I would like to remind you that comments made during today's call contain certain forward looking statements within the meaning of section 27, a of the Securities Act of 1933 and section 21 E of the Securities Exchange Act and banks and 34, all statements other than statements of historical fact, including without limitation those.

Vincent Anzalone: 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,

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, the receipt of future milestone and licensing payments and expected future development and commercialization activities.

Vincent Anzalone: The receipt of future milestone and licensing payments and expected future development and commercialization activities. These statements represent management's current expectations and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statement. For further details concerning these risks and uncertainties, please visit www.cdc.gov.au. Also, please refer to our SEC filing. Including our most recent annual report on Form 10-K and subsequent quarterly reports on Form 10-Q. However, Arrowhead disclaims any intent and undertakes no duty to update any of the forward-looking statements.

These statements represent management's current expectations and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed and any and 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.

Arrowhead disclaims any intent and undertakes no duty to update any other 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 Chris.

Christopher R. Anzalone: Anzalone, President and CEO of the company. Good afternoon, everyone, and thank you for joining us today.

Thanks, Vince and.

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

Christopher R. Anzalone: The fiscal third quarter, the period since our last conference call, has been incredibly busy for Arrowhead. We made important advances in several of our development programs. This includes discovery stage programs and early, mid, and later stage clinical programs. It also includes programs from existing partnerships, as well as a new business development transaction. At The Platform Company, there are a few areas of critical importance where we focus our attention. First, we need to always push the boundaries of what is possible and make our trim platform better.

Fiscal third quarter and the period since our last conference call has been incredibly busy for arrowhead.

Made important advances and several of our development programs. This includes discovery stage programs and early mid and later stage clinical programs and it also includes programs from existing partnerships as well as the new business development transaction.

And as a platform company there are a few areas of critical importance, where we focus our attention.

First we need to always push the boundaries of what is possible and make our trim platform better.

Christopher R. Anzalone: Second, we need to expand the early-stage pipeline rapidly and efficiently with new clinical candidates as this will be an important source of growth in the future. Third, we need to move our mid and later stage pipeline programs through clinical studies as we get closer to our goal of bringing important new medicines to patients without adequate treatment options. And lastly, we need to selectively use partnering to expand the reach and maximize the value of our trim platform and bring in non-dilutive capital that helps to fund our internal development. I think we're doing well in all these.

Second we need to expand the early stage pipeline rapidly and efficiently with new clinical candidates and this will be an important source of growth and the future.

Third we need to move our mid and later stage pipeline programs through clinical studies as it gets closer and as it gets closer to our goal of bringing important new medicines to patients without adequate treatment options and lastly, we need to selectively use partnering to expand the reach and maximize the value of our trim platform and bring and non dilutive capital that helps to fund our internal.

And.

I think we're doing well on all of these areas, let's take a moment to briefly review some key events and the last quarter that are good examples of this.

Christopher R. Anzalone: Let's take a moment to briefly review some key events in the last quarter that are good examples. For our discovery and early-stage clinical pipeline, we had a very productive quarter. We completed discovery and optimization work on two new pulmonary programs and nominated them both as clinical candidates. They are now in the IND enabling stage, which includes GLB toxicology studies and manufacturing of drug products for clinical studies.

From a discovery and early stage clinical pipeline, we had a very productive quarter, we completed and discovery and optimization work on 2 new pulmonary programs and nominated them. Both as clinical candidates. They are now and the IND, enabling stage, which includes <unk> toxicology studies and manufacturing of drug product preclinical studies, we have not yet disclosed the gene and does.

These targets, but we will be talking more about these programs later in the year.

We also presented very promising preclinical data on Aero Dux for our first and muscle targeted program being developed as a treatment for patients with vascular scapulohumeral muscular dystrophy or F. S. H D and the 20th annual F. S. H D Society International Research Congress.

Christopher R. Anzalone: We have not yet disclosed the gene and disease targets, but we'll be talking more about these programs later in the year. We also presented very promising preclinical data on Arrow Dux4, our first muscle-targeted program being developed as a treatment for patients with fascio-scapulohumeral muscular dystrophy, or FSHD, at the 28th annual FSHD Society International Research Conference. The data show that the TRIMM muscle delivery platform can achieve functional delivery to various types of skeletal muscle and achieve deep, durable, and dose-dependent knockdown of target genes.

And the data showed that the trim.

The data showed that the trim and muscle delivery platform and can achieve functional delivery to various types of skeletal muscle and achieved deep durable and dose dependent knockdown of target genes. In addition, aero dux for improved multiple measures.

S H D like muscle phenotype and relevant preclinical animal models.

<unk> 4 expression is recognized as the cause and muscle pathology and if its HD patients Arrowhead believes that the selective targeting and knockdown of ducts for using RNA I may prevent or reverse downstream and bio toxicity and lead to muscle repair and improvement and muscle function and patients.

Christopher R. Anzalone: In addition, Arrow Ducts IV improved multiple measures of FSHD-like muscle phenotype in relevant preclinical animals. As DUX4 expression is recognized as the cause of muscle pathology in FSHD patients, Arrowhead believes that the selective targeting and knockdown of DUX4 using RNAi may prevent or reverse downstream myotoxicity and lead to muscle repair and improvement in muscle function in patients. There are currently no effective treatments specifically for

There are currently no effective treatments, specifically for Fsh D. So patients need new therapeutic options and address the root cause of the disease.

We've been pushing aggressively toward the clinic with <unk> 4 as well as the 2 new pulmonary candidates. We nominated this year, we expected to file Cta is for all 3 of them by the end of the year, but securing timely slots and crows for IND, enabling toxicology studies has been challenging so scheduling on the Cta and will be pushed into the first half of next year.

Christopher R. Anzalone: So patients need new therapeutic options that address the root cause of the disease. We've been pushing aggressively toward the clinic with AeroDUX4 as well as the two new pulmonary candidates we nominated this year. We expected to file CTAs for all three of them by the end of the year, but securing timely slots at CROs for IND-enabling toxicology studies has been challenging, so scheduling on the CTAs will be pushed into the first half of next year. That is unfortunate, but we have seen this become more of a bottleneck in the industry since the beginning of the pandemic.

That is unfortunate, but we have seen this become more of a bottleneck and the industry since the beginning of the pandemic.

We have continued to work on a number of other early programs and I'm pleased to announce a previously undisclosed target. We recently nominated <unk> 3 and a pad site directed candidates against complement C. III.

Over activation of the complement Cascade is thought to be causative of a number of diseases, including proximal nocturnal hemoglobinuria and C. III merial apathy and complement mediated injuries involved and many other conditions, including and Iga nephropathy as well as many other renal vascular hematologic and neurologic conditions.

Christopher R. Anzalone: We have continued work on a number of other early programs, and I'm pleased to announce a previously undisclosed target. We recently nominated Arrow C3 as a Patasite-directed candidate against Complement C3. Overactivation of the complement cascade is thought to be causative of a number of diseases, including paroxysmal nocturnal hemoglobinuria and C3 glomerulopathy, and complement-mediated injury is involved in many other conditions, including IGA nephropathy as well as many other renal vascular hematologic and neurologic conditions. Complement C3 is a central node in all three of the complement pathways, including the classical, lectin, and alternative pathways of complement activation.

Compliments <unk> 3 as a central node and all 3 of the comp on pathways, including the classical and lectin and alternative pathways of complement activation and has recently been shown that inhibition of C..3 can be both safe and effective and the treatment of complement mediated diseases.

We have a strong track record and trim enabled hepatocytes directed candidates, including Aro HBV Aro LTA Arrow, a T arrow and 3 Aero Apoc, III and Aero HST clinical.

Clinical data from these programs gives us confidence that positive and non clinical data from the <unk> 3 may translate well in humans, we believe that and S owner and a capable and substantially reducing C..3 levels for 3 months from war could be the modality and choice for <unk> and ambition and we expect to file a cta for <unk> by the end of this year.

During the quarter, we also announced positive interim data for 2 of our early stage clinical programs Arrowhead, II and Aero HST I'll start with Arrowhead, II, which is our first tumor targeted program being developed as a potential treatment for patients with clear cell renal cell carcinoma or CCR RCC.

To date, and investigational Arrowhead and <unk> has been generally well tolerated at doses of up to 525 milligrams weekly. The study has now progressed to a dose of 1050 milligrams weekly, which is currently enrolling and dosing patients. We believe that in the first 2 dose cohorts Arrowhead II is showing clear signs of meaningful target engagement and potentially some early.

Christopher R. Anzalone: And it has recently been shown that inhibition of C3 can be both safe and effective in the treatment of complement-mediated diseases. We have a strong track record in trim-enabled hepatocyte-directed candidates, including Arrow HBV, Arrow LPA, Arrow AAT, Arrow ANG3, Arrow APOC3, and Arrow HSD. Clinical data from these programs gives us confidence that positive non-clinical data from Arrow C3 may translate well in humans. We believe that an sRNA capable of substantially reducing C3 levels for three months or more could be the modality of choice for C3 inhibition, and we expect to file a CTA for Arrow C3 by the end of this year.

And so if efficacy and at least 1 patient specifically the hip to Alpha protein H score was assessed via immunohistochemistry non.

<unk> 17 patients had tumor samples and it could be evaluated and 7 of those 9 demonstrated reductions and hip 2 alpha protein H scores. These reductions range from -9% to -82% with a mean reduction of -48%.

In addition, 1 subject had a partial response with approximately 65% tumor shrinkage and 5 subjects and a best response of stable disease. We think these early results and are heavily pretreated population are encouraging for arrowhead II and are tumor targeted platform broadly.

Christopher R. Anzalone: During the quarter, we also announced positive interim data for two of our early-stage clinical programs, Arrow HIF-2 and Arrow HSD. I'll start with Arrow HIF-2, which is our first tumor-targeted program being developed as a potential treatment for patients with clear-cell renal cell carcinoma, or CCRC. To date, investigational Arrowhead 2 has been generally well tolerated at doses of up to 525 milligrams weekly. The study has now progressed to a dose of 1,050 mg weekly, which is currently enrolling patients.

We also presented positive interim data for Aero HST being developed as a potential treatment for patients with liver diseases, such as Nash at the easel International liver Congress Airwave.

<unk> was well tolerated and healthy volunteers given a single dose at 25 milligrams 50 milligrams 100 milligrams or 200 milligrams and and 5 patients with suspected Nash given a 100 milligram dose of Aero HST on days, 1 and 29.

All 5 patients with suspected Nash showed a strong pharmacodynamic effect as measured by liver biopsy at day 71 HST.

<unk> 17 day to 13 protein was reduced by 92% and 97% and 2 patients while the other 3 patients day 71 measurements reduced below the lower limit of quantitation and.

Importantly, <unk> showed a mean reduction from baseline of 46% with all patients showing reductions ranging from 26% to 53%. We believe that arrow HST is the first investigational therapeutic to demonstrate robust inhibition of hepatic HST 17, beta <unk> mrna and protein expression.

Christopher R. Anzalone: We believe that in the first two dose cohorts, Arrowhead 2 is showing clear signs of meaningful target engagement and potentially some early signs of efficacy in at least one patient. Specifically, the hip 2 alpha protein H-score was assessed via immunohistochemistry. 9 of 17 patients had tumor samples that could be evaluated, and 7 of those 9 demonstrated reductions in HIF-2 alpha protein age scores. These reductions ranged from minus 9 percent to minus 82 percent, with a mean reduction of minus 48 percent.

We're also highly encouraged to see a LP levels dropped significantly following just 2 doses of Barrow HST.

In addition to progress on our early stage pipeline and we also achieved some important milestones for our mid and later stage pipeline.

I'll start with our cardio metabolic programs Arrow <unk> 3 being developed as a potential treatment for hyper triglyceride anemia, and arrow and 3 being developed as it pretends to treatment from mixed dyslipidemia.

We recently started 2 phase <unk> studies, 1 for each program.

Christopher R. Anzalone: In addition, one subject had a partial response with approximately 65% tumor shrinkage, and five subjects had a best response of stable disease. We think these early results in a heavily pre-treated population are encouraging for ARF2 and our tumor-targeted platform broadly. We also presented positive interim data for Arrow HSD, being developed as a potential treatment for patients with liver diseases, such as NASH, at the Easel International Liver Congress. Arrow HSD was well-tolerated in healthy volunteers, given a single dose at 25 mg, 50 mg, 100 mg, or 200 mg, and in 5 patients with suspected NASH, given a 100 mg dose of Arrow HSD on days 1 and 29.

We intend to initiate 4 or more studies across the 2 programs, including our phase III study Javier will give more details about the studies.

And that have already started dosing and a few minutes, but we believe the studies together will give us a robust picture on the pharmacy and pharmacologic activity of each medicine and various targeted patient populations. We are intending to identify the often low dose and dose intervals to enable us to move confidently into multiple phase III studies and.

And listen to our cardio metabolic programs, we had multiple important events and the last quarter for <unk> also known as Tak 999, being co developed with Takeda as a treatment for a rare genetic liver disease associated with Alpha 1 antitrypsin deficiency.

First we presented additional positive interim 48 week liver biopsy results at the <unk> International liver Congress.

These results demonstrated that <unk> treatment led to rapid improvements and multiple measures of liver health, including fibrosis with substantial and sustained reductions and the level of mutant <unk> protein.

Christopher R. Anzalone: All five patients with suspected NASH showed a strong pharmacodynamic effect as measured by liver biopsy at day 71. HSD 17 beta 13 protein was reduced by 92% and 97% in two patients, while the other three patients' day 71 measurements were reduced below the lower limit of quantitation. Importantly, ALT showed a mean reduction from baseline of 46%, with all patients showing reductions ranging from 26% to 53%. We believe that Arrow HSD is the first investigational therapeutic to demonstrate robust inhibition of hepatic HSD17beta13 mRNA and protein expression. We are also highly encouraged to see ALT levels drop significantly following just two doses of Arrow HSD.

<unk> broke and has been identified as the cause of progressive liver disease and patients with Alpha 1 antitrypsin deficiency.

Treatment was generally well tolerated after up to 1 year of treatment. This is very important data and suggest to us that the drug is doing what it's designed to do and that removing the mutant <unk> protein can give deliberate chance to begin the healing process, even when intervening and patients with late stage liver disease.

We and our partners at Takeda, we're thrilled to see these results and we have received similar responses from physicians and others in the Alpha 1 treaty and community.

We also fully enrolled the <unk> phase 2 Sequoia study with a 48 patient being dosed recently combined with the various cohorts on the open label 2002 study, we will have paired biopsies from approximately 50 patients receiving various dose levels and various treatment durations.

Christopher R. Anzalone: In addition to progress on our early stage pipeline, we also achieved some important milestones for our mid and later stage pipeline. I'll start with our cardiometabolic programs, ArrowApoC3 being developed as a potential treatment for hypertriglyceridemia, and ArrowANS3 being developed as a potential treatment for mixed dyslipidemia. We recently started two Phase IIb studies, one for each program. We intend to initiate four or more studies across the two programs, including a phase three study.

Lastly for Arrowhead.

Granted breakthrough therapy designation by the U S FDA.

<unk> was also previously granted orphan drug designation and fast track designation from the FDA and orphan designation from the European Commission on.

Our goal is to expedite the development path of barrel and each of these important designations provide potential ways to achieve that we will work with regulatory authorities and our partners from Takeda to identify the best path to bring this important drug to patients quickly.

Now moving on to progress that we've made with partnering as I mentioned, we believe our platform companies use partner and selectively to expand the reach and maximize the value of the platform technology and to bring and non dilutive capital that helps to fund internal development. This is a key component of our business strategy and an area, where we've seen important recent progress.

Christopher R. Anzalone: Javier will give more details about the studies that have already started dosing in a few minutes, but we believe the studies together will give us a robust picture of the pharmacologic activity of each medicine in various target patient populations. We intend to identify the alpha dose and dose intervals to enable us to move confidently into multiple phase three studies. In addition to our cardiometabolic programs, we had multiple important events in the last quarter for Arrow AAT, also known as TAC-999, being co-developed with Takeda as a treatment for the rare genetic liver disease associated with alpha-1 angiotrypsin deficiency.

The collaboration with Janssen, which was executed toward the end of 2018 for Aro HBV against chronic hepatitis B infection included and an option on 3 additional programs during the previous quarter Janssen and delivered written notice of its intent to exercise its option right for the first of those programs Aero J&J won this.

And this earned arrowhead of $10 million of option exercise fee and signals janssens intent to move forward with clinical studies.

Also during the quarter, we announced the global collaboration and license agreement with Horizon Therapeutics for Aero ex D. H, a previously undisclosed discovery stage candidate being developed by Arrowhead as a potential treatment for people with uncontrolled gout.

Christopher R. Anzalone: First, we presented additional positive interim 48-week liver biopsy results at the Easel International Liver Conference. These results demonstrated that Arrow AAT treatment led to rapid improvements in multiple measures of liver health, including fibrosis, with substantial and sustained reductions in the level of mutant AAT proteins. Mutant AAT protein has been identified as the cause of progressive liver disease in patients with alpha-1 antitryption deficiency.

Arrowhead received $40 million and upfront payment from horizon and is eligible to receive up to $660 million and potential development regulatory and commercial milestones and further eligible to receive royalties and the low to mid teens range on net product sales.

Ryzen and will receive a worldwide exclusive license to the therapeutic and will be wholly responsible for clinical development and commercialization.

Christopher R. Anzalone: Arrow AT treatment was generally well tolerated after up to one year of treatment. This is very important data and suggests to us that the drug is doing what it is designed to do and that removing the mutant AAT protein can give the liver a chance to begin the healing process, even when it is used in patients with late stage liver disease. We and our partners at Takeda were thrilled to see these results, and we have received similar responses from physicians and others in the Alpha 1 treating community.

This is a great example of an attractive partnering opportunity and expanded the reach of our technology to an area that we had not intended to enter independently and brought in non dilutive capital and also brought in needed expertise and the GAAP field to help understand the disease, the clinical path the tremendous unmet medical need and.

And a dominant player in this space with an existing commercial organization.

And for all these reasons, we thought horizon was the ideal partner and the deal and make perfect sense for both of our companies. We look forward to working closely with horizon as we advance this potential new therapy for patients in need.

Christopher R. Anzalone: We also fully enrolled the Arrow AAT Phase 2 Sequoia Study with the 40th patient being dosed. Combined with the various cohorts in the Open Label 2002 study, we will have paired biopsies from approximately 50 patients receiving various dose levels and various treatment durations.

<unk> heard this was a busy quarter with lots of exciting events, However, drug development doesn't progress and a straight line and invariably there are surprises.

Sometimes he surprised and lead to leaps forward such as the faster than expected liver healing and our <unk> program and sometimes these surprises can be more and welcome.

Christopher R. Anzalone: Lastly, for Arrow AT, we have been granted breakthrough therapy designation by the U.S. FDA. Arrow AT was also previously granted orphan drug designation and fast track designation from the FDA and orphan designation from the European Commission. Our goal is to expedite the development path of Arrow AAT, and each of these important designations provides potential ways to achieve that. We will work with regulatory authorities and our partners from Takeda to identify the best path to bring this important drug to patients quickly.

We experienced the ladder and the arrow and that program our candidate being developed as potential treatment for cystic fibrosis last quarter.

To review, we voluntarily paused the clinical study of <unk> after receiving a preliminary update from and ongoing chronic toxicology study in rats that contained unexpected signals of local lung inflammation.

<unk> of this preliminary update we instructed investigators to pause and new screening enrollment and any further dosing of investigational arrow enact pending additional data from the ongoing chronic rat toxicology study and an additional ongoing chronic primate toxicology study.

