Q3 2022 Arrowhead Pharmaceuticals Inc Earnings Call

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals Conference call.

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call.

Throughout today's recorded presentation, all participants will be in listen-only mode.

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

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

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

I will now hand the conference over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead.

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

Please go ahead, Vince.

Jordan Good afternoon, everyone. Thank you for joining us today to discuss arrowheads results for its fiscal 2022 third quarter ended June 32022 with US today from management are president and CEO , Dr. Christopher Anzalone, who will provide an overview of the quarter Dr. Javier San Martin.

Jordan, good afternoon, everyone.

Thank you for joining us today to discuss Arrowhead's results, for its fiscal 2022 third quarter ended June 30, 2022.

With us today for 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 mid and later stage clinical pipeline.

Our Chief Medical Officer, who will provide an update on our mid and later stage clinical pipeline Dr. James Hamilton, Our senior Vice President Discovery, and translational medicine, who will provide an update on our earlier stage programs and Ken Moskovsky, Our Chief Financial Officer, who will give her.

Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, who will provide an update on our earlier stage programs.

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

In addition, Tracy Oliver, our newly appointed, Chief Commercial Officer, and Patrick O'Brien, who was recently promoted to Chief Operating, Officer and General Counsel, will both be available during the Q&A portion of the call.

A review of the financials. In addition, Traci Oliver our newly appointed Chief Commercial Officer, and Patrick O'brien, who was recently promoted to Chief operating Officer, and General Counsel will both be available during the Q&A portion of the call.

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

We began I would like to remind you that comments made during today's call contains certain forward looking statements within the meaning of section 27 a of.

Of the Securities Act of 1933 and section 21 E of the Securities Exchange Act of 1934, all statements other than statements of historical fact are forward looking statements and are subject to numerous risks and uncertainties that could cause actual results to mature to differ materially from those expressed in any form.

All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements.

We're looking statements for further details concerning these risks and uncertainties. Please refer to our SEC filings, including our most recent annual annual report on Form 10-K, and our quarterly reports on Form 10-Q with that.

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 our quarterly reports on Form 10-Q.

That said I'd like to turn the call over to Christopher Anzalone, President and CEO of the company Chris.

With that said, I'd like to turn the call over to Christopher Anzalone, President and CEO of the company.

Chris?

Thanks Vince.

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

Thanks, Vince.

Before I cover key events and progress during the previous quarter I wanted to talk about some recent management additions that make us a stronger company today and importantly, as we grow into a vertically integrated commercial stage pharmaceutical company.

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

We are currently conducting one phase III study for our wholly owned drug candidates and I expect us to begin one or two additional phase III studies next year as such they are important strategic decisions, we need to begin considering that will affect how we ultimately commercialize. These drug candidates. We are thrilled to welcome Tracy Oliver as our Chief commercial officer to start to build out.

Before I cover key events and progress during the previous quarter, I want to talk about some recent, management additions that make us a stronger company today and, importantly, as we grow into a vertically integrated commercial-stage pharmaceutical company.

We are currently conducting one Phase 3 study for a wholly-owned drug candidate, and I expect us to begin one or two additional Phase 3 studies next year. As such, there are important strategic decisions we need to begin considering that will affect how we ultimately commercialize these drug candidates.

Our commercial infrastructure and more immediately contribute to the planning of our late stage programs to ensure that our future commercial requirements are harmonized with clinical datasets and ultimate drug labels.

We are thrilled to welcome Tracy Oliver as our Chief Commercial Officer to start to build out, our commercial infrastructure and, more immediately, contribute to the planning of our late-stage programs to ensure that our future commercial requirements are harmonized with clinical data sets and ultimate drug labels.

He has over 30 years of global experience in the biopharmaceutical industry lead in both R&D and commercial organizations.