We have not seen any concerning safety or tolerability signals and people enrolled in the arrow and <unk> 1001 study. However, we place the safety of patients that participated on our clinical trials above all else. So we will continue to keep the arrow and that clinical study on pause for now we do not yet have full data back from the toxicology studies, nor from additional studies that.

Christopher R. Anzalone: Now moving on to progress that we've made with partnering. As I mentioned, we believe a platform company should use partnering selectively to expand the reach and maximize the value of the platform technology and to bring in non-dilutive capital that helps to fund internal development. This is a key component of our business strategy and an area where we've seen important recent progress. The collaboration with Janssen, which was executed toward the end of 2018 for Arrow HPV against chronic hepatitis B infection, included an option on three additional programs. During the previous quarter, Janssen delivered written notice of its intent to exercise its option right for the first of those programs, Arrow J&J 1.

We are conducting internally so we do not yet know the extent of the findings. We are investigating this fully and are still on the information gathering stage, we should know more on the coming weeks and months and we intend to provide an update when we are able.

With that overview I'd now like to turn the call over to Dr. Javier San Martin Javier.

Thank you Kris and good afternoon, everyone I want to give you an update on our clinical studies and provide details on the design of a couple of our newest studies.

I will discuss <unk>, which is designed to inhibit the pollution and the <unk> 2 alpha to Threep, DSL renal cell carcinoma or RCC.

Christopher R. Anzalone: This earned Arrowhead a $10 million option exercise fee and signals Janssen's intent to move forward with clinical studies. Also, during the quarter, we announced a global collaboration and license agreement with Horizon Therapeutics for ArrowXDH, a previously undisclosed discovery stage candidate being developed by Arrowhead as a potential treatment for people with uncontrolled gout. Arrowhead received $40 million as an upfront payment from Horizon and is eligible to receive up to $660 million in potential development, regulatory, and commercial milestones, and is further eligible to receive royalties in the low to mid-teens range on net product sales.

We're encouraged by the positive interim results from the first 2 cohorts of <unk> to.

<unk> 1000, and what a phase 1 dose finding clinical study in 3 cohorts with advanced.

So RCC, but are currently enrolling cohort 3 which is designed to include up to 10 patients who will receive a weekly IV infusion of 1050 milligrams of <unk> to this day.

And these designed to evaluate the safety of Arrowhead II to determine the recommended phase 2 dose emphasis pharmacokinetics and preliminary efficacy based on receipts and.

Post dose 2 minute and exploration of <unk>.

Associated genes.

Christopher R. Anzalone: Horizon will receive a worldwide exclusive license to the therapeutic and will be wholly responsible for clinical development and commercialization. This is a great example of an attractive partnering opportunity. It expanded the reach of our technology to an area that we had not intended to enter independently and brought in non-dilutive capital. It also brought in needed expertise in the gout field to help understand the disease, the clinical path, the tremendous unmet medical need, and a dominant player in the space with an existing commercial organization.

Patients will continue to receive weekly arrowhead II indefinitely and can they experienced disease progression and a complete response or they discontinued.

Our intention is to share additional interim data from this study, including data from cohort 1.2 and initial results from cohort 2 feet on the appropriate medical meeting and the future we have not yet selected and tenants.

The next bill and I want to be Dennis <unk>, our investigational candidate for the potential treatment of alcohol and non alcohol related liver disease within the interim data we presented at Isa was highly encouraging and in fact, our presentation was highlighted in the ESO official scientific conference.

On <unk> mesh and he was exciting to see and C level dropped significantly following chest 2 doses of 8 on HST.

Christopher R. Anzalone: For all these reasons, we thought Horizon was the ideal partner, and the deal made perfect sense for both of our companies. We look forward to working closely with Horizon as we advance this potential new therapy for patients in need. As you've heard, this was a busy quarter with lots of exciting events.

With respect to the high level of targeted gene knockdown, because our team has been extraordinary consistent across our different liver directed programs are implemented and ALC and at this early time point and was very welcome surprise.

Christopher R. Anzalone: However, drug development doesn't progress in a straight line, and invariably, there are surprises. Sometimes these surprises lead to leaps forward, such as the faster-than-expected liver healing in our Arrow AT program, and sometimes these surprises can be more unwelcome. We experienced the latter in the Arrow ENAC program, our candidate being developed as a potential treatment for cystic fibrosis last quarter. To review, we voluntarily paused the clinical study of Arrow-ENAC after receiving a preliminary update from an ongoing chronic toxicology study in rats that contained unexpected signals of local lung inflammation.

These data and the stone and genetic evidence of HST 17, and beat the Athena and potential to that both the target and provide us with increased confidence as we design our the clinical study for <unk> and HST West.

We're thinking about innovative designs to seek to answer key questions about the <unk> never seen the Dcs and the makings of <unk> 17 and <unk>.

And any signs of improvement may look like.

We're approaching this in a similar way to how we approach.

In the meantime.

We're still conducting the phase 1 and 2 in patients with Nash or suspected Nash and we're happy to report that the study is fully enrolled.

Christopher R. Anzalone: Because of this preliminary update, we instructed investigators to pause new screening, enrollment, and any further dosing of investigational arrow ENAC pending additional data from the ongoing chronic rat toxicology study and an additional ongoing chronic primate toxicology study. We have not seen any concerning safety or tolerability signals in people enrolled in the Arrow ENAC 1001 study. However, we place the safety of patients that participate in our clinical trials above all else, so we will continue to keep the Arrow ENAC clinical study on pause for now.

As Cliff mentioned, we started dosing in 2 phase <unk> studies of our cardio metabolic candidates.

<unk> and <unk> during the last quarter. We gave a brief description of these study designs. So you all kind of theme to potential timing.

And then to initiate additional studies shortly and we will provide details on the design of the additional studies when they start.

For <unk>, we initiated a positive 2000 on what a double blind placebo control phase II study to evaluate the efficacy and safety of <unk> in adults with severe hypercholesterolemia or S. H D G.

Christopher R. Anzalone: We do not yet have full data back from the toxicology studies, nor from additional studies that we are conducting internally, so we do not yet know the extent of the findings. We are investigating this fully and are still in the information-gathering stage. We should know more in the coming weeks and months, and we intend to provide an update when we are able. With that introduction, I'd now like to turn the call over to Dr. Javier San Martin. Javier? Thank you, Chris.

And those level of AIA policy and milligrams 25 million from 50 million going on will be evaluated against placebo and participant.

And first and thickness of greater than or equal to 500 milligrams per deciliter at screening.

And total of approximately 300 participant will be enrolled in this study all of those cohorts will and going in parallel with 100 participants per dose cohort randomly assigned and a 3 to 1 ratio to receive Italy, plus <unk> or placebo each participant will receive subcutaneous injection.

Javier San Martin: Thank you, Chris, and good afternoon, everyone. I want to give an update on our clinical studies and provide details on the design of a couple of our newest studies. First, I will discuss Arrow HIF-2, which is designed to inhibit the production of HIF-2 alpha to treat clear cell renal cell carcinoma or RCA. We were encouraged by the positive interim results from the first two cohorts of Arrowhead 2-1001, a Phase Ib dose-finding clinical study in three cohorts with advanced clear-cell RCC who are currently enrolling Cohort 3, which is designed to include up to 10 patients who will receive a weekly The study is designed to evaluate the safety of Arrow HIF-2 to determine the recommended phase 2 dose and to assess pharmacokinetics and preliminary efficacy based on resistance and post-dose tumor expression of HIF-2-alpha and HIF-associated genes.

Day, 1 week 12, and the duration of the study is approximately 54 weeks force clean into the week 48, and a steady examination.

And when you have shaped the study is to evaluate the safety and efficacy of annual Apoc, III and apples FH digi and to select and dosing regimen and for later stage clinical studies in these patient populations.

For <unk>, we initiated <unk> 2001, a double blind placebo controlled phase II study to evaluate the efficacy and safety of investigation on aim.

In other words with mixed Dyslipidemia 3 dose levels and should.

Fee 50 meeting on <unk>, 100, 200 milligrams will be evaluated against placebo and participant with mix.

Lithemia, who had the following.

Premium.

LDL cholesterol and greater than or equal to 70 milligrams per deciliter, or and non HDL cholesterol and greater than or equal to 100 milligrams per day.

And mean fast and triglycerides between $1.50, and $500 million previously.

Javier San Martin: Patients will continue to receive weekly Arrow HIF-2 indefinitely until they experience disease progression, have a complete response, or they discontinue treatment. Our intention is to share additional entry data from this study, including data from Cohort 1, 2, and initial results from Cohort 3, at an appropriate medical meeting in the future. We have not yet selected the intended, The next program I want to detail is Arrowhead Pharmacy, our investigational candidate for the potential treatment of alcohol and non-alcohol related liver disease.

And total of approximately 180 participant will be enrolled in this study.

All of those cohorts will enroll in parallel with 60 persistent GERD cohort randomly assigned in a 3 to 1 ratio to receive a subcutaneous injection of <unk> 3 or placebo on day, 1 week 12.

And with that is approximately 42 weeks from screening to the week 76, and a steady examination.

The complete and that was 76 and this is a defense will be eligible to continuing continue and an open label extension study. The primary objective of the Arrow and <unk> fee 2001 study is to evaluate the safety and efficacy of <unk> in adults with mixed Dyslipidemia and selected dosing regimen for later.

Javier San Martin: The interim data we presented at ESOL was highly encouraging, and in fact, our presentation was highlighted in the ESOL official scientific press conference on NAFLD. It was exciting to see ALT levels drop significantly following just two doses of AeroHSP. We expected a high level of target gene note down because our twin system has been extraordinarily consistent across our different liver-directed programs. But the improvement in ALT at this early time point was very welcome.

Stage clinical studies in this patient population.

I will now turn the call over to Ken Moskovsky Auto has chief Financial Officer, Ken. Thank you Javier and good afternoon, everyone.

As we reported today, our net loss for the quarter ended June 32021 was $29.9 million or <unk> 29 per share based on $104.1 million and fully diluted weighted average shares outstanding.

Javier San Martin: This data and the strong genetic evidence of HSD17-beta-13 as a potential therapeutic target provide us with increased confidence as we design further clinical studies for 808 and are thinking about innovative designs that seek to answer key questions about the medicine, the disease, and the mechanism of HSD-17 beta 3 inhibitors and what other science films may look like. We're approaching this in a similar way to how we approach Arrowhead. In the meantime... We're still conducting the Phase I, II inpatient trials with NASH or suspected NASH, and we're happy to report that the study is fully enrolled.

This compares with net loss of $13.6 million or <unk> 13 per share on $101.8 million fully diluted weighted average shares outstanding for the quarter ended June 32012.

Revenue for the quarter ended June 32021, and is $45.9 million compared to $27.4 million for the quarter ended June 32020.

Revenue and the current period, primarily relates to the recognition of a portion of the $300 million upfront payment received under our collaboration agreement with Takeda as well as a $10 million option exercise payment received from Janssen.

Javier San Martin: As Cliff mentioned, we started dosing in two Phase IIb studies of our cardiometabolic candidates, Arrow ApoC3 and Arrow H3, during the last quarter. I will give a brief description of these study designs, so you all can think through potential timing. We intend to initiate additional studies shortly, and we will provide details on the design of the additional studies when they start.

The Arrow J&J, 1 program and May 2021.

Revenue for the Takeda agreement will be recognized as we continue to work toward completing our performance obligations of managing clinical trials and process and certain manufacturing related services.

The remaining $230 million of revenue associated with the Takeda collaboration is anticipated to be recognized over approximately 2 years.

Javier San Martin: For AeroApoc3, we initiated AeroApoc32001, a double-blind placebo-controlled, face-to-face study to evaluate the efficacy and safety of AeroApoc3 in adults with severe hypertriglyceridemia, or SHTG. Three dose levels of Arrowhead Pocitri, 10 mg, 25 mg, and 50 mg, will be evaluated against placebo in participants who have mean fasting triglycerides of greater than A total of approximately 300 participants will be enrolled in the study. All those cohorts will enroll in parallel, with 100 participants per dose cohort randomly assigned in a 3-to-1 ratio to receive HeroApoC-3 or placebo. Each participant will receive a subcutaneous injection on day one. And we...

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

Revenue in the prior period, primarily related to the recognition of a portion of the milestones received from our license and collaboration agreements with Janssen.

Our performance and revenue recognition under the Janssen agreement or HBV is substantial is substantially complete.

Total operating expenses for the quarter ended June 32021 were $77.8 million compared to $43.3 million for the quarter ended June 32020.

This increase was primarily due to increased candidate specific and discovery R&D costs as the company's pipeline of clinical candidates has both increased and advanced.

Net cash used by operating activities. During the quarter ended June 32021 was $29.6 million compared with net cash used by operating activities of $33.4 million during the quarter ended June 32020.

Javier San Martin: The duration of the study is approximately 54 weeks from screening to the week 48 end of study examination. The primary objective of the study is to evaluate the safety and efficacy of Arrowhead Positri in adults with SHDT and to select a dosing regimen for later stage clinical studies in these patient populations. For AeroH3, we initiated AeroH3-2001, a double-blind placebo-controlled phase 2B study to evaluate the efficacy and safety of investigational AeroH3 in adults with mixed dyslipidemia.

The key driver of this change was the $10 million option exercise payment received from Janssen.

For Aero J&J, 1 program and May 'twenty 'twenty 1.

Excluding any potential milestones from our collaboration partners, we estimate our cash burn run rate to be $50 million to $60 million per quarter.

Turning to the balance sheet, our cash and investments totaled $644.7 million at June 32021, compared to $453 million at September 32020.

The increase on our cash and investments was primarily due to the appropriate and received from Takeda offset by cash used by operating activities.

Javier San Martin: Three dose levels of AeroH3, 50 milligrams, 100, and 200 milligrams, will be evaluated against placebo in participants with mixed dyslipidemia who have the following screen: LDL cholesterol greater than or equal to 70 milligrams per deciliter or non-HDL cholesterol greater than or equal to 100 milligrams per deciliter, and Mean Fasting Triglycerides between 150 and 500 mg per week.

On July we also collected the $40 million upfront payment due under our recent collaboration with horizon.

Our common shares outstanding at June 32021 were $104.2 million.

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

Thanks, Ken.

As I mentioned, we think we're making strong progress across the spectrum of activities required to be successful platform company.

We are innovating on the platform and pushing the bounds of what our trim technology can do we are rapidly and efficiently, beating the early stage pipeline with new candidates that may be engines of growth for arrowhead and the future.

Javier San Martin: A total of approximately 180 participants will be enrolled in the studies. All those cohorts will enroll in parallel, with 60 participants per cohort randomly assigned in a 3-to-1 ratio to receive a subcutaneous injection of arrowh3 or placebo on day 1 and week 2. The duration of the study is approximately 42 weeks from screening to the week 36 end of study examination. After completing the week 36 visit, participants will be eligible to continue in an open-level extension.

And we're moving our mid and later stage clinical programs progressively closer to our goal of bringing important new medicines and patients who need them.

And lastly, we are selectively and responsibly using partnering and business development when it makes sense to do so.

And this last quarter, so important and tangible progress on all of these areas.

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

Thank you, Chris and as a reminder to ask a question just press Star and then the number 1 on your telephone keypad again, just press Star and then the number 1 on your telephone keypad and move your line from the Q and just press the pound key.

Javier San Martin: The primary objective of the ArrowH3 2001 study was to evaluate the safety and efficacy of ArrowH3 in adults with mixed dyslipidemia and select a dosing regimen for later stage clinical studies in this patient population. I will now turn the call over to Ken Myszkowski, Arrowhead's Chief Financial Officer.

And by while we compile the Q&A roster.

Your first question comes from the line of Maury Raycroft from Jefferies. Your line is open.

Kenneth A. Myszkowski: Financial Officer, Ken. Thank you, Javier, and good afternoon, everyone.

Yeah, Hi, Thanks for taking my questions and congrats on the progress.

Kenneth A. Myszkowski: As we reported today, our net loss for the quarter ended June 30, 2021 was 29.9 million, or 29 cents per share, based on 104.1 million fully diluted weighted average shares outstanding. This compares with a net loss of $13.6 million, or $0.13 per share, on 101.8 million fully diluted weighted average shares outstanding for the quarter ended June 30, 2020. Revenue for the quarter ended June 30, 2021 was $45.9 million compared to $27.4 million for the quarter ended June 30, 2020.

I was wondering for the bottleneck for the CPA filings for Ducks floor and the 2 pulmonary candidate can you comment on whether this has anything to do with waiting for additional preclinical data from <unk>.

It does not.

It has to do with with.

Finding slots of zeros, there as we talked about this I think.

A few conference calls ago that their debt since the pandemic there has been a.

Non human primate shortage and also.

These pulmonary.

Studies are a bit a bit more difficult to do because there because there's not many zeroes and do them and so given all that we just we've just had a bit of a bottleneck and so we'll get these done and just that we're going to get them done.

Quarter or 2 later than we had hoped.

Got it Okay and then also just wanted to check on.

If you are providing a status update on how the enact study.

Studies going and you mentioned you may know more on the next few weeks and months is it fair to assume that there could be and update on.

Kenneth A. Myszkowski: Revenue in the current period primarily relates to the recognition of a portion of the $300 million upfront payment received under our collaboration agreement with Takeda, as well as a $10 million option exercise payment received from Janssen for the ARO J&J 1 program in May 2021. Revenue for the Takeda Agreement will be recognized as we continue to work toward completing our performance obligations of managing clinical trials in process and certain manufacturing-related services.

On this and <unk> and and the next update are you going to provide some of the clinical data that you saw.

Yes, so I just don't know so with respect to the Tox data I just don't know when we're going to have better clarity, we're not going to have NH P data until towards the end of the year and.

So that will be a black box until then and we haven't yet that's still ongoing and so theres just no data there yet.

We don't have final reports for the for the road and piece of that.

And that's still ongoing we just got.

And interim update on which caused us to press pause and now we're doing some of the other internal programs and some other internal experiments and so I can't give you good guidance on when we're going to know something.

Kenneth A. Myszkowski: The remaining $230 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. Revenue in the prior period primarily related to the recognition of a portion of the milestones received from our license and collaboration agreements with Janssen. Our performance and revenue recognition under the Janssen Agreement, or HBV, is substantially complete.

We're working on it right now and I think beyond that it doesn't make sense for us to talk.

To talk about.

The clinical program until we have a better idea about where this is going to go in and and.

And how quickly we might be able to get back on track. If in fact, that's going to work out.

Okay that makes sense and last question from me is just for Arrow have 2 the first data and the refractory RCC looks good at this point do you have more insight into their relationship between knockdown and related tumor activity and how do you think activity could change at a higher dose.

So we don't we expect that the first question, we don't we don't yet have any more information.

Kenneth A. Myszkowski: Total operating expenses for the quarter ended June 30, 2021 were $77.8 million, compared to $43.3 million for the quarter ended June 30, 2020. This increase is primarily due to increased candidate-specific and discovery R&D costs as the company's pipeline of clinical candidates has both increased and advanced. Net cash used by operating activities during the quarter ended June 30, 2021 was $29.6 billion, paired with net cash used by operating activities of $33.4 million during the quarter ended June 30, 2020.

With respect to the second question.

And I don't know hopefully.

We're seeing this only.

We're looking at this and real time, and and we haven't seen data from the <unk>.

From a higher dose yet so we'll see where that goes.

What was encouraging to me at least was that it appears that we're on the board and we're getting good.

Target engagement. It appears we're getting knocked down and so now, let's just see where this goes.

I don't I would not expect.

A rapid sort of physiological response, if you will.

And with respect to tumor shrinkage and such.

Kenneth A. Myszkowski: The key driver of this change was the $10 million option exercise payment received from Janssen for the ARO J&J 1 program, May 2021. Excluding any potential milestones from our collaboration partners, we estimate our cash burn run rate to be $50 to $60 million per quarter. Turning to the balance sheet, our cash and investments totaled $644.7 million at June 30, 2021, compared to $453 million at September 30, 2020. The increase in our cash and investments was primarily due to the upfront payment received from Takeda offset by cash used by operating activities. In July, we also collected the $40 million upfront payment due under our recent collaboration with Verizon. Our common shares outstanding at June 30, 2021 were $104.2 million.

Christopher R. Anzalone: With that brief overview, I will now turn the call back to Chris. Thanks, Ken. As I mentioned, we think we're making strong progress across the spectrum of activities required to be a successful platform company. We are innovating on the platform, pushing the boundaries of what our trim technology can do. We are rapidly and efficiently feeding the early stage pipeline with new candidates that may be engines of growth for Arrowhead in the future.

And target.

And the muscle cells that we use a peptide charging lay and vs third antibody or antibody fragment approach. So that's I think that's the main difference as far as comparing and there's really no way to compare and efficacy or knockdown levels.

Christopher R. Anzalone: We are moving our mid and later stage clinical programs progressively closer to our goal of bringing important new medicines to the patients who need them. And lastly, we are selectively and responsibly using partnering and business development when it makes sense to do so. This last quarter saw important and tangible progress in all of these areas. Thanks again for joining us today. I would now like to open the call to your questions, operator.

Is the.

Other competing programs and that shared any data at this point and then the other question was around the fulcrum read through is that right.

Yeah. It's it's it's tough to say I mean, it's a very different compound and different mechanism I think they did highlight the the challenges associated with a biopsy study in and.

Operator: Thank you Chris, and as a reminder to ask a question just press star and then the number one on your telephone keypad. Again, just press star and then the number one on your telephone keypad, and to remove your line from the queue, just press the pound. Please stand by while we...

And this population and with this specific target where there's this sort of stochastic expression of the target that may be difficult to catch her to monitor if you will with biopsied. So.

Operator: Please stand by while we compile the Q&A route.

We will look at downstream gene expression, but will likely also look at other parameters that might help us selected dose for later stage clinical studies.

Operator: Your first question comes from the line of Maurice Raycroft from Jeffreys. Your line is open.

Maurice Thomas Raycroft: Thanks for taking my questions and congrats on the progress.

Yeah.

Christopher R. Anzalone: I was wondering about the bottleneck for the CTA filings for Dux4 and the two pulmonary candidates. Can you comment on whether this has anything to do with waiting for additional preclinical data for MEAN-X? It does not. It has to do with, with, with just, you know, finding slots at CROs. You know, there's, we talked about this, I think, Okay. Got it. Okay.

Christopher R. Anzalone: And then also just wanted to check on whether you're providing a status update on how the ENAC NHP study is going, and you mentioned you may know more in the next few weeks and months. Is it fair to assume that there could be an update on this in 4Q then? And in the next update, are you going to provide some of the clinical data that you saw? Yeah, so I just don't know.

Christopher R. Anzalone: So with respect to the TOCS data, I just don't know when we're going to have better clarity. We're not going to have the NHP data until towards the end of the year. And so that will be a black box until then. We haven't, you know; that's still ongoing, and so there's just no data there yet. We don't have, you know, final reports for the rodent piece of that. You know, that's still ongoing.

Christopher R. Anzalone: We just got, you know, an interim update, which caused us to press pause. And now we're doing some other internal experiments. And so I can't give you good guidance on when we're going to know something. You know, we're working on it right now. And I think beyond that, it doesn't make sense for us to, you know, talk about the clinical program until we have a better idea about where this is going to go and how quickly we might be able to get back on track if, in fact, that's going to work.

Broader.

Issues.

We don't know if that specie specific because as I said, we don't have.

And HP data yet we don't know if it if it is sequent specific or target specific theirs.

We were really just starting to get into this and just what was the other part of the question.

Christopher R. Anzalone: Okay, that makes sense. And the last question for me is just for

It is.

But the other part of the question was if you. If you said it consistently see that the toxic when you get the N H P data I can see the toxic.

Christopher R. Anzalone: For me, it is just for Arrow HIF-2; the first data and the refractory RCC looked good. At this point, do you have more insight into the relationship between knockdown and related tumor activity? And how do you think activity could change at a higher dose? So we don't, with respect to the first question, we don't yet have any more information. With respect to the second question, I don't know. We're only seeing this, we're looking at this in real time, and we haven't seen data from a higher dose yet, so we'll see where that goes.

And limited to the lung would it.

I mean, how would you interpret that is it would it is it is that a good thing because you know the drug is getting to the lung and you just have to find another target that that works, maybe and a different indication or do you or would you have to go back and change the chemistry.

Well, if the talks being limited to the lung as Chris stated is not.

It is not surprising I mean the on the.

And the systemic bioavailability with inhalation on Oligos is not that great. So it's not unexpected that would we would only see talks and.

Christopher R. Anzalone: What was encouraging to me, at least, was that it appears that we're on the board, we're getting good target engagement, and it appears that we're getting knockdowns, so now let's just see where this goes. But I would not expect, you know, a rapid sort of physiological response, if you will, with respect to tumor shrinkage and such through this pathway. That may take a bit longer. So the fact that we are seeing right now, some knockdowns, suggests to us that our platform is working, and so now we just need to see how that's going to go going forward.

And in the lung and I think it depends on what.

What we would see in the final results from the Red and then the NH Peace study in terms of what with the toxicity is and at what dose levels and dose frequencies there.

You know again, depending on the results and we don't have figures results, yet there may be and opportunity to.

Resume the study as is or 2 to them and taking a look at different dose levels different dose intervals.

Christopher R. Anzalone: Okay, that's helpful. Thanks for taking my questions, and I'll hop back in the queue.

And Ed.

And a follow on to that remember that we are where.

And we doses that we can doses.

Operator: Thank you. Your next question comes from Alicia Young of Cantro. Your line is open.

Reasonably high but also we dose it relatively frequently and so to James is point or has he alludes.

Alicia Young: Hi, this is...

Alicia Young: on behalf of Aletheia, and thank you for taking our questions. We are wondering,

And if we are if this appears to be clean and NH piece and it could be that we have an opportunity just to space out the.

Alicia Young: We are wondering if you could share more on your DUX4 program and how it compares to competitors and also if there's any read-through from the Phase 2b results for Lost Mapa Mod, which missed the primary endpoint in change for DUX4.

The dosage is a bit more that's all speculation, let's let's see where the data come in and and we can go from there.

Got it. Thank you and then on <unk> are you still on track to revisit the Registrational trial design with the FDA and other.

I think that and the third quarter late summer or or thereafter.

Christopher R. Anzalone: Yeah, so I'll let I'll let James comment on that. I don't I don't.

And you say the initiation of the phase III study.

James C. Hamilton: Well, I'll let him comment on that. I don't know that there's read through, you know, with the other one, because it's different. You know, it's a different compound entirely, of course, but James. Sure, maybe I'll take the first question first about how we compare with the competing programs. And there's not a whole lot out there.

Yeah.

Are they and good afternoon, Yes, US you probably know we've been granted breakthrough designation and by a week or 2 weeks ago.

Already working on the briefing document and to engage in the first 1 is called multidisciplinary and median in the queue.

Q3 Q4 timeframe.

Thank you.

Thank you.

Thank you. Your next question comes from the line of Joel Beatty from Baird. Your line is open.

Hi, Congrats on the progress a couple of questions on the.

James C. Hamilton: And, you know, with regard to the other oligo programs, the targeted antisense programs are all preclinical, and there's really not much data available. And so the primary difference would be the way that we target the muscle cells that we use, a peptide targeting ligand versus their antibody or antibody fragment approach. So that's, I think that's the main difference as far as comparing them, and there's really no way to compare efficacy or knockdown levels as other competing programs have not shared any data.

And <unk> program.

<unk> is was a dose response and reduction of hit to a scene and among the 3 doses and that study.

And I and then I have a follow up.

Yeah.

James.

Dose response between the first 2 cohorts.

Yeah, I think we're.

We're still in the process of dose escalating and analyzing all the data from the second.

Second cohort and a lot of those patients are still on drug so.

Think.

James C. Hamilton: And then the other question was around the fulcrum read-through, is that right? Yeah, it's tough to say. I mean, it's a very different compound, different mechanism. But I think they did highlight the challenges associated with a biopsy study in this population and with this specific target, where there's this sort of stochastic expression of the target that may be difficult to catch or to monitor, if you will, with biopsies. You will look at downstream gene expression, but we'll likely also look at other parameters that might help us select a dose for later stage clinical studies.

Javier San Martin: This is Javier. I wanted to add another comment about this data, which I think, despite the biomarkers, the clinical data, in some aspects, was positive. So I think the target still is in a good place because if you look at the PRO and the physical function, there is a number of those that were statistically significant. We don't know how clinically relevant those changes are, and we're looking at that to try to see if some of those changes correspond with the minimum relevant changes.

Javier San Martin: And that, I think, will help us to understand this. So I think there are mixed results here. Despite the biomarker now being positive, there are clinical signs of potential improvement in this patient population, which I think is reassuring for the path.

Thanks.

Thank you. Your next question comes from the line of solving reach Sir from Goldman Sachs or your line is open.

Particular question. This is Sonya on for Sulking, and we were just wondering like beyond the pulmonary target and muscle target what other extra hepatic tissues would you be looking to go into on the forward.

Alicia Young: Okay, that's helpful. Thank you.

Operator: Thank you. Your next question comes from the line of Esfer Rejovelu from UBS. Your line is open.

So we have active programs and and number of areas we have not disclosed.

Esfer Rejovelu: Hey, thank you for taking my question. I have two. One on ENAC.

Other areas.

Or the world working on so you have to stay tune of that look we have we have mentioned in the past, though that the CNS clearly as a target rich environment and so it's place and we want to go at some point, we are not there yet.

Esfer Rejovelu: So it's historically been a tough target, but what are some takeaways from the tox signals that you're seeing? Is it specific to the lung, or is there evidence of exposure in other tissues? And what would your considerations be if you find that the tox is limited to the lung?

But there's a number of tissue types that we're looking at.

Thanks.

Sure.

Thank you. Your next question comes from the line of Luka E C from Royal Bank of Canada, and your line is open.

Christopher R. Anzalone: So let me just say two words and then I'll hand it over to James on this. The talks that we saw or that we heard about, you know, again, we haven't had a final report on this RAD study yet, so we have limited data, but what we understand is that it was local lung inflammation. We don't see that. We don't see broader issues. We don't know if that's species specific because, as I said, we don't have the NHP data yet. We don't know if it is sequence specific or is target specific.

Oh, great. Thanks for taking my question. This is Lisa on for Luka, just 1 year on on on a T. Can you give us some directional color here on more with the ongoing dialogue with the F. D. A now that you have the break to designation and there may be a scenario where.

And the data from the 2 O 2 studying and the first day 36 patients from the coil will be sufficient for accelerated approval and I also have a follow up on <unk>.

This is have you yeah I was thinking about all of those options right now we would need to focus on the first introduction and typically these first and connection and as I say this and we'll do the Cincinnati media and what would touch up on decent and us off the filing process discuss the phase 3 studies.

James C. Hamilton: We are really just starting to get into this.

Esfer Rejovelu: Well, the other part of the question was, if you sort of consistently see that the top says

Esfer Rejovelu: When you get the NHP data, if you see the toxin limited to the lung, would it, I mean

James C. Hamilton: Would you interpret that? Is that a good thing? Because you know the drug is getting to the lungs, and you just have to find another target that...

Sign and they have to level and point and the time to file and it's going to be critical by the snow and 1 skull conversation and he says it's a process. So it's a good salt and we will of course and.

James C. Hamilton: Find another target that works, maybe in a different indication, or would you have to go back and change the chemistry?

Entertain the Pinky and on the potential for and and we've had really so far and limited interactions with the idea and that's particularly with the current division.

James C. Hamilton: Well, the tox being limited to the lung, as Chris has stated, is not surprising. I mean, the systemic bioavailability of inhalational oligos is not that great. So it's not unexpected that we would only see toxin in the lung.

But our interactions have been have been quite positive and collaborative.

And they clearly I appreciate that this is an unmet medical need and I and and I think that they are really interested in and working with us to to to get this to patients who needed and so we haven't had so we're really excited to have his breakthrough destination. So we can we can sit down and have these more in depth discussions and to your fall and break to this.

Esfer Rejovelu: I think it depends on what we see in the final results from the RAD and in the NHP study in terms of what the toxicity is and at what dose levels and dose frequencies. You know, again, depending on the results, and we don't have these results yet, there may be an opportunity to resume the study as is or to, you know, amend, look at different dose levels and different dose intervals.

Ignition essentially opens the past.

And 2 and exited approve other based on his surrogate like to translate into clinical benefit and that's precisely what we will discuss.

And the next time around that was significant component of the victim designation briefing document. So yeah, we're gonna talk about these.

Throughout the process.

Esfer Rejovelu: Right. And as a follow-on to that, you know, remember that we can dose this reasonably high, but we also dose it relatively frequently. And so to James's point, or as he alludes, you know, if this appears to be clean in the NHPs, it could be that we have an opportunity, you know, just to space out the dosages a bit more. That's all speculation. You know, let's see where the data comes in, and we can go from there.

Great. That's that's helpful. And then just on on <unk> I'm. Just wondering if you can talk about the doses at what she was seeing the the the talk shows all and and rats and how those doses scale and do human just trying to figure out here, whether the signal the topic.

And to talk signal scene and off the scene at needy super therapeutic doses or at doses that scale within the 40 to 180, Meg range that are being tested and human and.

Esfer Rejovelu: Got it. Thank you. And then on AAP, are you still on track?

Sure sure and I appreciate the question, but look at it as it has been our policy not to talk about about talks data in particular, because we don't even have have a final report here. We just we we've just been given.

Esfer Rejovelu: I'm still on track to revisit the registrational trial design with the FDA in, I think it's set in the third quarter, late summer or thereafter. You say the initiation of

A a small synopsis about about about part of a rat study and we don't even know anything about the about the and H P. So so so we're unable to it to give you any more color on that at this point.

Javier San Martin: Javier, you say the initiation of the phase 3 study? [inaudible] 3Q4 time.

Okay got it thanks for taking my question sure.

Operator: Thank you. Your next question comes from the line of Joel Beatty from Baird. Your line is open.

Thank you. Your next question comes from the line of Patrick Tokyo from H C. When you're on your line is open.

Joel Lawrence Beatty: Hi, congrats on the progress. A couple of questions on the HIF-2A program. The first is, was the dose response to reduction of HIF-2A seen in

[noise] alright. Thanks, Good evening, just a couple of follow up questions on the C. C..3 program, but first can you discuss what if any potential advantages are on it's hurting C..3 rather and see 5 and secondly, you know and which indication on invitations and the C..3 program would initially focus on when the clinical development could begin.

Joel Lawrence Beatty: has two A's seen among the two doses in that study, and then I have a follow-up.

Christopher R. Anzalone: Dose response between the first two cohorts? Yeah, I think we're still in the process of dose escalating and analyzing all the data from the second cohort. A lot of those patients are still on drugs, so I think it's too early for us to really give a clear answer on dose response. And a further complicating factor is that, I might get these numbers wrong, you know, we had 17 individuals, but I think we only had usable biopsy material from nine of them. And so it may be difficult to know if we have a dose response at this point. The only thing I would add is that with this

And is this a program you would bring and 2 clinical development on your own or would you seek a collaboration partner.

I will and the last of those questions and then on hand at all and and the rest over to the James.

And so weak we do not have plans to to seek a partner right now for for this program, you'll look that may change and the future, but right now we are happy to take this forward. This is this is directly and our wheelhouse in terms of of of of.

Ah frequently on development. This is this is a and a side.

Directed contract, we feel good about but I'll go into a clinic and so let's see what the day to look like and then we can make a decision on partner vs on partner at some point and the future James and.

Christopher R. Anzalone: I think that we did see knockdown in both doses.

Christopher R. Anzalone: And in the press release, we were just giving kind of the overall top line on this. And so our intent, as we said in our prepared remarks, is to present a more full data set and an appropriate medical meeting, which would include the top dose level as well. So stay tuned on that.

Sure I'll take the first part of the question that I think was about 6.3 vs C..5.

So.

C 3 and the complement Cascade is a central node that is involved and all 3 different components of the pathway the lectern.

Joel Lawrence Beatty: Yeah, you got it. That all makes sense. It is helpful. So I guess just one follow-up on that: you mentioned how there's one responder with a fairly strong response. Are you able to share anything about the

The alternative and the the classical pathways. So if you can inhibit C..3 you can really take out everything that's downstream.

Joel Lawrence Beatty: about the F2A reduction that was seen in that patient.

Of of C, 3 and and so the effects should be broadly applicable to various complement mediated diseases now.

Christopher R. Anzalone: Not at this time, but I think we can share that when we present the full data set at an upcoming medical meeting.

Operator: Thank you. Your next question comes from the line of Solveen Richter from...

Specifically to too.

Interesting indications PNA, each and see 3 culinary logothete that Chris mentioned during the earlier remarks P and H as a disease, that's been reasonably well treated with C..5 inhibition. However, there is a component of that population.

Solveen Richter: Reacher from Goldman Sachs. Sir, your line is open to taking our question. This is Sonia from for Salveen. We were just wondering, beyond the pulmonary target and the muscle target, what other extra hepatic tissues would you be looking to go into on the forward?

Christopher R. Anzalone: So we have active programs in a number of areas. We have not disclosed other areas that we'd like to go after or that we're working on. So yeah, just stay tuned on that. Look, we have mentioned in the past though that CNS clearly is a target-rich environment. So it's a place that we wanna go to at some point. We are not there yet, but there are a number of tissue types.

Operator: Thank you. Your next question comes from the line of Luca Issi from the Royal Bank of Canada. Your line is open.

Luca Issi: Oh, great. Thanks for taking the question. This is Lisa on behalf of Luca.

Luca Issi: Just one here on one a Um, can you give us some directional color here on more with the ongoing dialogue with the FDA? Now that you have the breakthrough designation, is there maybe a scenario where the data from the 202 study and the first 36 patients from Sequoia will be sufficient for accelerated approval? And I also have a follow-up on ENAC.

Javier San Martin: This is Javier. Yeah, we're thinking about all of those options. Right now, we will need to focus on the first interaction. Typically, this first interaction, as I say, is a multidisciplinary meeting where we will touch upon different aspects of the filing process, discuss the phase three study design, the approvable end point, and the time to file. It's going to be critical, but it's not a one-sided conversation. It's a process. So it's a good thing, and we will, of course, entertain that thinking and potential step forward.

Javier San Martin: And we've had, really, so far, limited interactions with the FDA, and that's particularly with the current division. But our interactions have been quite positive and collaborative. They clearly appreciate that this is an unmet medical need, and I think that they're really interested in working with us to get this to patients who need it. But we haven't had... So we're really excited to have this breakthrough designation so we can sit down and have these more in-depth discussions.

And it is $660 million a potential milestone payments and.

And could be achieved.

Uhm with respect to how this could fit into.

Clinical paradigm.

This is this is 1 of the reasons, we chose the horizon as a partner. This is this is their business and and we'll be working closely with them, but ultimately this is their decision and so I don't Wanna step on their toes and and tell you something that we believe when when when this is really going to be their business.

Javier San Martin: And to your point, Breakthrough Designation essentially opens the path to an accelerated approval based on a surrogate likely to translate into clinical benefit. And that's precisely what we will discuss the next time around. That was a significant component of the Breakthrough Designation briefing document. So yeah, we're going to talk about this shortly, throughout the process.

And with respect to what you asked when's it going to gain the clinic, we don't know the answer to that still and early program.

We're just working on it right now and so.

We still have a ways to go.

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

Welcome.