Tracy has over 30 years of global experience in the biopharmaceutical industry, leading both R&D and commercial organizations. Prior to joining Arrowhead, she had her own consulting practice focused on providing guidance, to small, emerging commercial-stage biotech companies on the proper strategy, timelines, methods, and ultimately the build-out of new commercial organizations. Those skills and experience are critical to Arrowhead as we look to take the next steps in our growth as a company. Prior to her consulting business, Tracy was with Shire Pharmaceuticals through the acquisition, of Baxalta and was global head of new product planning and device strategy. Prior to that, she held several commercial roles at Baxter and Baxalta, including establishing, a new oncology franchise and leading the North America Immunology Business Unit and autoimmune franchise.

Prior to joining arrowhead she had her own consulting practice focused on providing guidance to small emerging commercial stage biotech companies on the proper strategy timelines methods and ultimately the build out of new commercial organizations those skills and experience are critical to arrowhead as we look to take the next steps in our growth as a company.

Prior to her consulting business Tracy was with Shire pharmaceuticals through the acquisition of Baxalta and was global head of the new product planning and device strategy.

Prior to that she held several commercial roles at Baxter, and Baxalta, including establishing a new oncology franchise and leading the North America immunology business units and autoimmune franchise.

Tracy began her career in the biopharmaceutical industry with Johnson & Johnson and served, as head of Ortho Biotech Nephrology Business Unit in Canada, Ortho McNeil Neurologics and, McNeil Pediatrics in the USA.

She began her career in the biopharmaceutical industry with Johnson <unk> Johnson and served as head of Ortho biotech Nephrology business unit in Canada, Ortho Mcneil neurologic and Mcneil pediatrics in the USA.

As we continue this type of growth in personnel and departments, we need to be more deliberate, in our drives to continue operational excellence.

As we continue this type of growth in personnel. It departments, we need to be more deliberate in our drive to continue operational excellence.

There can be a tendency toward an inverse relationship between the size of an organization, and its ability to operate efficiently, creatively, and rapidly. It is important to us that we maintain our operational excellence as we grow, and Patrick, O'Brien, our General Counsel, will now also take on the role of Chief Operating Officer to help ensure this.

It can be a tendency toward an inverse relationship between the size of an organization and its ability to operate efficiently creatively and rapidly. It is important to us that we maintain our operational excellence as we grow and Patrick O'brien, Our general counsel.

Now also take on the role of Chief Robb, Chief operating officer to help ensure this.

I'll now move on to review some of our recent progress.

I will now move on to review some of our recent progress.

We view setbacks as a normal part of innovation and if we can learn something from them. They may serve as an investment in the future.

We view setbacks as a normal part of innovation, and if we can learn something from them, they, may serve as an investment in the future.

The recent progress we've made in our pulmonary platform is a good example of this and a powerful, illustration of how fast Arrowhead can move. As you know, our first candidate in the clinic using the pulmonary targeted trim platform, was Arrow-ENAC for the treatment of cystic fibrosis. Last year, we decided to pause enrollment in the Arrow-ENAC first in human clinical, study as we further investigated some findings from a non-clinical toxicology study that suggested some local lung inflammation after chronic treatment at certain high doses.

The recent progress we've made in our pulmonary platform is a good example of this and a powerful illustration of how fast arrowhead can move.

As you know our first candidate in the clinic using the pulmonary targeted trim platform was <unk> for the treatment of cystic fibrosis.

Last year, we decided to pause enrollment in the <unk> first in human clinical study as we further investigated some findings from a non clinical toxicology study that suggested some local lung inflammation after chronic treatment at certain high doses.

Many open questions remained. James will speak to what we learned in more detail later in the call, but after extensive, investigation, consultation with internal and external toxicology experts, and additional studies, it appears that findings were consistent with what is called lung macrophage overload. Essentially, the volume of material, not necessarily the specific drug or target, was swamping the, lung's clearance mechanisms and causing an inflammatory response.

Any open questions remained.

James will speak to what we learned in more detail later in the call, but after extensive investigation consultation with internal and external toxicology experts and additional studies. It appears that findings were consistent with what is called lung macrophage overload.

Essentially the volume of material not necessarily especially in a drug or target with swamping the lungs clearance mechanisms and causes an inflammatory response, so the clear way to move forward is to understand the amount of material that triggers this phenomenon and develop more potent longer acting candidates to stay below the assumed accumulative dose threshold.