Thank you and next question comes from the line of Ted and half from 5% on your line is open.

And I appreciate all of the.

And I just wanted to give us a little bit more on the new pulmonary targets.

Luca Issi: Great. That's very helpful. And then just one on ENAC. I was just wondering if you could talk about the doses at which you have seen the toxic result in rats and how those doses scale to humans. Just trying to figure out here whether the signal, the tox signal seen in rats, was seen at maybe supertherapeutic doses or at doses that scale within the 40 to 180 mg range that are being tested in humans. Thanks.

You know what on our keeping factors and is there anything and expect a little from the Enoch program that could impact those programs coming into the clinic. Thank you very much.

Yeah. So that's a good question debt that I don't really enter that and it.

Still just too early and we don't know what's going on with what happened in those rats and the Enoch program and so until we have more information and I just don't know how that might lead on future programs. I can tell you that it has not slowed us down. This is still we think a big opportunity for us and we're still moving as quickly as we can.

Christopher R. Anzalone: I appreciate the question, but look, it has been our policy not to talk about TOCS data in particular because we don't even have a final report here. We've just been given a small synopsis about part of a RAT study, and we don't even know anything about the outcome.

We are excited about these 2 new programs and we haven't talked about the gene target you haven't talked about the disease areas.

And I expect that we will maybe later this year.

We were disappointed that we couldn't get the slots that we that we wanted to move this and the clinic and this year, but but that's just the way the world turns right now and so we and we look forward to get and this and the clinic and the first half of next year.

Luca Issi: Okay, got it. Thanks for taking the question. Thank you. Your next question comes from the line of Patrick Trucchio from HC Wainwright.

Operator: Alright, your line is open.

I will say, though that that that what we what we think.

Patrick Ralph Trucchio: Hi, thanks, and good evening. Just a couple of follow-up questions on the C3 program. First, can you discuss what, if any, potential advantages there are to targeting C3 rather than C5? And secondly, do you know which indication or indications the C3 program would initially focus on when clinical development could begin, and is this a program you would bring into clinical development on your own, or would you seek a collaboration partner?

We have seen and because again with only see.

Small and a data from that study, but what we what we have seen there has caused us to do a bit more.

Work, while we're waiting just internally on on on chronic on chronic studies vs. A non guilty toxicity and these are just so we understand a bit more internally on.

On the other programs.

Okay, let me pull on her and <unk> <unk> <unk>.

Luna.

With the patients who have already been dosed.

Christopher R. Anzalone: I will answer the last of those questions and then I'll hand the rest over to James. So, we do not have plans to seek a partner right now for this program. Look, that may change in the future, but right now, we are happy to take this forward. This is directly in our wheelhouse in terms of preclinical development. This is a hepatocyte-directed construct we feel good about going to the clinic, and so let's see what the data look like. And then we can make a decision on partner versus non-partner at some point in the future.

Oh, how do we anticipate hearing about that day and I know you're not those women going forward, but is that going to be a substance of and up through the sets and it's gonna be informative and and sets up a richer publicly.

Yeah, and again I'm, sorry, I can't give you a definitive answer on average because we don't know we don't know what's gonna happen with that program and and if we can restart it when a when we don't know when we can restart it.

So so until we have more information and we just would rather not giving any sort of other items, 1 way or the October those cramps, yeah totally understand on some quick. Thanks. So much from you up and I'm really a lot of great progress notes here and have a credit for it back up.

James C. Hamilton: Sure, I'll take the first part of the question that I think was about C3 versus C5. So, you know, C3 in the complement cascade is a central node that is involved in all three different components of that pathway, the lectin, the alternative, and the classical pathways. So if you can inhibit C3, you can really take out everything that's downstream of C3. And so the effects should be broadly applicable to various complement-mediated diseases.

And.

Thank you. Your next question comes from the 9 F T Mckee from share them with your line is open.

Yeah, Hi, Thanks, Yeah, Chris just just following up on the the new lung programs. So you know what.

What are the similarities similarities between the construct for those vs. <unk> can be and obviously, you're gonna have it a different sequence for the targeted chain, but are are you using the same targeting log in and so you know help us.

James C. Hamilton: Now, specifically, to two interesting indications, PNH and C3 glomerulopathy, that Chris mentioned during his earlier remarks. PNH is a disease that's been reasonably well treated with C5 inhibition. However, there is a component of that population that is refractory to treatment due to extravascular hemolysis that's primarily driven by C3. So that residual population with the residual anemia that's refractory to C5 inhibition could be specifically treated with potentially C3 inhibition. There is another population, the C3 glomerulopathy patients, where their disease is really driven by excess C3 activity and deposition of C3 fragments in the glomeruli.

Try to better understand what the potential read across a risk is from the <unk>.

Right and so we're we're using the same target and log in.

As you say different sequences.

I I would expect that will be using less material.

And the and the next 2 because at least and animal studies. They both appear to be more potent and arrow enact is that important I don't know.

James C. Hamilton: So that's really a C3-driven disease. Beyond those, there are other conditions where the disease is complement-mediated, maybe not as specific to C3 as those other two conditions, but complement-mediated, and we think that C3 inhibition may have applicability in those other complement-mediated conditions. So I think that covers maybe both the first and the second question about C3 versus. 5, as well as the other indications.

But I believe that's that's well I know that's the case per animal studies, and and we'll see if it translates into humans and so it again and again until we have more data. It just too early to speculate on how or if.

What we saw and and a crock talks interest may translate to other other.

Sequences.

James C. Hamilton: One other question was about when we could enter clinical development.

Okay. Thanks for that and then just for him.

The the biopsy biopsies that you received and the.

James C. Hamilton: By the end of the year. Or we'll be filing a CTA by the end of the year.

Patrick Ralph Trucchio: Got it. That's helpful. And then just a follow-up on the gout program. Can you tell us where Arrow XDH would fit in the gout treatment paradigm and the potential cadence of the $660 million in potential milestones from Horizon? And, to the extent that you could comment, when the program could be expected to enter clinical development?

The fact that some of them you know war use what can you just further characterize that and how do we think about the risks they're going forward on not being able to get good data to do your assessments.

Okay.

Yeah, so far.

Well, maybe I'll make 1 comment about the the study design and the the protocol allows us to to city and.

Christopher R. Anzalone: I can't tell you too much about that, about any of those actually. So the we did not split out what the, you know, how the $660 million of potential milestone payments could be achieved. With respect to how this could fit into a clinical paradigm, you know, this is one of the reasons we chose Horizon as a partner. This is their business, and we'll be working closely with them, but ultimately, this is their decision, and so I don't want to step on their toes and tell you something that we believe when this is really going to be their business.

And roll up to a sufficient number of pages to get enough biopsies that we think are adequate.

Paired biopsies to make to do our analyses and as was described and the press release and have the biopsy samples are not always and.

Analyzable.

But so far and the first and second cohort and and and so far and the third as well and and we've been able to get enough biopsy samples to do the work that we need to.

Patrick Ralph Trucchio: Got it. That's helpful. Thank you very much.

Okay and <unk>.

Operator: Thank you. Your next question comes from the line of Ted Tenthoff from Piper Sander. Your line is open.

Yeah. Thank you.

Your next question comes from the line of man come on tiny from the rainy here and I need something.

Edward Andrew Tenthoff: Thank you very much. I appreciate all the updates. Can I just get a sense of a little bit more...

Hi, Good afternoon. This is Tyler caused me on from my and thanks for taking our questions maybe a break on on on him too could you provide any color on kind of how the enrollment has been tracking maybe in the context of the Mark program nearing nearing approval or just increased awareness on H L disease associated with R. C C.

Edward Andrew Tenthoff: And I just wanted to get a sense of a little bit more on the new pulmonary targets.

Christopher R. Anzalone: You know, what are the gating factors, and is there anything you expect to learn from the ENAC program that could impact those programs going into the clinic? Thank you very much.

Christopher R. Anzalone: Yeah, so that's a good question, Ted. You know, I don't know the answer to that. You know, it's still just too early.

Yeah enrollment has been actually really good and and that program throughout we've not seen any challenges with enrollment and all the slots has failed and I'm very rapidly so and I know the Merck studies ongoing but it has not as to.

Christopher R. Anzalone: We don't know what's going on with or what happened to those rats in the ENAC program. And so until we have more information, I just don't know how that might read on future programs. But I can tell you that it's not slowed us down. You know, this is still, we think, a big opportunity for us, and we're still moving as quickly as we can.

Attracted from enrollment into this study.

Alright, and then maybe on H B B do you have any insight into kind of what forum J&J. My present, the 24 week off treatment data from rape and or any high level thoughts on on kind of what we can incrementally learn from that study.

Christopher R. Anzalone: We are excited about these two new programs, but we haven't talked about the gene targets yet. We haven't talked about the disease areas yet, but I expect that we will maybe later this year. We were disappointed that we couldn't get the slots that we wanted to move this into the clinic this year, but that's just the way the world turns right now. And so we look forward to getting this into the clinic in the first half of next year.

Oh Boy [laughter] no [laughter].

I can't give any guidance on that.

And we look forward to to see and those data, but I don't I don't I don't know what their plans are to be honest about where that could be presented.

[noise] got a fair and thanks for taking my questions and congrats on Nevada.

Thank you.

Thank you <unk> next session comes from the line F Miami, Florida, and Ohio from S V B and.

Christopher R. Anzalone: I will say, though, that what we think we have seen, because again, we've only seen a small amount of data from that rat study, but what we have seen there has caused us to do a bit more work while we're waiting, just internally, on chronic studies. These are non-GLD toxin. These are just so we understand a bit more internally on the other programs.

And your line is open.

Hey, Good afternoon. This is Rick on on the line for money and thanks for taking our questions to 2 from us.

And so first for for him to could you speak to some of the variability of knockdown scene and the data I know there are and a lot of data sets exploring our and AI and tumors. So cause some of his furry Dougherty just be due to the heterogeneity of tumors and general or is it something that could potentially be resolved by looking at higher doses are either earlier.

Edward Andrew Tenthoff: That makes a lot of sense. And with respect to..., with the patients who have already been dosed, um, how how do we do it?

Mine's appreciates.

Edward Andrew Tenthoff: How do we anticipate hearing about that data? I know you're not doing it and going forward, but is that going to be a substantive enough data set that it's going to be informative, and is that something you would share publicly?

Christopher R. Anzalone: Yeah, and again, I'm sorry I can't give you a definitive answer on that because we don't know what's going to happen with that program, and if we can restart it, we don't know when we can restart it. So, until we have more information, we just would rather not give any sort of guidance one way or the other. I totally understand. Yeah. I totally understand. Awesome, Chris. Thanks so much for the update and really a lot of great progress this year. So excited for the book to come out.

Operator: Thank you. Your next question comes from the line of Keay Nakae from Shoredam.

Keay Thomas Nakae: For them, their line is always open.

Christopher R. Anzalone: Yeah, hi, thanks. Yeah, Chris, just following up on the new lung program. So, what are the similarities between the construct for those versus ENAC? I mean, obviously you're gonna have a different sequence for the targeted gene, but are you using the same targeting ligand? And so, help us try to better understand what the potential read across of risk is from the ENAC talk.

Christopher R. Anzalone: Right. So we're using the same targeting ligand, but as you say, different sequences. I would expect that we'll be using less material in the next two because, at least in animal studies, they both appear to be more potent than Arrow-ENAC.

Christopher R. Anzalone: Is that important? I don't know. But I believe that's the case for animal studies, and we'll see if it translates into humans. And so it's, again, until we have more data, it's just too early to speculate on how or if, you know, that what we saw in the Cronk Talks in rats may translate to other animals. Frequencies.

Keay Thomas Nakae: Okay, thanks for that. And then just for HIFS, the biopsies that you received, and, you know, the fact that some of them weren't usable, can you just further characterize that? And how do we think about the risk there going forward of not being able to get good data to do your assessment?

Molecule or.

Something else.

Okay, Great I appreciate all the details.

Yes, thank you very much.

Christopher R. Anzalone: Yeah, so far, well, maybe I'll make one comment about the study design of the protocol that allows us to enroll up to a sufficient number of patients to get enough biopsies that we think are adequate, paired biopsies to do our analysis. And as was described in the press release, you know, the biopsy samples are not always analyzable. But so far, in the first and second cohorts, and so far in the third as well, we've been able to get enough biopsy samples to do the work that we need.

Thank you there and no other questions on queue I will now turn the call over back to Chris. Please go ahead.

Thank you all for joining us today and I Hope you have a nice evening and afternoon.

This concludes today's conference call. Thank you for participating you may now disconnect.

[music].

Keay Thomas Nakae: Okay. All right. Yeah, thank you.

Operator: Your next question comes from the line of Mayank Mamtani from BRiley. Your line is open.

Mayank Mamtani: Hi, good afternoon. This is Tahoe Casmeon for Mayank.

Mayank Mamtani: Thanks for taking our questions. Maybe a brief one on HIF-2. Could you provide any color on kind of how the enrollment's been tracking, maybe in the context of the Merck program nearing approval, or just increased awareness of VHL disease associated with RCC? Yeah, enrollment has actually been really good in that program throughout. We've not seen any challenges with enrollment, and all the slots have filled very rapidly. So I know that the Merck study is ongoing, but it has not.

Mayank Mamtani: Attracted from enrollment into this study, Great. And then maybe on HBV, do you have any insight into kind of what forum J&J might present the 24 week off treatment data from REEF and or any high-level thoughts on kind of what we can incrementally learn from that study?

Christopher R. Anzalone: [inaudible]

Christopher R. Anzalone: Boy, no. I can't give you any guidance on that. Look, we look forward to seeing the data, but I don't know what their plans are, to be honest, about where that got it. Fair enough. Thanks for taking our questions and congrats on the progress. Thank you.

Operator: Thank you. Your next question comes from the line of Mani Foroohar from SVB Lyrinc. Your line is open.

Mani Foroohar: Hey, good afternoon. This is Rick on the line for Mani. Thanks for taking

Mani Foroohar: and for Mani, thanks for taking our questions, just two from us. So first, for HIC-2, could you speak to some of the variability of knockdowns seen in the data? I know there aren't a lot of data sets exploring RNAi in tumors, so could some of this variability just be due to the heterogeneity of tumors in general, or is it something that could potentially be resolved by looking at higher doses or either earlier lines of patient care? Yes, I think so.

Mani Foroohar: Yes, I think that you hit the nail on the head. I mean, I think there's that heterogeneity of expression in the tumors and across from patient to patient and also heterogeneity in between. With paired biopsies, you're not necessarily getting into the same area of the tumor. So heterogeneity is definitely an issue and probably explains a good component of the variability.

[music].

Christopher R. Anzalone: All right, I got it.

Mani Foroohar: All right, thanks. But I also have a much more broad question.

Mani Foroohar: So just in general, Arrowhead's approach to extrahypotic delivery seems to be focused around targeting integrins with specific ligand conjugates. But could you maybe speak to why these are so favorable to target as a class of molecules? And if the company is currently exploring any other targeting strategies?

Christopher R. Anzalone: Any strategies pre-clinically? Yeah, so I'll let James take it as well.

James C. Hamilton: Yeah, so I'll let James take it as well, but I'll just say broadly, we are not an integrin targeting company. We're an RNAi company. And so, you know, we tend to use what works best, and we are agnostic. For example, we have done work with antibodies, with antibody fragments, with peptides, with small molecules, and such. And so, you know, we just, you know, we have ideas about what might work best, but ultimately, the data will tell us. And so it's just so happened that we've found that integrin-based targeting has been quite good for us. James. I'll echo that.

James C. Hamilton: We go with what works, and we went with integrin-receptor ligand pairs, not because that was our area of expertise, but because that was what looked the best, and we continue to, we've historically evaluated multiple different receptor ligand pairs and continue to do so, and I think we'll continue to go with what works, regardless of what the modality is, if it's an antibody or a small molecule or something else

Mani Foroohar: All right, great. I appreciate all the detail.

Operator: Thank you. There are no other questions in the queue. I will now turn the call over back to Chris. Please go ahead.

Christopher R. Anzalone: Thank you all for joining us today, and I hope you have a nice evening and afternoon. This concludes today's conference call. Thank you for participating.

Operator: This concludes today's conference call. Thank you for participating. You may now disconnect.

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Vincent Anzalone: 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

Vincent Anzalone: I called over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead.

Vincent Anzalone: Thank you.

Vincent Anzalone: Results for its fiscal 2021 3rd quarter.

Vincent Anzalone: Reporter, and June 30, 2021. With us today from management are President

Vincent Anzalone: CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter, Dr. Javier San Martin, our Chief Medical Officer, who will provide an update on our pipeline, and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, James Hazard, our Chief Commercial Officer, and Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, will be available during the Q&A session of today's call. Thank you all for joining us today.

Vincent Anzalone: Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934.

Vincent Anzalone: All statements, other than statements of historical fact, including, without limitation, those with respect to Arrowhead's goals, plans, and strategies, are forward-looking.

Vincent Anzalone: Login Statements These include statements

Vincent Anzalone: regarding our expectations around the development, safety, and efficacy of our drug candidates, projected cash runway, the receipt of future milestone and licensing payments, and expected future development and commercialization activities. These statements represent management's current expectations and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statement.

[music].

Vincent Anzalone: 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.

Christopher R. Anzalone: And now I'd like to turn the call over to Chris Anzalone, President and CEO of the company. Good afternoon, everyone.

Christopher R. Anzalone: Thank you for joining us today. The fiscal third quarter, a period since our last conference call, has been incredibly busy for Arrowhead. We made important advances in several of our development programs, including discovery stage programs and early, mid, and later stage clinical programs. It also includes programs from existing partnerships, as well as a new business development transaction. As a platform company, there are a few areas of critical importance where we focus our attention. First, we need to always push the boundaries of what is possible and make our trim platform better.

Christopher R. Anzalone: Second, we need to expand the early-stage pipeline rapidly and efficiently with new clinical candidates as this will be an important source of growth in the future. Third, we need to move our mid and later stage pipeline programs through clinical studies as we get closer to our goal of bringing important new medicines to patients without adequate treatment options. And lastly, we need to selectively use partnering to expand the reach and maximize the value of our trim platform and bring in non-dilutive capital that helps to fund our internal development. I think we're doing well in all these. Let's take a moment to briefly review some key events in the last quarter that are good examples.

Christopher R. Anzalone: For our discovery and early-stage clinical pipeline, we had a very productive quarter. We completed discovery and optimization work on two new pulmonary programs and nominated them both as clinical candidates. They are now in the IND enabling stage, which includes GLB toxicology studies and manufacturing of the drug product for clinical studies. We have not yet disclosed the gene and disease targets, but we'll be talking more about these programs later in the year. We also presented very promising preclinical data on Arrow Dux4, our first muscle-targeted program being developed as a treatment for patients with fascioscapulohumeral musculodystrophy, or FFHD, at the 28th Annual FFHD Society International Research Conference.

Christopher R. Anzalone: The data show that the TRIMM muscle delivery platform can achieve functional delivery to various types of skeletal muscle and achieve deep, durable, and dose-dependent knockdown of target genes. In addition, Arrow Ducts IV improved multiple measures of FSHD-like muscle phenotype in relevant preclinical animals. As DUX4 expression is recognized as the cause of muscle pathology in FSHD patients, Arrowhead believes that the selective targeting and knockdown of DUX4 using RNAi may prevent or reverse downstream myotoxicity and lead to muscle repair and improvement in muscle function in patients. There are currently no effective treatments specifically for FSHD.

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 and aborts any of you to ask questions.

I will now hand, the conference call over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead Sir.

Thank you good afternoon, everyone. Thank you for joining us today to discuss arrowheads results for its fiscal 2021 third quarter ended June 30th 2020, 1 with US today from management are president and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter, Dr. Javier San Martin our Chief Medical Officer.

And who will provide an update on our pipeline and Ken Moskovsky, Our Chief Financial Officer, who will give a review of the financials and addition, James Hazard, our Chief commercial officer and Dr. James Hamilton, Our senior Vice President of Discovery and translational medicine will be available during the Q&A session of today's call.

Christopher R. Anzalone: So patients need new therapeutic options that address the root cause of the disease. We've been pushing aggressively toward the clinic with Aeroducts IV as well as the two new pulmonary candidates we nominated this year. We expected to file CTAs for all three of them by the end of the year, but securing timely slots at CROs for IND-enabling toxicology studies has been challenging, so scheduling on the CTAs will be pushed into the first half of next year. That is unfortunate, but we have seen this become more of a bottleneck in the industry since the beginning of the pandemic.

Before we begin and I would like to remind you that comments made during today's call contain certain forward looking statements within the medium section 27 day of the Securities Act of 1933 injections and 21 E of the Securities Exchange Act and Thanks from 34, all statements other than statements of historical fact, including without limitation those with.

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, the receipt of future milestone and licensing payments and expected future development and commercialization activities. These.

Christopher R. Anzalone: We have continued work on a number of other early programs, and I'm pleased to announce a previously undisclosed target. We recently nominated Arrow C3 as a Patasite-directed candidate against Complement C3. Overactivation of the complement cascade is thought to be causative of a number of diseases, including paroxysmal nocturnal hemoglobinuria and C3 glomerulopathy, and complement-mediated injury is involved in many other conditions, including IGA nephropathy as well as many other renal vascular hematologic and neurologic conditions. Complement C3 is a central node in all three of the complement pathways, including the classical, lectin, and alternative pathways of complement activation.

Statements represent management's current expectations and are subject to numerous risks and uncertainties that could.

That could cause actual results to differ materially from those expressed and any and 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 other forward looking statements discussed on today's call with that said I'd like to turn the call over to Christina <unk>, President and CEO of the company Chris.

Christopher R. Anzalone: And it has recently been shown that inhibition of C3 can be both safe and effective in the treatment of complement-mediated diseases. We have a strong track record in trim-enabled hepatocyte-directed candidates, including Arrow HBV, Arrow LPA, Arrow AAT, Arrow ANG3, Arrow APOC3, and Arrow HSD. Clinical data from these programs gives us confidence that positive non-clinical data from Arrow C3 may translate well in humans. We believe that an siRNA capable of substantially reducing C3 levels for three months or more could be the modality of choice for C3 inhibition, and we expect to file a CTA for Arrow C3 by the end of this year.

Thank you Vince.

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

Our fiscal third quarter and the period since our last conference call has been incredibly busy for arrowhead.

Made important advances and several of our development programs. This includes discovery stage programs and early mid and later stage clinical programs and it also includes programs from existing partnerships as well as the new business development transaction.

As a platform company there are a few areas of critical importance, where we focus our attention first we need to always push the boundaries of what is possible and make our trim platform better.

Second we need to expand the early stage pipeline rapidly and efficiently with new clinical candidates and this will be an important source of growth and the future.

Christopher R. Anzalone: During the quarter, we also announced positive interim data for two of our early stage clinical programs, Arrow HIF-2 and Arrow HSD. I'll start with Arrow HIF-2, which is our first tumor targeted program being developed as a potential treatment for patients with clear cell renal cell carcinoma, or CCRC. To date, investigational Arrowhead 2 has been generally well tolerated at doses of up to 525 milligrams weekly. The study has now progressed to a dose of 1050 mg weekly, which is currently enrolling patients.

Third we need to move our mid and later stage pipeline programs through clinical studies as it gets closer and as it gets closer to our goal of bringing important new medicines to patients without adequate treatment options and lastly, we need to selectively use partnering to expand the reach and maximize the value of our trim platform and bring and non dilutive capital that helps to fund our internal.

<unk>.

I think we're doing well on all of these areas, let's take a moment to briefly review some key events and the last quarter that are good examples of this.

For our discovery and early stage clinical pipeline, we had a very productive quarter, we completed and discovery and optimization work on 2 new pulmonary programs and nominated them. Both as clinical candidates. They are now and the IND, enabling stage, which includes <unk> toxicology studies and manufacturing of drug product preclinical studies, we have not yet disclosed the gene and does.

Christopher R. Anzalone: We believe that in the first two dose cohorts, Arrowhead 2 is showing clear signs of meaningful target engagement and potentially some early signs of efficacy in at least one patient. Specifically, the H2-alpha protein H-score was assessed via immunohistochemistry. 9 of 17 patients had tumor samples that could be evaluated, and 7 of those 9 demonstrated reductions in HIF-2 alpha protein age scores. These reductions ranged from minus 9 percent to minus 82 percent, with a mean reduction of minus 48 percent.

These targets, but we will be talking more about these programs later in the year.

We also presented very promising preclinical data on Aero Das for our first and muscle targeted program being developed as a treatment for patients with vascular scapulohumeral muscular dystrophy, or <unk> HD and the 20th annual FSA HD Society International Research Congress.

And the data showed that the trim.

Christopher R. Anzalone: In addition, one subject had a partial response with approximately 65% tumor shrinkage, and five subjects had the best response of stable disease. We think these early results in a heavily pre-treated population are encouraging for ARF2 and our tumor-targeted platform broadly. We also presented positive interim data for ArrowHSD being developed as a potential treatment for patients with liver diseases such as NASH at the Easel International Liver Congress. ArrowHSD was well tolerated in healthy volunteers given a single dose of 25 mg, 50 mg, 100 mg, or 200 mg and in 5 patients with suspected NASH given a 100 mg dose of ArrowHSD on days 1 and 29. All five patients with suspected NASH showed a strong pharmacodynamic effect as measured by liver biopsy at day 71.

Today's show that the tremor muscle delivery platform and can achieve functional delivery to various types of skeletal muscle and achieve deep durable and dose dependent knockdown of target genes. In addition, aero decks for improved multiple measures of FX HD like muscle phenotype and relevant preclinical animal models.

<unk> 4 expression is recognized as the cause and muscle pathology and if its HD patients Arrowhead believes that the selective targeting and knockdown of ducks for using RNA I may prevent or reverse downstream bio toxicity and lead to muscle repair and improvement and muscle function and patients.

There are currently no effective treatments, specifically for Fsh D. So patients need new therapeutic options and address the root cause of the disease.

We've been pushing aggressively towards the clinic with <unk> 4 as well as the 2 new pulmonary candidates. We nominated this year. We expect you to file Cta is for all 3 of them by the end of the year, but securing timely slots and crows for IND, enabling toxicology studies has been challenging so scheduling on the Cta will be pushed into the first half of next year.

Christopher R. Anzalone: HSD 17 beta 13 protein was reduced by 92% and 97% in two patients, while the other three patients' day 71 measurements were reduced below the lower limit of quantitation. Importantly, ALT showed a mean reduction from baseline of 46%, with all patients showing reductions ranging from 26% to 53%. We believe that Arrow HSD is the first investigational therapeutic to demonstrate robust inhibition of hepatic HSD 17 beta 13 mRNA and protein expression. We are also highly encouraged to see ALT levels drop significantly following just two doses of Arrow HSV.

That is unfortunate, but we have seen this become more of a bottleneck and the industry since the beginning of the pandemic.

We will continue to work on a number of other early programs and I am pleased to announce a previously undisclosed target. We recently nominated <unk> 3 as a pad sites directed candidates against complement <unk> III.

Over activation of the complement Cascade is thought to be causative of a number of diseases, including proximal nocturnal hemoglobinuria and C. III merial apathy and complement mediated injury is involved and many other conditions, including and Iga nephropathy as well as many other renal vascular hematologic and neurologic conditions.

Complement and C III as a central node and all 3 of the comp on pathways, including the classical lectern and alternative pathways of complement activation and has recently been share on the inhibition of <unk> can be both safe and effective and the treatment of complement mediated diseases.

Christopher R. Anzalone: In addition to progress on our early stage pipeline, we also achieved some important milestones for our mid and later stage pipeline. I'll start with our cardiometabolic programs, Arrow ApoC3 being developed as a potential treatment for hypertriglyceridemia, and Arrow ANG3 being developed as a potential treatment for mixed dyslipidemia. We recently started two Phase IIb studies, one for each program. We intend to initiate four or more studies across the two programs, including a phase three study.

We have a strong track record and trim enabled <unk> direct and candidates, including Aro HBV, Aro, LTA Aero and Aero and 3 Aero Apoc, III and Aero HST clinical.

Clinical data from these programs gives us confidence that positive and non clinical data from the <unk> 3 may translate well in humans, we believe that on SA RNA capable and substantially reducing C. III levels for 3 months from war could be the modality choice for <unk> and ambition and we expect to file a cta for Aro <unk> by the end of this year.

During the quarter, we also announced positive interim data for 2 of our early stage clinical programs Arrowhead, II and Aero HST I will start with Arrowhead II, which is our first tumor targeted program being developed as a potential treatments for patients with clear cell renal cell carcinoma or CCR RCC.

Christopher R. Anzalone: Javier will give more details about the studies that have already started dosing in a few minutes, but we believe the studies together will give us a robust picture of the pharmacologic activity of each medicine in various target patient populations. We intend to identify the optimal dose and dose intervals to enable us to move confidently into multiple phase 3 studies.

Today's investigational Arrowhead II has been generally well tolerated at doses of up to 525 milligrams weekly. The study has now progressed to a dose of 1050 milligrams weekly, which is currently enrolling and dosing patients.

We believe that in the first 2 dose cohorts Arrowhead II is showing clear signs of meaningful target engagement and potentially some early signs of efficacy and at least 1 patient specifically the hip to alpha protein H score was assessed via immunohistochemistry.

Christopher R. Anzalone: In addition to our cardiometabolic programs, we had multiple important events in the last quarter for Arrow AAT, also known as TAC-999, being co-developed with Takeda as a treatment for the rare genetic liver disease associated with alpha-1 angiotrypsin deficiency. First, we presented additional positive interim 48-week liver biopsy results at the Easel International Liver Conference. These results demonstrated that Arrow AAT treatment led to rapid improvements in multiple measures of liver health, including fibrosis, with substantial and sustained reductions in the level of mutant AAT proteins. Mutant AAT protein has been identified as the cause of progressive liver disease in patients with alpha-1 antitryption deficiency.

917 patients had tumor samples and it could be evaluated and 7 of those 9 demonstrated reductions and hip 2 alpha protein H scores. These reductions range from -9% to -82% with a mean reduction of -48%.

In addition, 1 subject had a partial response with approximately 65% tumor shrinkage and 5 subjects and a best response of stable disease with <unk>.

These early results and are heavily pretreated population are encouraging for arrowhead II and are tumor targeted platform broadly.

We also presented positive interim data for Aero HST being developed as a potential treatment for patients with liver diseases, such as Nash and the easel International liver Congress.

<unk> was well tolerated in healthy volunteers, given a single dose at 25 milligrams 50 milligrams 100 milligrams or 200 milligrams and and 5 patients with suspected Nash given a 100 milligram dose of Aero HST on days, 1 and 2009.

Christopher R. Anzalone: Arrow AT treatment was generally well tolerated after up to one year of treatment. This is very important data and suggests to us that the drug is doing what it's designed to do and that removing the mutant AAT protein can give the liver a chance to begin the healing process, even when it is used in patients with late stage liver disease. We and our partners at Decatur were thrilled to see these results, and we have received similar responses from physicians and others in the Alpha One treating community.

All 5 patients with suspected Nash showed a strong pharmacodynamic effect as measured by a liver biopsy at day 71 HFC.

<unk> 17, and beta <unk> protein was reduced by 92% and 97% and 2 patients while the other 3 patients day 71 measurements reduced below the lower limit of quantitation and.

Importantly, <unk> showed a mean reduction from baseline of 46% with all patients showing reductions ranging from 26% to 53%.

Christopher R. Anzalone: We also fully enrolled the Arrow AAT Phase 2 Sequoia Study with the 40th patient being dosed. Combined with the various cohorts in the Open Label 2002 study, we will have paired biopsies from approximately 50 patients receiving various dose levels and various treatment durations.

We believe that Arrow HST is the first investigational therapeutic to demonstrate robust inhibition of hepatic HST 17 day to 13 mrna and protein expression we.

We're also highly encouraged to see <unk> levels dropped significantly following just 2 doses of Barrow HSV.

Christopher R. Anzalone: Lastly, for Arrow AT, we have been granted breakthrough therapy designation by the U.S. FDA. Arrow AT was also previously granted orphan drug designation and fast track designation from the FDA and orphan designation from the European Commission. Our goal is to expedite the development path of Arrow AAT, and each of these important designations provides potential ways to achieve that. We will work with regulatory authorities and our partners from Takeda to identify the best path to bring this important drug to patients quickly.

In addition to progress on our early stage pipeline and we also achieved some important milestones for our mid and later stage pipeline I'll start with our cardio metabolic programs Arrow and <unk> 3 being developed as a potential treatment for hyper triglyceride anemia, and arrow and 3 being developed as it pretends to treatment from mixed dyslipidemia.

We recently started 2 phase <unk> studies, 1 for each program.

We intend to initiate 4 or more studies across the 2 programs, including our phase III study Javier will give more details about the studies.

And that have already started dosing and a few minutes, but we believe the studies together will give us a robust picture on the Pharmacodynamic and pharmacologic activity of each medicine and various targeted patient populations. We are intending to identify the optimal dose and dose intervals to enable us to move confidently into multiple phase III studies.

Christopher R. Anzalone: Now moving on to progress that we've made with partnering. As I mentioned, we believe a platform company should use partnering selectively to expand the reach and maximize the value of the platform technology and to bring in non-dilutive capital that helps to fund internal development. This is a key component of our business strategy, and an area where we've seen important recent progress. The collaboration with Janssen, which was executed toward the end of 2018 for Arrow HBV against chronic hepatitis B infection, included an option on three additional programs. During the previous quarter, Janssen delivered written notice of its intent to exercise its option right for the first of those programs, Arrow J&J-1.

In addition to our cardio metabolic programs, we had multiple important events and the last quarter for <unk> also known as Tak 999, being co developed with Takeda as a treatment for a rare genetic liver disease associated with Alpha 1 antitrypsin deficiency.

First we presented additional positive interim 48 week liver biopsy results at the <unk> International liver Congress.

These results demonstrated that <unk> treatment led to rapid improvements and multiple measures of liver health, including fibrosis with substantial and sustained reductions and the level of mutant <unk> protein.

Christopher R. Anzalone: This earned Arrowhead a $10 million option exercise fee and signals Janssen's intent to move forward with clinical studies. Also, during the quarter, we announced a global collaboration and license agreement with Horizon Therapeutics for ArrowXDH, a previously undisclosed discovery stage candidate being developed by Arrowhead as a potential treatment for people with uncontrolled gout. Arrowhead received $40 million as an upfront payment from Horizon and is eligible to receive up to $660 million in potential development, regulatory, and commercial milestones, and is further eligible to receive royalties in the low to mid-teens range on net product sales.

<unk> broke and has been identified as the cause of progressive liver disease and patients with Alpha 1 antitrypsin deficiency.

Treatment was generally well tolerated after up to 1 year of treatment. This is very important data and suggest to us that the drug is doing what it's designed to do and that removing the mutant <unk> protein can give deliberate chance to begin the healing process, even when to intervene and patients with late stage liver disease.

We and our partners at Takeda, we're thrilled to see these results and we have received similar responses from physicians and others and the alpha 1 and treating community.

We also fully enrolled the arrow and <unk> phase II Sequoia study with a 40th patient being dosed recently.

Combined with the various cohorts and the open label 2002 study, we will have paired biopsies from approximately 50 patients receiving various dose levels and various treatment durations.

Christopher R. Anzalone: Horizon will receive a worldwide exclusive license to the therapeutic and will be wholly responsible for clinical development and commercialization. This is a great example of an attractive partnering opportunity. It expanded the reach of our technology to an area that we had not intended to enter independently and brought in non-dilutive capital. It also brought in needed expertise in the gout field to help understand the disease, the clinical path, the tremendous unmet medical need, and a dominant player in the space with an existing commercial organization.

Lastly for Aero and <unk>, we are.

Granted breakthrough therapy designation by the U S FDA.

<unk> was also previously granted orphan drug designation and fast track designation from the FDA and orphan designation from the European Commission or.

Our goal is to expedite the development path a barrel <unk>.

And each of these important designations provide potential ways to achieve that.

We'll work with regulatory authorities and our partners from Takeda to identify the best path to bring this important drug to patients quickly.

Now moving on to progress that we've made with partnering as I mentioned and we believe a platform company should use partner and selectively to expand the reach and maximize the value of the platform technology and to bring and non dilutive capital that helps to fund internal development.

Christopher R. Anzalone: For all these reasons, we thought Horizon was the ideal partner, and the deal made perfect sense for both of our companies. We look forward to working closely with Horizon as we advance this potential new therapy for patients in need. As you've heard, this was a busy quarter with lots of exciting events.

As a key component of our business strategy and an area, where we've seen important recent progress.

The collaboration with Janssen, which was executed toward the end of 2018 for Aro HBV against chronic hepatitis B infection included and an option on 3 additional programs during the previous quarter Janssen delivered written notice of its intent to exercise its option right for the first of those programs Aero J&J 1.

Christopher R. Anzalone: However, drug development doesn't progress in a straight line, and invariably, there are surprises. Sometimes these surprises lead to leaps forward, such as the faster-than-expected liver healing in our Arrow AT program, and sometimes these surprises can be more unwelcome. We experienced the latter in the Arrow ENAC program, our candidate being developed as a potential treatment for cystic fibrosis last quarter. To review, we voluntarily paused the clinical study of Arrow-ENAC after receiving a preliminary update from an ongoing chronic toxicology study in rats that contained unexpected signals of local lung inflammation.

This earned arrowhead of $10 million option exercise fee and signals janssens intent to move forward with clinical studies.

Also during the quarter, we announced the global collaboration and license agreement with Horizon Therapeutics for Aero ex D. H, a previously undisclosed discovery stage candidate being developed by Arrowhead as a potential treatment for people with uncontrolled gout.

Arrowhead received $40 million and upfront payment from horizon and is eligible to receive up to $660 million and potential development regulatory and commercial milestones and further eligible to receive royalties and the low to mid teens range on net product sales.

Christopher R. Anzalone: Because of this preliminary update, we instructed investigators to pause new screening, enrollment, and any further dosing of investigational arrow ENAC pending additional data from the ongoing chronic rat toxicology study and an additional ongoing chronic primate toxicology study. We have not seen any concerning safety or tolerability signals in people enrolled in the Arrow ENAC 1001 study. However, we place the safety of patients that participate in our clinical trials above all else, so we will continue to keep the Arrow ENAC clinical study on pause for now.

Horizon will receive a worldwide exclusive license to the therapeutic and will be wholly responsible for clinical development and commercialization.

This is a great example of an attractive partnering opportunity and expanded the reach of our technology to an area that we had not intended to enter independently and brought in non dilutive capital and also brought in needed expertise and the gout field to help understand the disease, the clinical path, the tremendous unmet medical need and and a dominant player in this space with.

And existing commercial organization.

For all these reasons, we thought horizon was the ideal partner and the deal made perfect sense for both of our companies. We look forward to working closely with horizon as we advance this potential new therapy for patients in need and.

Christopher R. Anzalone: We do not yet have full data back from the toxicology studies, nor from additional studies that we are conducting internally, so we do not yet know the extent of the findings. We are investigating this fully and are still in the information gathering stage. We should know more in the coming weeks and months, and we intend to provide an update when we are able. With that introduction, I'd now like to turn the call over to Dr. Javier San Martin. Javier? Thank you, Chris.