So the clear way to move forward is to understand the amount of material that triggers this, phenomenon and develop more potent, longer-acting candidates to stay below the assumed cumulative dose threshold. I believe we have done that for our next generation candidates, Arrow-RAGE and Arrow-MUC5AC, resulting, in three important improvements. First, we think we can now achieve better knockdown with less exposure. Second, we think we can give a single dose as opposed to our previous need to dose on, three consecutive days.

I believe we have done that for our next generation candidates Aero Rage and era marked by basi, resulting in three important improvements.

Burst.

First we think we can now achieve better knockdown with less exposure second we think we can give a single dose as opposed to our previous need to dose three consecutive days.

And third, we believe we can now stretch the dose interval substantially. For example, Arrow-ENAC was going to be dosed three times, I'm sorry, three times every, two or three weeks, and Arrow-RAGE has duration that potentially lasts multiple months after a single dose.

Third we believe we can now stretch the dose interval substantially for example, <unk> was going to be dosed three times I'm, sorry, three times every two or three weeks and Aero rage has duration that potentially last multiple months after a single dose.

Each of these improvements are important on their own, but together, we believe they dramatically, change the profile of our next generation pulmonary candidates.

Each of these improvements are important on their own but together, we believe they dramatically changed the profile of our next generation pulmonary candidates.

So where are we now.

Where are we now?

The work and lessons that went into this happened over an extended period, culminating this, quarter, this last quarter, in two important events. We held a pulmonary R&D day to go over our findings and present non-clinical data from, our next generation candidates, Arrow-RAGE and Arrow-MUC5AC. And then shortly after, we began dosing patients in two clinical studies.

The work and lessons that went into this happened over an extended period, culminating this quarter in this last quarter and two important events.

We held the pulmonary R&D day to go over our findings and present non clinical data from our next generation candidates Arrow Rage and Euro block five AC and then shortly after we began dosing patients in two clinical studies.

As I said, I think this is a great example of what Arrowhead is capable of.

As I said I think this is a great example of what Arrowhead is capable of we went from pausing enrollment of the <unk> clinical program to initiating clinical studies and dosing human subjects with next generation candidates that potentially have dramatically improved profiles in about 12 months.

We went from pausing enrollment of the Arrow-ENAC clinical program to initiating clinical studies, and dosing human subjects with next-generation candidates that potentially have dramatically improved profiles in about 12 months. There was an enormous amount of work, thought, creativity, technology, and innovation that, enabled this result.

There was an enormous amount of work thoughts creativity technology and innovations that enable this result, the pulmonary trim platform is an important expansion of our technology that we expect will help a large number of patients and create a substantial amount of value, but it is just one example of how we are growing our platform. We expect many more going forward.

The pulmonary trim platform is an important expansion of our technology that we expect, will help a large number of patients and create a substantial amount of value, but it is just one example of how we are growing our platform.

We expect many more going forward.

Another set of key accomplishments during the quarter related to execution on our later stage programs for our cardio metabolic candidates Arrow, Apoc, III and Arrow and story.

Another set of key accomplishments during the quarter relate to execution on our later, stage programs for our cardiometabolic candidates, Arrow ApoC3 and Arrow ANZ3. Between the two candidates, we have five active clinical studies that range from ultra-rare, disease populations to high-prevalence diseases. The design and execution of clinical studies for diseases on opposite ends of the size, spectrum typically have different tactics and require specialized expertise.

Between the two candidates we have five active clinical studies that range from ultra rare disease populations to high prevalence diseases.

<unk> execution of clinical studies for disease for diseases on opposite ends of the size spectrum typically have different tactics and require specialized expertise.

I'm happy to report that our clinical development and clinical operations teams have been successfully, running all of these studies.

P to report that our clinical development and clinical operations teams have been successfully running all of these studies.

On the rare disease side, the phase three Palisade study of Arrow ApoC3 in patients, with FCS is efficiently enrolling patients, and we have worked hard during the quarter to identify and open new countries and sites that should contribute to rapid enrollment of the study.