You have heard this was a busy quarter with lots of exciting events. However, drug development doesn't progress and a straight line and and variably. There are surprises, sometimes you surprised and lead to leaps forward such as the faster than expected liver healing and our Arrowhead program and sometimes these surprises can be more and welcome we.

And we experienced the ladder and the arrow in that program are candidate being developed as a potential treatment for cystic fibrosis last quarter.

Javier San Martin: Thank you, Chris, and good afternoon, everyone. I want to give an update on our clinical studies and provide details on the design of a couple of our newest studies. First, I will discuss Arrow HIF-2, which is designed to inhibit the production of HIF-2 alpha to treat clear cell renal cell carcinoma or RCA. We were encouraged by the positive interim results from the first two cohorts of Arrowheads 2-1001, a Phase IB dose-finding clinical study in three cohorts with advanced clear cell, We are currently enrolling Cohort 3, which is designed to include up to 10 patients who will receive a weekly IV The study is designed to evaluate the safety of Arrowhead 2 to determine the recommended phase 2 dose and to assess pharmacokinetics and preliminary efficacy based on resistance and post-dose tumor expression of HIF-2-alpha and HIF-associated genes.

To review, we voluntarily paused the clinical study of <unk> after receiving a preliminary update from and ongoing chronic toxicology study in rats that contained unexpected signals of local lung inflammation.

Because of this preliminary update we instructed investigators to pause new screening enrollment and any further dosing of investigational arrow <unk> pending additional data from the ongoing chronic rat toxicology study and an additional ongoing chronic primate toxicology study.

We have not seen any concerning safety or tolerability signals and people enrolled and the Arrow <unk> 1001 study. However, we placed the safety of patients that participated on our clinical trials above all else. So we will continue to keep the arrow and that clinical study on pause for now we do not yet have full data back from the toxicology studies, nor from additional studies that we.

And are conducting internally so we do not yet know the extent of the findings. We are investigating this fully and are still on the information gathering stage, we should know more on the coming weeks and months and we intend to provide an update when we are able.

With that overview I'd now like to turn the call over to Dr. Javier San Martin and Javier. Thank you Kris and good afternoon, everyone.

Javier San Martin: Patients will continue to receive weekly Arrow HIF-2 indefinitely until they experience disease progression, have a complete response, or they discontinue treatment. Our intention is to share additional entry data from this study, including data from Cohort 1, 2, and initial results from Cohort 3, at an appropriate medical meeting in the future. We have not yet selected the intended, The next program I want to detail is Arrowhead Pharmacy, our investigational candidate for the potential treatment of alcohol and non-alcohol related liver disease.

I want to give you an update on our clinical studies and provide details on the design of a couple of our newest studies first I will discuss his 2 which is designed to inhibit the pollution on <unk> 2 alpha to treat clear cell renal cell carcinoma or RCC.

We were encouraged by the positive interim results from the first 2 cohorts of <unk>, 2.1 south and on what a phase 1 dose finding clinical study and 3 cohorts with advanced clear cell RCC. We're currently enrolling cohort 3 which is designed to include up to 10 patients who will receive a weekly.

Javier San Martin: The interim data we presented at ESOL was highly encouraging, and in fact, our presentation was highlighted in the ESOL official scientific press conference on NAFLD. It was exciting to see ALT levels drop significantly following just two doses of Arrow HSP. We expected a high level of target gene note down because our trim system has been extraordinarily consistent across our different liver-directed programs. But the improvement in ALT at this early time point was very welcome.

IV infusion of 1050 milligrams of Arrowhead III. This study is designed to evaluate the safety of Arrowhead II to determine the recommended phase II dose and sustained pharmacokinetics and preliminary efficacy based on receipts and post dose 2 minute expression of <unk> 2 alpha and.

Associated genes.

Patients will continue to receive weekly arrowhead, II indefinitely, and and they experienced disease progression and a complete response or they discontinued.

Javier San Martin: This data and the strong genetic evidence of HSD17-beta-13 as a potential therapeutic target provide us with increased confidence as we design further clinical studies for AROH. We're thinking about innovative designs that seek to answer key questions about the medicine, the disease, and the mechanism of HSD-17 beta 3 inhibitors and what early signs of improvement may look like. We're approaching this in a similar way to how we approach Arrowhead. In the meantime... We're still conducting the Phase I, II inpatient trials with NASH or suspected NASH, and we're happy to report that the study is fully enrolled.

Our intention is to share additional interim data from this study, including data from cohort 1.2 and initial results from cohort 2.

And the appropriate medical meeting and the future we have not yet selected and tenant.

Okay.

The next bill and I want to detail is Aero HST, our investigational candidate for the potential treatment of alcohol and non alcohol related liver disease. We think the interim data we presented on easily was highly encouraging and in fact, our presentation was highlighted in the ESO official scientific price confidence on <unk>.

And that's it.

What's exciting to see ANC levels dropped significantly following chest 2 doses of 8 on HST.

Javier San Martin: As Chris mentioned, we started dosing in two Phase IIb studies of our cardiometabolic candidates, AeroApoC3 and AeroH3, during the last quarter. I will give a brief description of these study designs so you all can think through potential timing. We intend to initiate additional studies shortly, and we will provide details on the design of the additional studies when they start.

With respect to the high level of targeted gene knockdown, because our team has been extraordinary consistent across our different lever the day.

Programs by the implement and ALC at this early time point was very welcome surprise.

These data and the stone and genetic evidence of these 17 beta 13, and simple potential good up both the target and provide.

Javier San Martin: For AeroApoC-3, we initiated AeroApoC-3-2001, a double-blind placebo-controlled face-to-face study to evaluate the efficacy and safety of AeroApoC-3 in adults with severe hypertriglyceridemia, or SHTG. Three dose levels of Arrowhead PC3, 10 mg, 25 mg, and 50 mg will be evaluated against placebo in participants who have mean fasting triglycerides The total of approximately 300 participants will be enrolled in the study. All those cohorts will enroll in parallel, with 100 participants per cohort randomly assigned in a 3-to-1 ratio to receive aeroepocytry or placebo.

As with increased confidence as we did sign on the clinical study for <unk> and HST.

We're thinking about negative designs that seek to answer key questions about the maybe seen the dcs and they make and <unk> inhibition.

And any signs of improvement May look like we're approaching this in a similar way to how we approach.

In the meantime.

And while it's still conducting the phase 1 and 2 in patients with Nash or suspected match and we're happy to report and the study is fully enrolled.

As Cliff mentioned, we started dosing in 2 phase <unk> studies of our cardio metabolic candidates.

You'll see 3 and on <unk> during the last quarter. We gave a brief description of these study designs and so you all kind of theme true potential timing, we intend to initiate additional studies shortly and we will provide details on the design of the additional studies when they start.

Javier San Martin: Each participant will receive subcutaneous injections on day 1 and week 2. The duration of the study is approximately 54 weeks from screening to the end of study examination. The primary objective of the study is to evaluate the safety and efficacy of Arrowhead Positri in adults with SHDG and to select a dosing regimen for later stage clinical studies in these patient populations. For Arrow H3, we initiate Arrow H3-2001, a double-blind placebo-controlled phase 2B study to evaluate the efficacy and safety of investigational Arrow H3 in adults with mixed dyslipidemia.

For <unk>, we initiated a positive 2000 on 1 a double blind placebo control phase II study to evaluate the efficacy and safety of <unk> in adults with severe hypercholesterolemia or S. H D. T..3 dose level of AIA per city 10 milligrams 20.

5 million from 50 milligram will be evaluated against placebo and participant, meaning fast and <unk> initiatives of greater than or equal to 500 milligrams per deciliter at screening.

Javier San Martin: Three dose levels of Arrow H3, 50 milligrams, 100, and 200 milligrams, will be evaluated against placebo in participants with mixed dyslipidemia who have the following screen: LDL cholesterol greater than or equal to 70 milligrams per deciliter or non-HDL cholesterol greater than or equal to 100 milligrams per deciliter, and Mean Fasting Triglycerides between 150 and 500 mg per week.

Total of approximately 300 participant will be enrolled in this study all of those cohorts will enroll in parallel with 100 participants per dose cohort randomly assigned and a 3 to 1 ratio to receive Italy, plus <unk> or placebo each participant will receive subcutaneous injection on the.

1 on week 12, and duration of the study is approximately 54 weeks force opinion to the week 48, and a steady examination.

And I appreciate your day studies to evaluate the safety and efficacy of annual Apoc, III and Apple's <unk> and to select a dosing regimen and for later stage clinical studies in these patient populations.

Javier San Martin: A total of approximately 180 participants will be enrolled in the studies. All those cohorts will enroll in parallel, with 60 participants per cohort randomly assigned in a 3-to-1 ratio to receive a subcutaneous injection of Arrow H3 or placebo on day one and week two. The duration of the study is approximately 42 weeks from screening to the week 36 end of study examination. After completing the week 36 visit, participants will be eligible to continue in an open-label extension.

For <unk>, we initiated <unk> 2001, a double blind placebo controlled phase II study to evaluate the efficacy and safety of investigation on Asia.

In other words with mixed Dyslipidemia.

Those levels and should see 50 million on 102 hundred milligrams will be evaluated against placebo and participant with mixed Dyslipidemia, who had the following free.

And.

LDL cholesterol and greater than or equal to 70 milligrams per deciliter, or and non HDL cholesterol and greater than or equal to 100 and meeting after this.

And mean fast and triglycerides between $1.50, and $500 million previously.

Javier San Martin: The primary objective of the ArrowH3 2001 study is to evaluate the safety and efficacy of ArrowH3 in adults with mixed dyslipidemia and select a dosing regimen for later stage clinical studies in this patient population. I will now turn the call over to Ken Myszkowski, Arrowhead's Chief Financial Officer.

A total of approximately 180 participant will be enrolled in this study all of those cohorts will enroll in parallel with 60 persistent GERD cohort randomly assigned in a 3 to 1 ratio to receive a subcutaneous injection of <unk> 3 or placebo on day, 1 week 12, the duration of the study is.

Similarly, 42 weeks from screening to day week, 36, and a steady examinations. After completing the week 76 vessels participants will be eligible to continuing continue and an open label extension and study. The primary objective of the Arrow and <unk> 2001 study is to evaluate the safety and efficacy.

Kenneth A. Myszkowski: Thank you, Javier, and good afternoon, everyone. As we reported today, our net loss for the quarter ended June 30, 2021, was 29.9 million, or 29 cents per share, based on 104.1 million fully diluted weighted average shares outstanding. This compares with a net loss of $13.6 million, or $0.13 per share on 101.8 million fully diluted weighted average shares outstanding for the quarter ended June 30, 2020. Revenue for the quarter ended June 30, 2021 is $45.9 million compared to $27.4 million for the quarter ended June 30, 2020.

NYSE and.

In adults with mixed Dyslipidemia and select a dosing regimen for later stage clinical studies in this patient population.

And I will now turn the call over to 10 East Coast Arrowhead, Chief Financial Officer, Ken. Thank.

Thank you Javier and good afternoon, everyone as.

As we reported today, our net loss for the quarter ended June 32021 was $29.9 million or 29 per share based on $104.1 million and fully diluted weighted average shares outstanding.

This compares with net loss of $13.6 million or <unk> 13 per share on $101.8 million fully diluted weighted average shares outstanding for the quarter ended June 32020.

Kenneth A. Myszkowski: Revenue in the current period primarily relates to the recognition of a portion of the $300 million upfront payment received under our collaboration agreement with Takeda, as well as a $10 million option exercise payment received from Janssen for the ARO J&J 1 program in May 2021. Revenue for the Takeda Agreement will be recognized as we continue to work toward completing our performance obligations of managing clinical trials in process and certain manufacturing-related services.

Revenue for the quarter ended June 32021 was $45.9 million compared to $27.4 million for the quarter ended June 32020.

Revenue and the current period, primarily relates to the recognition of a portion of the $300 million upfront payment received under our collaboration agreement with Takeda as well as a $10 million option exercise payment received from Janssen.

The Arrow J&J, 1 program and May 2021.

Revenue for the Takeda agreement will be recognized as we continue to work toward completing our performance obligations of managing clinical trials and process and certain manufacturing related services.

Kenneth A. Myszkowski: The remaining $230 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. Revenue in the prior period primarily related to the recognition of a portion of the milestones received from our license and collaboration agreements with Janssen. Our performance and revenue recognition under the Janssen Agreement, or HBV, is substantially complete.

The remaining $230 million of revenue associated with the Takeda collaboration is anticipated to be recognized over approximately 2 years.

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

Revenue in the prior period, primarily related to the recognition of a portion of the milestones received from our license and collaboration agreements with Janssen.

Our performance on revenue recognition under the Janssen agreement or HBV is substantial is substantially complete.

Kenneth A. Myszkowski: Total operating expenses for the quarter ended June 30, 2021 were $77.8 million, compared to $43.3 million for the quarter ended June 30, 2020. This increase is primarily due to increased candidate-specific and discovery R&D costs as the company's pipeline of clinical candidates has both increased and advanced. Net cash used by operating activities during the quarter ended June 30, 2021 was $29.6 billion, paired with net cash used by operating activities of $33.4 million during the quarter ended June 30, 2020.

Total operating expenses for the quarter ended June 32021 were $77.8 million compared to $43.3 million for the quarter ended June 32020.

This increase is primarily due to increased candidate specific and discovery R&D costs as conference pipeline of clinical candidates has both increased and advanced.

Net cash used by operating activities. During the quarter ended June 32021 was $29.6 million compared with net cash used by operating activities of $33.4 million during the quarter ended June 32020.

Kenneth A. Myszkowski: The key driver of this change was the $10 million option exercise payment received from Janssen for the ARO J&J 1 program, May 2021. Excluding any potential milestones from our collaboration partners, we estimate our cash burn run rate to be $50 to $60 million per quarter. Turning to the balance sheet, our cash and investments totaled $644.7 million at June 30, 2021, compared to $453 million at September 30, 2020. The increase in our cash and investments was primarily due to the upfront payment received from Takeda offset by cash used by operating activities. In July, we also collected the $40 million upfront payment due under our recent collaboration with Verizon. Our common shares outstanding at June 30, 2021 were $104.2 million.

The key driver of this change was the $10 million option exercise payment received from Janssen.

For Aero J&J, 1 program and May 2021.

Excluding any potential milestones from our collaboration partners, we estimate our cash burn run rate to be $50 million to $60 million per quarter.

Turning to the balance sheet, our cash and investments totaled $644.7 million at June 32021, compared to $453 million at September 32020.

The increase and our cash and investments was primarily due to the appropriate and receive from Takeda offset by cash used by operating activities.

On July we also collected the $40 million upfront payment due under our recent collaboration with horizon.

Our common shares outstanding at June 32021 were $104.2 million.

Christopher R. Anzalone: With that brief overview, I will now turn the call back to Chris. Thanks, Ken. As I mentioned, we think we're making strong progress across the spectrum of activities required to be a successful platform company. We are innovating on the platform, pushing the boundaries of what our trim technology can do. We are rapidly and efficiently feeding the early stage pipeline with new candidates that may be engines of growth for Arrowhead in the future.

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

Thanks, Ken.

As I mentioned, we think we're making strong progress across the spectrum of activities required to be successful platform company.

We are innovating on the platform and pushing the bounds of what our trim technology can do we are rapidly and efficiently feeding the early stage pipeline with new candidates that may be engines of growth for arrowhead and the future.

Christopher R. Anzalone: We are moving our mid and later stage clinical programs progressively closer to our goal of bringing important new medicines to the patients who need them. And lastly, we are selectively and responsibly using partnering and business development when it makes sense to do so. This last quarter saw important and tangible progress in all these areas. Thanks again for joining us today. I would now like to open the call to your questions, Operator.

We're moving our mid and later stage clinical programs progressively closer to our goal of bringing important new medicines and patients who need them.

And lastly, we are selectively and responsibly using partnering and business development when it makes sense to do so is.

This last quarter, so important and tangible progress on all of these areas.

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

Operator: Thank you Chris, and as a reminder to ask a question, just press star and then the number one on your remote control.

Thank you, Chris and as a reminder to ask a question just press Star and then the number 1 on your telephone keypad again, just press Star and then the number 1 on your telephone keypad and Jay move your line from the Q and just press the pound key.

Operator: telephone keypad again this fresh star and then the number one

Operator: on your telephone keypad, and to remove your line from the queue, just press the pound key. Please stand by while we conclude.

Operator: Please stand by while we compile the Q&A rush.

And I will be compile the Q&A roster.

Maurice Thomas Raycroft: Your first question comes from the line of Maurice Raycroft from Jeffreys. Your line is open.

Your first question comes from the line of Maury Raycroft from Jefferies. Your line is open.

Maurice Thomas Raycroft: Thanks for taking my questions and congrats on the progress.

Yeah, Hi, Thanks for taking my questions and congrats on the progress.

Maurice Thomas Raycroft: I was wondering what the bottleneck for the CPA filings for

I was wondering for the bottleneck for the CPA filings for ducts floor and the 2 pulmonary candidate can you comment on whether this has anything to do with waiting for additional preclinical data from <unk>.

Christopher R. Anzalone: Michael Neck for the CPA filings for Duxfloor and the two pulmonary candidates. Can you comment on whether this has anything to do with waiting for additional preclinical data from ENAC? It does not. It has to do with just finding slots at CROs.

And does not.

It has to do with with.

Finding slots and zeros there as we talked about this I think.

A few conference calls ago that they're that incentive dynamic there has been a.

Christopher R. Anzalone: [inaudible]

Christopher R. Anzalone: Okay, and then also just wanted to check if you're providing a status update on how the eNet is going.

Non human primates shortage and Alt.

So.

These pulmonary.

Studies are a bit a bit more difficult to do because there because there's not many zeroes and do them and so given all of that and we just we just had a bit of a bottleneck and so we will get this done and just that we're going to get them done.

Christopher R. Anzalone: Providing a status update on how the ENAC NHP study is going, and you mentioned you may know more in the next few weeks and months. Is it fair to assume that there could be an update on this in 4Q then, and in the next update, are you going to provide some of the clinical data that you saw? Yeah, so I just don't know. With respect to the TOCS data, I just don't know when we're going to have better clarity.

Quarter or 2 later than we had hoped.

Got it Okay and then also just wanted to check on.

If you are providing a status update on how they enact and HP.

Studies going and you mentioned you may know more on the next few weeks and months is it fair to assume that there could be and update on.

On this and <unk> and and the next update are you going to provide some other clinical data that you saw.

Yes, so I just don't know so with respect to the to the Tox data I just don't know when we're going to have better clarity, we're not gonna have NHL data until towards the end of the year and.

Christopher R. Anzalone: We're not going to have the NHP data until towards the end of the year, and so that will be a black box until then. We haven't, you know; that's still ongoing, and so there's just no data there yet. We don't have, you know, final reports for the rodent piece of that, you know; that's still ongoing. We just got an interim update which caused us to press pause, and now we're doing some other internal experiments.

So that will be a black box until then and we haven't yet that's still ongoing and so there is just no data there yet.

We don't have final reports for the for the road and piece of that.

That's still ongoing we just got.

And interim update on which caused us to press pause and now we're doing some of the other internal programs and some other internal experiments and so I can't give you good guidance on when we're going to know something.

Christopher R. Anzalone: So I can't give you good guidance on when we're going to know something. You know, we're working on it right now, and I think, beyond that, it doesn't make sense for us to talk about the clinical program until we have a better idea about where this is going to go and how quickly we might be able to get back on track if, in fact, that's what happens.

We're working on it right now and I think beyond that it doesn't make sense for us to.

To talk about about the clinical program until we have a better idea about where this is going to go and and.

And how quickly we might be able to get back on track. If in fact, that's going to work out.

Christopher R. Anzalone: Okay, that makes sense. And the last question for me is just about Arrow HIF-2; the first data and the refractory RCC looked good. At this point, do you have more insight into the relationship between knockdown and related tumor activity? And how do you think activity could change at a higher dose? So we don't, with respect to the first question, we don't yet have any more information. With respect to the second question, I don't know, you know, we're seeing this only in real time, and we haven't seen data from a higher dose yet, so we'll see where that goes.

Okay that makes sense and last question from me is just for Arrowhead 2 the first data and their refractory RCC looks good at this point do you have more insight into their relationship between knockdown and the related tumor activity and how do you think activity could change at a higher dose.

So we don't we expect that the first question, we don't we don't yet have any more information.

With respect and a second question.

And I don't know hopefully.

We're seeing this only we're looking at this and real time and and we haven't seen data from the <unk>.

From a higher dose yet so we'll see where that goes what was encouraging to me at least was that it appears that we're on the board and we're getting good.

Christopher R. Anzalone: What was encouraging to me, at least, was that it appears that we're on the board, you know, we're getting good target engagement, it appears that we're getting knocked down, so now let's just see where this goes. I don't, I would not expect, you know, a rapid sort of physiological response, if you will, with respect to tumor shrinkage and such through this pathway. That may take a bit longer. So the fact that we are seeing right now, you know, some knockdowns suggests to us that our platform.

Target engagement it appears and we're getting knocked down and so now, let's just see where this goes.

I don't I would not expect.

A rapid sort of physiological response, if you will.

With respect to tumor shrinkage and such.

Through this pathway that may take a bit longer. So the fact that we are seeing right now.

Some knockdown suggest to us that our platform is working and so on it now we just need to see how thats going to go going forward.

Maurice Thomas Raycroft: Okay, that's helpful. Thanks for answering my questions, and I'll hop back in the...

Okay. That's helpful. Thanks for taking my questions and I'll hop back in the queue.

Operator: Thank you. Your next question comes from Alicia Young of Cantro. Your line is open.

Sure. Thanks Martin.

Thank you and your next question comes from the line of from Alethia Young of Cantor. Your line is open.

Alicia Young: Hi, this is Nenon from Aletheia, and thank you for taking our question.

Hi, This is Nate on from EPS and thank you for taking our questions.

Alicia Young: Thank you for taking our questions. We were wondering if you could share more on your DUC4 program and how it compares to competitors, and also if there's any read-through from the Phase 2b results for Lost Map Mod, which missed the primary endpoint in change for DUC4.

And we're wondering if you can share more on your ducks from our program and how it compares to competitors and also if theres any read through from the phase <unk> results for last month, which.

On the primary endpoint and.

Alicia Young: Yeah, so I'll let I'll let James comment on that. I don't I don't.

And change of Ducks force.

Yes so.

Christopher R. Anzalone: Well, I'll let him comment on that. I don't know that there's read through, you know, with the other one, because it's different. You know, it's a different compound entirely, of course, but James, sure, maybe I'll take the first question first about how we compare with the competing programs. And there's not a whole lot out there.

And I'll, let I'll, let James comment on that I don't I don't well I'll, let him comment on that I don't know that there's read through.

With that with the other 1 because it's different it's different compound entirely of course, but James.

And maybe I'll take the first question first about the how we compare with the competing programs.

There's not a whole lot out there.

James C. Hamilton: And, you know, with regard to the other oligo programs, the targeted antispense programs are all preclinical, and there's really not much data available. And so the primary difference would be the way that we target the muscle cells that we use, a peptide targeting ligand versus their antibody or antibody fragment approach. So that's, I think that's the main difference as far as comparing them, and there's really no way to compare efficacy or knockdown levels as other competing programs have not shared any data.

With regards to the other <unk> programs.

The targeted anti <unk> programs are all preclinical and theres really not much day.

Available.

And so the primary difference would be.

We target.

And the muscle cells that we use.

Peptide targeting ligand vs antibody or antibody fragment approach. So thats I think thats. The main difference as far as comparing and there's really no way to compare.

Efficacy or knockdown.

Levels.

The other competing programs have not shared any data at this point and then the other question was around the fulcrum read through is that right.

James C. Hamilton: And then the other question was around the fulcrum read-through, is that right? Yeah, it's tough to say. I mean, it's a very different compound, different mechanism. But I think they did highlight the challenges associated with a biopsy study in this population and with this specific target, where there's this sort of stochastic expression of the target that may be difficult to catch or to monitor, if you will, with biopsy. You will look at downstream gene expression, but we'll likely also look at other parameters that might help us select a dose for later stage clinical studies.

Yes. It is.

Tough to say I mean, it's.

Very different compound different mechanism.

They did highlight the.

The challenges associated with a biopsy study.

And in.

This population and with this specific target where there's the stochastic expression of the target that may be difficult to to catch on to monitor and if you will with biopsy. So.

Yes.

We will look at downstream gene expression, but will likely also look at other parameters that might help on selected dose for later stage clinical studies.

James C. Hamilton: Yeah, out here.

Yes.

Javier San Martin: This is Javier. I wanted to add another comment about this data, which I think, despite the biomarkers, the clinical data, in some aspects, was positive. So I think the target still is in a good place, because if you look at the PRO and the physical function, there is a number of those that were statistically significant. We don't know how clinically relevant those changes are, and we're looking at that to try to see if some of those changes correspond with the minimal relevant changes, and that, I think, will help us to understand this. So I think there is a mix of results here. Despite the biomarker now being positive, there are clinical signs of potential improvement in this patient population, which I think is reassuring for the pathway.

And I want it was another comment about this data.

Which I think the despite the biomarkers the clinical data and some other was positive so.

I think the target is still is and a group place because if you look on the P&L and the physical function and that it's a number of those that work statistical significant and we don't know how clinical relevant and those changes and we're looking at that and tied to see if some of those changes.

And with a minimal relevant changes and that I think will help us to understand this so I think that is it makes a free.

Yourself here, despite the biomarker and now being positive and there is clinical sciences potential improvement in this patient population, which I think is issued and for the.

Alicia Young: Okay, that's helpful. Thank you.

Absolutely.

Okay. That's helpful. Thank you.

Operator: Thank you. Your next question comes from the line of Esfer Rejavelu from UBS. Your line is open.

Thank you.

Thank you. Your next question comes from the line of ex for reservoir Liu from UBS. Your line is open.

Esfer Rejovelu: Hey, thank you for taking my question. I have two. One on ENAC.

Hey, Thank you Pablo Thank you for taking my question I have 2.1 on <unk>.

Esfer Rejovelu: So it's historically been a tough target, but what are some takeaways from the tox signals that you're seeing? Is it specific to the lung, or is there evidence of exposure in other tissues? And what would your considerations be if you find that the tox is limited to the lung?

Historically been a tough target, but what are some takeaways from the tox signals that you're seeing is it specific to the long or is there evidence that the exposure and other tissues and what consideration fee. If you find.

And that the Tox is limited to the lung.

Christopher R. Anzalone: So

So and so let me just say with tours and then I'll hand, it over to <unk>.

Christopher R. Anzalone: So, let me just say two words and then I'll hand it over to James on this. The talks that we saw, or that we heard about, again, we haven't had a final report on this RAD study yet, so we have limited data, but what we understand is that it was local lung inflammation. We don't see it. We didn't see broader issues. We don't know if that's species specific because, as I said, we don't have the NHP data yet. We don't know if it is sequence specific either.

James on this.

The task that we saw when we heard about again, we haven't had a final report on on this on this rat study yet so and so we have we have limited data, but what we understand is that it was it was local lung inflammation and we don't we don't see we didn't see broader.

Issues I don't know if that species specific because as I said, we don't have.

The HP data yet we don't know if it if it is sequence specific or as target specific theirs.

Esfer Rejovelu: Well, the other part of the question was, if you if you sort of consistently see that the toxic when you get the NHP data, if

We are really just starting to.

To get into this channel.

And what was the other part of the question.

It is.

Well the other part of the question was if you if you sort of consistently see that the taxes. When you get the NH P data do you see the toxic.

Esfer Rejovelu: When you get the NHP data, if you see the toxin limited to the lung, how would you interpret that? Is that a good thing because you know the drug is getting to the lung, and you just have to find another target that works, maybe in a different indication, or would you have to go back and change the chemistry?

And limited to the lung would it.

I mean, how would you interpret that as it.

Is that a good thing because you know the drug is getting to the lung and you just have to find another target that and what's maybe and a different indication. What do you would you have to go back and change the chemistry.

James C. Hamilton: Well, the tox being limited to the lung, as Chris has stated, is not surprising. I mean, the systemic bioavailability of inhalational oligos is not that great. So it's not unexpected that we would only see toxin in the lung.

Well, if the talks being limited to the lung as Chris stated is not.

And is not surprising I mean the.

The systemic bioavailability with inhalation on Oligos.

Not that it creates so it's not unexpected that we would only see tox and.

And in the long.

James C. Hamilton: I think it depends on what we see in the final results from the RAD and in the NHP study in terms of what the toxicity is and at what dose levels and dose frequencies they're at. You know, again, depending on the results, and we don't have these results yet, there may be an opportunity to resume the study as is, or to, you know, amend, to look at different dose levels, different dose intervals.

It depends on.

What we would see in the final results from the Red and then and Hp's study in terms of what what the toxicity is and at what dose levels and dose frequency there.

And again, depending on the results and we don't have to use results, yet and there may be and opportunity.

Resume the study is or 2 to them and taking a look at different dose levels different dose intervals.

James C. Hamilton: Right. And to follow up on that, you know, remember that we can dose this reasonably high, but also, we dose it relatively frequently. And so to James's point, or as he alludes, you know, if this appears to be clean in the NHPs, it could be that we have an opportunity, you know, just to space out the dosages a bit more. That's all speculation. You know, let's see where the data comes in, and we can go from there.

And it's.

And the fall into that remember that we are doses that we can doses.

Reasonably high but also we dose it roughly.

And so to James's points, whereas you lose.

If we are if this appears to be clean and the NHL.

It could be that we have an opportunity just to space out the.

The dosage is a bit more.

It's all speculation and let's let.

See what the data come in and and we can go from there.

Esfer Rejovelu: Got it. Thank you. And then, on AAP, are you still on track to revisit?

Got it. Thank you and then on <unk> are you still on track to revisit the Registrational trial design with the FDA and I think that and the third quarter late summer.

Esfer Rejovelu: to Revisit the Registrational Trial Design with the FDA in, I think you had said in the third quarter, late summer or thereafter. You say the initiation of the...

Javier San Martin: Javier? You say the initiation of the Phase 3 study? The introduction, yes. So, as you probably know, we've been granted breakthrough designation about a week or two weeks ago, and we're already working on the briefing document to engage in the first, what is called, multidisciplinary meeting in the coming months. 3Q4 time.

The last day.

And you take the initiation of the phase III study.

Yeah.

Hi, Good afternoon, yes, so as you probably know we've been granted breakthrough designation and by a week or 2 weeks ago. We're on.

Already working on the briefing document and to engage in the first what is called multi disciplinary meeting, yes, and the cute.

Q3 Q4 timeframe.

Operator: Thank you. Your next question comes from the line of Joel Beatty from Baird. Your line is open.

Thank you.

Thank you.

Thank you and your next question comes from the line of Joel Beatty from Baird. Your line is open.

Joel Lawrence Beatty: Hi, congrats on the progress. A couple of questions on the HIF-2A program, but the first is, would the dose

Yes, hi, congrats on the progress a couple of questions on the 2 day program.

First is it was a dose response and reduction of hit to a scene and among the 2 doses and debt.

Joel Lawrence Beatty: The first question is, was the dose response in reduction of HIF-2A seen among the two doses in that study? And then I have a follow-up.

Study and I.

And then I have a follow up.

Christopher R. Anzalone: Dose response between the first two cohorts? Yeah, I think we're still in the process of dose escalating and analyzing all the data from the second cohort. A lot of those patients are still on drugs, so I think it's too early for us to really give a clear answer on dose response. And a further complicating factor is that, I might get these numbers wrong, so correct me if I'm wrong, we had 17 individuals, but I think we only had usable biopsy material from nine of them, and so it may be difficult to know if we have a dose response at this point. The only thing I would add is that we did it.

James.

The dose response between the first 2 cohorts.

I think we are.

And we're still in the process of dose escalating and analyzing all the data from the B.

The second cohort a lot of those patients are still on drug so I think.

It's too early for us to really give a clear answer on dose response and a further complicating factor is that making these numbers wrong. So correct me, but we're on it we had up 17 of 70 individuals I think we only had we only had usable.

Biopsy material from 9 of them.

And so and so it's so it may be it may be difficult to with too.

No we havent those funds at this point the other thing.

Christopher R. Anzalone: The only thing I can add is that we did see knockdown in both of them.

We did see no doubt in both doses.

Christopher R. Anzalone: And in the press release, we were just giving kind of the overall top line on this. And so our intent, as we said in prepared remarks, is to present a more full data set and an appropriate medical meeting, which would include the top dose level as well. So stay tuned.

Thats.

Yes.

And the press release, we were just giving kind of overall top line on this and so our and Ted We said this on the prepared remarks is to present, a more full data set and an appropriate medical meeting, which will include the top dose level as well so stay tuned on that.

Joel Lawrence Beatty: Yeah, you got it. That all makes sense and is helpful. So I guess just one follow-up on that is you mentioned there was one responder with a fairly strong response. Are you able to share anything about the F2A reduction that was seen in that patient?

Yes that all makes sense and is helpful and so I guess, just 1 follow up on that.

And so no there isn't 1 responder, but with a fairly strong response.

Are you able to share anything about the <unk> reduction that was seen in that patient.

Joel Lawrence Beatty: Not at this time, but I think we can share that when we present the full data set at an upcoming medical meeting.

Yes.

And at this time I think we can share that when we present the full data set at an upcoming medical meeting.

Operator: Thank you. Your next question comes from the line of Solvene Richter.

Great. Thank you so much.

Okay.

Thank you. Your next question comes from the line of solving which Theyre from Goldman Sachs. Sir Your line is open.

Solveen Richter: Levine Reichter from Goldman Sachs, sir, your line is open, for taking our question. This is Sonia from Salveen. We were just wondering, beyond the pulmonary target and the muscle target, what other extrahepatic tissues would you be looking to go into on the forward?

For taking our question this is sonya on for Celgene.

Just wondering like beyond the pulmonary target and the muscle target 1 other extra hepatic tissues would you be looking to go into on the forward.

Christopher R. Anzalone: So we have active programs in a number of areas. We have not disclosed other areas that we'd like to go after or that we're working on. So yeah, just stay tuned on that. Look, we have mentioned in the past though that CNS clearly is a target-rich environment, so it's a place that we wanna go to at some point. We are not there yet, but there are a number of tissue types.

So we have active programs and a number of areas we have not disclosed.

Other areas.

And go after or that we're working on.

And so you have to stay tuned on that.

Have we have mentioned in the past, though debt that CNS clearly is a target rich environment and so that's in place and we want to go at some point, we are not there yet.

But theres a number of tissue types that we're looking at.

Operator: Thank you. Your next question comes from the line of Luca Issi from the Royal Bank of Canada. Your line is open. Oh, great. Thanks for taking the question. This is Lisa on behalf of Luca.

Thanks.

Sure.

Thank you. Your next question comes from the line of Luca <unk> from Royal Bank of Canada. Your line is open.

Oh, great. Thanks for taking my question and this is Lisa on for Luka.

Luca Issi: One here on A1AT, can you give us some directional color here on more of the ongoing dialogue with the FDA now that you have it?

Yes.

And youre on on.

And <unk>.

Can you give us some directional color here on more with the ongoing dialogue with the FDA now that you have.

Luca Issi: Breakthrough Designation. There may be a scenario where the data from the 202 study and the first 36 patients from Sequoia

Ignition.

Maybe a scenario where the data from the <unk> study and the first 36 patients from Sequoia.

Javier San Martin: Patients from Sequoia will be sufficient for accelerated approval, and I also have a follow-up on ENAC.

And will be sufficient for accelerated approval and I also have a follow up on <unk>.

Javier San Martin: This is Javier. Yeah, we're thinking about all of those options. Right now, we will need to focus on the first interaction. Typically, this first interaction, as I said, is a multidisciplinary meeting where we will touch upon different aspects of the filing process, discuss the phase three study design, the approvable end point, and the time to file. It's going to be critical, but it's not a one-sided conversation. It's a process. So it's a good thing. We will, of course, entertain that thinking and potential step forward. And we've had really good, so far.

Yeah.

Javier.

And we're thinking about all of those options right now we would need to focus on the first interaction and typically this presentation and as I say this and multidisciplinary meeting we would touch up on decent and as of the filing process.

Discuss the phase III study design and the approval end point and the time to filing it's going to be critical but if no 1 stock compensation is.

Process so.

Good.

And we'll of course.

And today and that thinking on the potential step forward and we've had really so far and limited interactions with the FDA and Thats, particularly with the current division.

Javier San Martin: And we've had, really, so far, limited interactions with the FDA, and that's particularly with the current division. But our interactions have been quite positive and collaborative. They clearly appreciate that this is an unmet medical need, and I think that they're really interested in working with us to get this to patients who need it. And so we haven't had, you know, so we're really excited to have this breakthrough designation so we can sit down and have these more in-depth discussions.

But our interactions have been have been quite positive and collaborative.

They clearly appreciate that this is on unmet medical need and.

And and I think that they are really interested in and working with us to.

And to get this to patients who need it and so we haven't had so we're really excited to have this breakthrough designation. So we can we can sit down and have these more in depth discussions and to European breakthrough designation and essentially opens the path to and extended approval based on a surrogate likely to translate into clinical benefit and that's precisely what we will discuss.

Javier San Martin: And to your point, breakthrough designation essentially opens the path to an accelerated approval based on a surrogate likely to translate into clinical benefit. And that's precisely what we will discuss the next time around. That was a significant component of the breakthrough designation briefing document. So, yeah, we're going to talk about that.

The next time around that was it.

<unk> company on the breakthrough designation briefing document so yes, we're going to talk about these.

Throughout the process.

Javier San Martin: Great. That's helpful. And then just one on ENAC. Just wondering if you can talk about the doses at which you have seen the tox result in rats and how those doses scale to humans. Just trying to figure out whether the signal, the tox signal seen in rats was seen at maybe supertherapeutic doses or at doses that scale within the 40 to 180 mg range that are being tested in humans.

Great. That's helpful and then just on on <unk>.

Wondering if you can talk about the doses at which you are seeing the debt.

And the talks with all and and rats, and how those doses scale into humans.

Just trying to figure out here, whether the signal.

The tox signals seen and ops, massena, and EDI super therapeutic doses or at doses that scale within the 40 to 180 Meg range that are being tested in humans.

Luca Issi: Thanks. Sure. And I appreciate it.

Christopher R. Anzalone: Sure. Sure. And I appreciate the question. But look, you know, it is it has been our policy not to talk about tox data in particular because we don't even have a final report here. We just, you know, have just been given a, you know, a small synopsis about part of a rat.

Sure sure and I appreciate the question, but look it is it has been our policy not to talk about about Tox data in particular, because we don't even have have a final report here and we just we've just been given.

And a small synopsys about about.

And part of a rat study and we don't even know anything about the about the NXP. So so.

Luca Issi: Okay, got it. Thanks for taking the question. Thank you. Your next question comes from the line of Patrick Trucchio from HC Wainwright. Your line is open.

And so we're unable to and to give you any more color on that at this point.

Okay.

Okay got it thanks for taking my questions sure.

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

Operator: Hi, thanks. Good evening.

Hi, Thanks, Good evening, just a couple of follow up questions on the <unk>.