On the rare disease side, the phase III palisade study of Aero Apoc, III and patients with FCS is efficiently enrolling patients and we have worked hard during the quarter to identify and open new countries and sites that should contribute to rapid enrollment of the study.

In addition, during the quarter, we initiated the phase two gateway study of Arrow ANZ3, in patients with HOFH. This study is also enrolling patients efficiently, and we look forward to seeing data in the, future.

In addition, during the quarter, we initiated the phase III Gateway study of <unk> three in patients with <unk>.

Study is also enrolling patients sufficiently and we look forward to seeing data in the future.

On the high-prevalence disease side, we have three ongoing studies. For Arrow ApoC3, we are running the Shasta 2 phase two study in patients with severe, hypertriglyceridemia and the Muir phase two study in patients with mixed dyslipidemia. We have executed well on both studies, and we believe we are on schedule for readouts, in both studies in 2023. In fact, we recently reached total planned enrollment for Muir.

And the high prevalence disease side, we have three ongoing studies for <unk>. Three we are writing the shafts two phase III study in patients with severe hypercholesterolemia and the mirror phase two study in patients with mixed dyslipidemia.

We have executed well on both studies and we believe we are on schedule for Readouts in both studies in 2023 and in fact, we recently reached total planned enrollment from Europe .

For Arrow and three there is one high prevalence disease study the phase III arches, two study in patients with mixed dyslipidemia.

For Arrow ANZ3, there is one high-prevalence disease study, the phase two Arches 2 study, in patients with mixed dyslipidemia. This study was fully enrolled earlier in the year and should be complete at the end of, the year and enable a readout in the first half of next year.

This study was fully enrolled earlier in the year and should be complete at the end of the year and enable a readout in the first half of next year.

The other two accomplishments.

The other two accomplishments from the recent quarter that I want to highlight are related, to corporate goals that aim to maximize the value of our technology over the long term. First, we announced that we broke ground on the construction of a new commercial-scale, manufacturing facility and received awards of up to $18.5 million in incentives to invest in the local region and create new jobs. This is an important investment in Arrowhead's future as a vertically-integrated commercial, stage pharmaceutical company.

From the recent quarter that I want to highlight are related to corporate goals that aim to maximize the value of our technology over the long term first we announced that we broke ground on the construction of a new commercial scale manufacturing facility and received upwards.

The awards of up to $18 $5 million in incentives to invest in the local region and create new jobs. This is an important investment to narrow its future as a vertically integrated <unk>.

<unk> stage pharmaceutical company it helps us control of the manufacturing process, both operationally and strategically for our wholly owned programs and potentially for our partner programs in the future potentially.

It helps us control the manufacturing process, both operationally and strategically, for, our wholly-owned programs and potentially for our partner programs in the future. It potentially reduces the cost of our clinical and commercial drug supply and importantly, helps eliminate any future bottlenecks related to drug manufacturing.

It potentially reduces the cost of our clinical and commercial drug supply and importantly helps eliminate any future bottlenecks related to drug manufacturing.

Lastly, related to corporate goals during the last quarter, we also announced that Arrowhead, formed Vicerna Therapeutics, a joint venture with Vivo Capital, in which Arrowhead is a majority shareholder, to expand the reach of innovative medicines in greater China. Arrowhead licensed four investigational RNAi therapeutics to Vicerna for cardiometabolic, diseases in mainland China, Hong Kong, Macau, and Taiwan. Vivo Capital provided $60 million in initial funding to Vicerna.

Lastly related to corporate goals during the last quarter. We also announced an arrowhead formed by sirna Therapeutics, a joint venture with vivo capital and which arrowhead as a majority shareholder to expand the reach of innovative medicines in greater China Arrowhead.

Arrowhead license for investigational <unk> therapeutics to buy sirna for cardio metabolic diseases in mainland, China, Hong Kong, Macau, and Taiwan vivo capital provided $60 million in initial funding device arena. This transaction potentially allows us to expand our reach into geographies that are beyond our core focus while retaining a substantial economic interest.

This transaction potentially allows us to expand our reach into geographies that are, So in summary, Arrowhead had a productive quarter where we saw progress in our pipeline of industry-leading RNAi therapeutics, our wide-reaching and expanding TRMM technology platform, and our corporate goals.

So in summary, Arrowhead had a productive quarter, where we saw progress in our pipeline of industry, leading RNA therapeutics, our wide, reaching an expanding trim technology platform and our corporate goals.

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

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

Javier?

Thank you, Chris, and good afternoon, everyone.

Thank you Kris and good afternoon, everyone.

First, I want to highlight data on the Phase 2, 2002 study of Fasirzidane, formerly called, Arrow AAT and TAC999, presented in July at the E-Cell International Liver Congress and published simultaneously in the New England Journal of Medicine. The presentation generated significant enthusiasm within the audience, welcoming positive data, to address the liver disease with no approved therapy and the validation of a New England publication.

I wanted to highlight data on the phase two 2002 study of <unk>, formerly called <unk> and Pac 99, 9% in July on the ECL International liver Congress and published simultaneously in the New England Journal of Medicine.

Patient generate the significant emphasis within the audience coming positive data to address in liver disease with no approved therapy and the validation of publication.

Fasirzidane is a potential first-in-class investigational RNAi therapy designed to reduce, production of a mutant form of alpha-1-antithrazine protein, called Z-AAT, as a potential treatment for the rare genetic liver disease associated with alpha-1-antithrazine deficiency. Z-AAT accumulation is believed to be the cause of progressive liver disease in patients with, AAT deficiency. Reducing production of pro-inflammatory Z-AAT protein has the potential to halt the progression, of liver disease and potentially allow the liver to regenerate and repair.

If you've seen any potential first in class investigation.

I decided to leave us.

One of the mutant form of Alpha one antitrypsin protein called Z AAP.

As a potential treatment for the rare genetic liver disease associated with Alpha one antitrypsin deficiency.

Efficiency.

The AAP accumulation, if you need to be because of progressive liver disease in patients with <unk> deficiency.

<unk> seen production of low inflammatory <unk> has the potential to hold the population of <unk> potentially allow the liver to regenerate and repair.

The data from this program are exciting and encouraging.

The data from this program at exciting and encourage.

The open-label Arrow AAT, 2002 Phase 2 study in 16 patients with AATD liver disease suggests, a strong effect and the potential to improve multiple downstream markers of liver health. Decreasing fibrosis severity of at least one stage occurred in 7 of 12 patients, or 58%, receiving the 200 milligram dose, including 2 patients with cirrhosis. All patients had reduction in accumulated total mutant Z-AAT in the liver with a median, reduction at week 24, or 48, of 83%.

The open label 882002 phase two study in <unk> patients with <unk> disease.

Strong effect and the potential to into multiple balance seen Microsoft Libre health.

Leasing fibrosis severity of at least one stage of growth in seven of 12 patients or 58%, receiving the 200 milligram dose, including two patients with cirrhosis.

All patients had reduction in accumulated total Newton the AAP in the Liberty with immediate dilution at week 24, or 48 of 83%.

Reductions in liver Z-AAT concentration were also associated with histological improvement, in inflammation. After treatment, all patients had a decreased histological global burden with a mean score, decreasing by 69% at week 24, or 48. Biomarkers of liver injury were also reduced.

The reductions in liver Z concentration was also associated with histological improvement in inflammation. After treatment all patients have a decreased histologically global burden with a mean score of decreasing by 69% at week two.

24 or 48.

Hello markers of liver injury would also reduce our baseline mean allt concentrations above the upper limit of normal range in all cohorts after treatment A&P concentration decreased in alcohol from week 16 to week 52.

At baseline, mean ALT concentrations were above the upper limit of normal range in all, cohorts. After treatment, ALT concentration decreased in all cohorts from week 16 through week 52. All 12 patients with ALT concentration above the upper limit of the normal range at baseline, had reduction to normal level at week 52.

All 12 patients with A&P concentration above the upper limit of the normal range at baseline.

To normal levels at week 52.