Patrick Ralph Trucchio: Just a couple of follow-up questions on the C3 program. First, can you discuss what, if any, potential advantages there are to targeting C3 rather than C5? And secondly, do you know which indication or indications the C3 program would initially focus on when clinical development could begin? And is this a program you would bring to clinical development on your own, or would you seek a collaboration partner?

C. III program first can you discuss what if any potential advantages there are and are targeting C..3 rather and <unk> and secondly, do you know on which indication or indications. The <unk> 3 program will initially focus on when the clinical development could begin and is this a program you would bring into clinical development on your own or would you seek a collar.

Christopher R. Anzalone: I will answer the last of those questions and then I'll hand the rest over to James. So, we do not have plans to seek a partner right now for this program.

<unk> partner.

I will answer the last of those questions and then I'll hand, it all and the rest over to James.

So we do not have plans to seek a partner right now for this program, you'll look that may change and the future, but right now we are happy to take this forward. This is this is directly in our wheelhouse in terms of.

Christopher R. Anzalone: You know, look, that may change in the future, but right now, we are happy to take this forward. You know, this is directly in our wheelhouse in terms of preclinical development. You know, this is a parasite-directed construct we feel good about going to the clinic, and so let's see what the data look like, and then we can make a decision on partner versus non-partner at some point in the future. Sure, I'll take the first part of the question that I think was about C3 versus C5.

Our preclinical development this is Pat.

Pass I directed contract we feel good about that go into the clinic and so let's see what the data look like and then we can make a decision on partner versus non partner at some point and the future James and <unk>.

I'll take the first part of the question that I think was about Q3 versus Q 5.

Christopher R. Anzalone: So, you know, C3 in the complement cascade is a central node that is involved in all three different components of that pathway, the lectin, the alternative, and the classical pathways. So if you can inhibit C3, you can really take out everything that's downstream of C3. And so the effects should be broadly applicable to various complement-mediated diseases. Now specifically to two interesting indications, PNH and C3 glomerulopathy, that Chris mentioned during his earlier remarks.

C..3 in the complement Cascade is a central node that is involved and all 3 different components of that pathway the lectern.

The alternative and the classical pathways. So if you can inhibit C..3 can really take out everything thats downstream of <unk>, 3 and and so the effects should be broadly applicable to various complement mediated diseases.

And specifically to 2.

Interesting indications PNA, H and Q3 culinary Allopathy that Chris mentioned during the earlier remarks and <unk>.

Christopher R. Anzalone: PNH is a disease that's been reasonably well treated with C5 inhibition. However, there is a component of that population that is refractory to treatment due to extravascular hemolysis that's primarily driven by C3. So that residual population with the residual anemia that's refractory to C5 inhibition could be specifically treated with potentially C3 inhibition. There is another population, the C3 glomerulopathy patients, where their disease is really driven by excess C3 activity and deposition of C3 fragments in the glomeruli.

And H is a disease, that's been reasonably well treated with <unk> inhibition. However, there is a component of that population.

That is refractory to treatment due to extra vascular hemolysis, and that's primarily driven by C. III so that residual.

Population with the residual anemia that's.

<unk>, 5 and inhibition could be and specifically and treated with potentially treated with <unk> 3 inhibition.

There is another population the C 3 equal and Merial apathy patients where their disease is really driven by excess.

C III activity and deposition of C..3 fragments and the glum area lives. So that's really a C III driven disease.

Christopher R. Anzalone: So that's really a C3-driven disease. Beyond those, there are other conditions where the disease is complement-mediated, maybe not as specific to C3 as those other two conditions, but complement-mediated, and we think that C3 inhibition may have applicability in those other complement-mediated conditions. So I think that covers maybe both the first and the second question about C3 versus C4. 5, as well as the other indications.

And knows there are other conditions that are.

And where the disease is.

Complement mediated and maybe not specific to see 3 as those other 2 conditions with complement mediated and we think that <unk> 3 inhibition may have applicability and those other complement mediated diseases.

I think that covers maybe both the first and the second question about Q3 versus 6.5 as well as the other indications.

James C. Hamilton: And one other question was about when we could enter clinical development.

1 other question was about when and when we can enter clinical development.

By the end of the inventories.

We'll be filing a cta by the end of the year.

James C. Hamilton: Got it. That's helpful. And then just a follow-up on the gout program. Can you tell us where ArrowXDH would fit in the gout treatment paradigm and the potential cadence of the $660 million in potential milestones from Horizon? And, to the extent that you could comment, when the program could be expected to enter clinical development?

Got it and that's helpful. And then just a follow up on on the gout program can.

Can you tell us where.

ROE ex <unk> would fit and the gout treatment paradigm and the potential cadence on the $660 million and potential milestones from horizon.

And to the extent that you could comment when when the program can be expected to enter clinical development.

Christopher R. Anzalone: I can't tell you too much about that or about any of those actually. So, we did not split out what the You know, how the $660 million of potential milestone payments could be achieved. With respect to how this could fit into a clinical paradigm, you know, this is one of the reasons we chose Horizon as a partner. You know, this is their business, and we'll be working closely with them, but ultimately, this is their decision, and so I don't want to step on their toes and tell you something that we believe when this is really going to be their business. And with respect to what you asked, when they're going to get into the clinic, we don't know the answer to that.

We can't tell you too much about that.

Any of those actually so we did not split out what the.

How the $660 million and potential milestone payments.

Could be achieved.

With respect to how this could fit into.

On clinical paradigm.

This is this is 1 of the reasons, we chose a horizon and as a partner. This is this is there business and we'll be working closely with them, but ultimately this is their decision and so I don't want step on their chosen and tell you something that we believe when when when this is really going to be their business.

And with respect to what you asked when is it going again and the clinic, we don't really answer to that still and early program.

Just working on it right now and so.

We still have a ways to go.

Patrick Ralph Trucchio: Got it. That's helpful. Thank you.

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

Operator: Thank you. Your next question comes from the line of Ted Tenthoff from Piper Sander. Your line is open.

You're welcome.

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

Edward Andrew Tenthoff: Thank you very much. I appreciate all the updates.

So I appreciate all the uptake and interest.

Edward Andrew Tenthoff: And I just wanted to get a sense of a little bit more on the new pulmonary targets.

And we could give a sense a little bit more on the.

New preliminary targets.

Christopher R. Anzalone: You know, what are the gating factors, and is there anything you expect to learn from the ENAC program that could impact those programs going into the clinic? Thank you very much.

Okay.

You know what our gating factors and is there anything you expect to learn from that.

Net program that could impact.

Those programs coming into the clinic. Thank you very much.

Christopher R. Anzalone: Yeah, so that's a good question, Ted. You know, I don't know the answer to that. You know, it's still just too early.

Yeah. So that's a good question Ted.

I don't know the answer to that.

Still just too early we don't know what's going on with what happened in those rats and the Enoch program and so until we have more information I just don't know how that might lead on future programs. I can tell you that it has not slowed us down. This is still we think a big opportunity for us and we're still moving as quickly as we can.

Christopher R. Anzalone: We don't know what's going on with or what happened to those rats in the ENAC program. And so until we have more information, I just don't know how that might read on future programs. But I can tell you that it's not slowed us down. You know, this is still, we think, a big opportunity for us, and we're still moving as quickly as we can.

Christopher R. Anzalone: We are excited about these two new programs, but we haven't talked about the gene targets yet. We haven't talked about the disease areas yet, but I expect that we will maybe later this year. We were disappointed that we couldn't get the slots that we wanted to move this into the clinic this year, but that's just the way the world turns right now. And so, you know, we look forward to getting this into the clinic in the first half of next year.

We are excited about these 2 new programs and we haven't talked about the gene target you Havent talked about the disease areas.

And I expect that we will maybe later this year.

And we were disappointed that we couldnt get the slots that we that we wanted to move this into the clinic and this year, but.

That's just the way the world turns right now and so we look forward to getting this in the clinic and the first half of next year.

I will say, though that the bad debt than what we what we think.

We have seen and because again, we've only seen.

Christopher R. Anzalone: I will say, though, that what we think we've seen, because again, we've only seen, you know, a small amount of data from that rat study, but what we have seen there has caused us to do a bit more work while we're waiting, just internally, on chronic studies. These are non-GLP toxin. These are just so we understand a bit more internally on the other programs.

A small amount of data from net rent study, but what we what we have seen there has caused us to do a bit more.

And <unk>, while we're waiting just internally on on on chronic ex on chronic.

Studies. These are non GOP toxicity and these are just so we understand a bit more internally.

On the other programs.

And that makes a lot of sense.

And.

Edward Andrew Tenthoff: That makes a lot of sense. And with respect to... With the patients who have already been dosed, how how do we anticipate hearing about that data? I know you're not dosing it, and going forward.

With respect to.

Linda.

With the patients who have already been dosed.

<unk>.

How do we anticipate hearing about that data.

I know youre, not dosing and even going forward, but it's not going to be a substantive enough data sets at its current will be informative and and so that's something we would share publicly.

Edward Andrew Tenthoff: Is that going to be a substantive enough data set that it's going to be informative, and is that something you would share publicly?

Yeah, and again I'm, sorry, I can't give you a definitive answer on average because we don't know we don't know what's going to happen with that program and and if we can restart window. When we don't know when we can restart it.

Christopher R. Anzalone: And again, I'm sorry I can't give you a definitive answer on that because we don't know what's going to happen with that program, and if we can restart it, we don't know when we can restart it. So until we have more information, we just would rather not give any sort of guidance one way or the other. I totally understand. Yeah. I totally understand. Awesome, Chris. Thanks so much for the update and really a lot of great progress this year. So excited for the book to come out.

So so until we have more information.

Just.

And would rather not give any sort of other items, 1 way or the other railroad.

Totally understand also Chris Thanks, so much for the update and really a lot of great progress this year, so credit per backup.

Thank you Ted.

Thank you. Your next question comes from the line of Keith Mckey from share Dan Your line is open.

Yes, hi, Thanks, Yes, Chris just just following up on the new loan programs and so what are the similarities similarities between.

Operator: Thank you. Your next question comes from the line of Keay Nakae from Shoredam.

Keay Thomas Nakae: Ma'am, your line is open.

Christopher R. Anzalone: Yeah, hi, thanks. Yeah, Chris, just following up on the new lung program. So what are the similarities between the construct for those versus ENAC? I mean, obviously you're gonna have a different sequence for the targeted gene, but are you using the same targeting ligand? And so, help us try to better understand what the potential read across of risk is from the ENAC talks.

The construct.

For those vs. Ina can be obviously youre going to have a different sequence for the targeted gene but.

Are you using the same targeting ligand and so it'll help us.

Try to better understand what the potential read across the risk is from.

And the E com.

And so we use.

And the same targeting ligand.

Christopher R. Anzalone: Right, so we're using the same targeting ligand, as you say, different sequences. I would expect that we'll be using less material in the next two because, at least in animal studies, they both appear to be more potent than Arrow-ENAC. Is that important? I don't know, but I believe that's, well, I know that's the case for animal studies, and we'll see if it translates into humans, and so it's, again, until we have more data, it's just too early to speculate on how or if, you know, what we saw in the Cronk Talks in rats may translate to other animals.

As you say different sequences.

I would expect that we'll be using less material.

And the next 2 because at least and animal studies. They both appear to be more potent than <unk> is that important I don't know.

But I believe that debt.

Well I know that's the case for animal studies, and we'll see if it translates into humans and so again until we have more data. It just too early to speculate on how or if.

What we saw in the and the chronic tox interest may translate to other other.

Christopher R. Anzalone: Okay, thanks for that. And then just for HIFS, the biopsies that you received, and, you know, the fact that some of them weren't usable, can you just further characterize that? And how do we think about the risk there going forward of not being able to get good data to do your assessment?

Sequences.

Okay. Thanks for that and then just free shifts.

The the biopsy.

Ifc's that you received and.

And the fact that some of them.

More useful can you just further characterize that and how do we think about the risk there going forward.

And not being able to get.

Get good data to do your assessments.

Christopher R. Anzalone: Yeah, so far, well, maybe I'll make one comment about the study design. The protocol allows us to enroll up to a sufficient number of patients to get enough biopsies that we think are adequate, paired biopsies to do our analysis. And as was described in the press release, you know, the biopsy samples are not always analyzable. But so far, in the first and second cohorts, and so far in the third as well, we've been able to get enough biopsy samples to do the work that we need.

Yes.

Yes, so far.

Well, maybe I'll make 1 comment about the study design and the protocol allows us to add.

And roll up to a sufficient number of patients to get.

<unk> biopsies that we think are adequate.

Paired biopsies to make to do our analysis.

And as was described in the press release, the biopsy samples are not always analyzable.

But so far and the first and second cohort and then and.

And so far and the third as well and we've.

And then able to get enough biopsy samples to do the work that we need to.

Keay Thomas Nakae: I hope that answers the question. Okay. Uh, yeah. Thank you.

Yeah.

Okay Alright.

Yes. Thank you.

Operator: Your next question comes from the line of Mayank Mamtani from B Riley. Your line is open.

Your next question comes from the line of May and Montana from B Riley. Your line is open.

Mayank Mamtani: Hi, good afternoon. This is Sahil Kazmiyan speaking for Mayank.

Hi, good afternoon, and there's a thought on what has me on for Mike and thanks for taking our questions.

Mayank Mamtani: Thanks for taking our questions. Maybe a brief one on HIF-2. Could you provide any color on kind of how the enrollment's been tracking, maybe in the context of the Merck program nearing approval, or just increased awareness of VHL disease associated with RCC? Yeah, enrollment has actually been really good in that program throughout. We've not seen any challenges with enrollment, and all the slots have filled very rapidly. So I know that the Merck study is ongoing, but it has not.

I'll do a brief 1 on on hip to could you provide any color on kind of how the enrollment has been tracking maybe in the context of the Merck program, there and nearing approval or just increased awareness on DHL disease associated with RCC.

Okay.

Enrollment has been actually really good and that program throughout we've not seen any challenges with enrollment and all the slots are filled.

Very rapidly and so.

And I know the Merck study is ongoing but it has not deterred.

Mayank Mamtani: Attracted From Enrollment Into This Study, Great. And then maybe on HBV, do you have any insight into kind of what forum J&J might present the 24 week off treatment data from REEF and or any high-level thoughts on kind of what we can incrementally learn from that study?

And as detracted from enrollment into this study.

Great and then maybe on the HBV do you have any insight into kind of what forum J&J might present, 24 week off treatment data from reef and or any high level thoughts on on kind of what we can incrementally learn from that study.

Christopher R. Anzalone: Incrementally, I learned from that study.

Boy.

No.

Christopher R. Anzalone: Boy, no. I can't give you any guidance on that. Look, we look forward to seeing the data, but I don't know what their plans are, to be honest, about where that could lead. Fair enough. Thanks for taking our questions and congrats.

And I can't give any guidance on that.

Look forward to to.

<unk> seen those data, but I don't I don't know what their plans are to be honest about where that could be presented.

Mayank Mamtani: Fair enough. Thanks for taking our questions and congratulations on the program.

Got it fair enough. Thanks for taking my questions and congrats on Nevada. Thank.

Operator: Thank you. Your next question comes from the line of Mani Foroohar from SBCC.

Thank you.

Thank you. Your next question comes from the line of Manny, Florida, Ohio from SBB Leerink. Your line is open.

Mani Foroohar: Mani Foroohar from SVB Lyrinc. Your line is open.

Mani Foroohar: Hey, good afternoon. This is Rick on the line for Mani. Thanks for taking our questions. We have just two from us. So first, for HIP-2, could you speak to some of the variability of knockdowns seen in the data?

Hey, Good afternoon. This is Rick on the line from Mani Thanks for taking my questions 2 from us.

So first for him to could you speak to some of the variability of knockdown and seen in the data I know there aren't a lot of datasets and exploring <unk> and tumors.

Mani Foroohar: Data. I know there aren't a lot of data sets exploring RNAi in tumors, so could some of this variability just be due to the heterogeneity of tumors in general? Or is it something that could potentially be resolved by looking at higher doses or either earlier lines of patients? Yes, I think that you hit the nail on the head.

And some of this variability due to the heterogeneity of tumors and general or is this something that could.

Potentially be resolved by looking at higher doses are either earlier lines of patients.

Yes, I think that you hit the nail on the head I mean, I think there's headroom.

Christopher R. Anzalone: Yes, I think that you hit the nail on the head. I mean, I think there's that heterogeneity of expression in the tumors and across from patient to patient. And also, you know, heterogeneity in between Paired biopsies; you're not necessarily getting into the same area of the tumors. So heterogeneity is definitely an issue and probably explains a good component of the variability.

Heterogeneity of <unk>.

Expression.

In the in the tumors and <unk>.

<unk> from patient to patient.

And also.

Heterogeneity.

And between.

And paired biopsies youre not necessarily getting into the same and.

Yes.

On.

And the tumors. So heterogeneity is definitely an issue and probably explains and good component of the variability.

Mani Foroohar: All right, I got it.

Mani Foroohar: All right, thanks. I also have a much more broad question. So, just in general, Arrowhead's approach to...

Alright got it.

Alright. Thanks.

Much more broad question.

And so just in general Arrowhead approach to extra hepatic delivery seems to be focused around targeting integrates with specific ligand conjugate and could you.

Mani Foroohar: Extrahypatic delivery seems to be focused around targeting integrins with specific ligand compounds.

Christopher R. Anzalone: [inaudible] Can you maybe speak to why these are so favorable to target as a class of molecules and if the company is currently exploring any other targeting strategies preclinically? Yeah, so I'll let James take care of that also.

And you speak to why these are so favorable to target are the class of molecules and if the company is currently exploring any other targeting strategies pre clinically.

Yeah, So I'll, let <unk> take it has also been budget take broadly.

James C. Hamilton: Yeah, so I'll let James take it as well, but I'll just say broadly, we are not an integrin targeting company. We're an RNAi company. And so, you know, we tend to use what works best, and we are agnostic. For example, we have done work with antibodies, with antibody fragments, with peptides, with small molecules, and such. And so, you know, we just, you know, we have ideas about what might work best, but ultimately, the data will tell us. And so it's just so happened that we've found that integrin-based targeting has been quite good for us. James, yep, I'll echo that.

We are not an integral and targeting company, we're an R&D company and so we tend to use what works best and we are agnostic, we have done and work with antibodies with antibody fragments with peptides with from molecules and such and.

So we just.

We have ideas about what might work best but ultimately the data will tell us and so it just so happened that that debt.

Debt, the interim and base targeting has been quite good for us and <unk>.

Yes, I'll echo that.

James C. Hamilton: We go with what works, and we went with integrin-receptor ligand pairs, not because that was our area of expertise, but because that was what looked the best, and we continue to, we've historically evaluated multiple different receptor ligand pairs and continue to do so, and I think we'll continue to go with what works, regardless of what the modality is, if it's an antibody or a small molecule or something else

And that.

And we go with what works and.

We went with integrin receptor ligand pairs not because that was our area of expertise, but because that was what was looking the best.

And we continue we've historically evaluated multiple different receptor ligand Paris and continue to do so and I think we will continue to go with what works regardless of what the other modality as if it's an antibody or small molecule or.

Mani Foroohar: All right, great. I appreciate all the detail.

Something else.

Okay, Great I appreciate all the detail.

Yes, thanks very much.

Operator: Thank you. There are no other questions in the queue. I will now turn the call over back to Chris. Please go ahead.

Thank you there are no other questions on queue I will now turn the call over and back to <unk>. Please go ahead.

Christopher R. Anzalone: Thank you all for joining us today, and I hope you have a nice evening and afternoon.

Thank you all for joining us today and I Hope you have a nice evening and afternoon.

Operator: This concludes today's conference call. Thank you for participating. You may now disconnect.

This concludes today's conference call. Thank you for participating you may now disconnect.