In addition to activity and efficacy measures, safety and tolerability measures continue, to be encouraged.

In addition to activity and efficacy measures and safety and Tolerability measures continue to be encouraged a CFC that was generally well tolerated in the 2002 study.

Fasciocinan was generally well-tolerated in the 2002 study. Over a period of 1.5 years, there were no deaths, discontinuation of treatment with fasciocinan, or dose interruptions. The most common adverse events that emerged or worsened after the first administration, of fasciocinan were atralgia and transient increased concentration of laucreatine kinase. There were no apparent dose-dependent increases in the frequency or severity of adverse events. So far, there have been no major pulmonary adverse events resulting in drug or trial discontinuation.

Okay.

One five yes. It we're not this is combination of treatment with CST, then or dose interruptions.

Common adverse event, then emerge or worse and in after the first administration of assisting them. We're at a place yet and pension increase concentration of Lal creatine kinase.

There were no ethane dose dependent increases in the frequency or severity of adverse events.

So far there have been no major pulmonary adverse events with opening they're all trial discontinuation photo of the six patients who entered the trial with receiving <unk> patient therapy had a history of emphysema.

Four of the six patients who entered the trial while receiving AAT augmentation therapy had, a history of emphysema and non-reported exacerbations.

Known reported access innovation.

PASIR-SIREN Phase 2 Placebo-Controlled Sequoia Study has also reached the end of the treatment period. We collected the final 12-month biopsy from the final patient recently and will now be, processing samples and analyzing data over the coming months.

<unk> phase II placebo controlled Sequoia study has also reached the end of the treatment period, we collected the final 12 months biopsy from the final patient increase simply.

We know now be processing persistent samples and analyzing data over the coming months.

The deadline is in September to submit a label to present at the ASLD liver meeting in November.

Did they let that they've learned is in September to submit a late breaker, 2% okay.

So the liver meeting in November .

The timing will be tight to have enough data to justify a late break, so it is a low probability, that we will be presenting data at that congress.

The timing will be tight to have enough data to justify a late break. So it is a low probability that we will be presenting data at that Congress. We shoot however, hasnt rather complete late this season Sequoia in the fourth quarter of this year, So we and our partner Takeda will together to determine if this way.

We should, however, have a rather complete data set on sequoia in the fourth quarter, of this year, so we and our partner at Takeda will together determine the best way to communicate those results publicly.

Communicate those publicly.

I think I've been starting with the phase III study, we and Takeda and in the process of having discussions with regulators under development path.

Regarding the status of the Phase 3 study, we and Takeda are in the process of having, discussions with regulators on the development path.

We do not want to comment specifically on those discussions as they are ongoing.

We do not want to comment specifically on those discussion.

Yeah.

Moving on to our cardiometabolic candidates, I will provide the status of the VISTA studies, of AROH3 and the SAMHIT studies of AROH-APOC3. The VISTA program of AROH3, our investigational medicine designed to reduce production of, angiopoietin-like protein 3 as a potential treatment for patients with dyslipidemia, has two ongoing studies. The first, ARDS2, in 2004 patients with mixed dyslipidemia is fully enrolled. We anticipate that the ARDS2 will be complete around the end of 2022 and top-line data, will be available to share in the first half of 2023. In addition to the planned study period, patients will be eligible to continue in an open-label, extension period after completing the week 36-36.

Moving on to our cardio metabolic candidates, we provide the status of these two studies of <unk> and <unk> studies.

<unk>.

The Vista program of <unk>, our investigational medicine designed to reduce production of Angiopoietin like protein three as a potential treatment for patients with Dyslipidemia has two ongoing studies.

<unk>.

Two in 2000 and for patients with mixed Dyslipidemia is fully enrolled we anticipate that they are just too will be complete around the end of 2022 and top line data would be available to share in the first half of 2023.

In addition to the planned study period patients will be eligible to continue in.

Open label extension period after completing the week 36.

Let's take one at the study of <unk> Gateway and up to 16, subsea with homozygous familial hypercholesterolemia or HOS H, we anticipate that this study would be fully enrolled.

The second active study of AROH3 is GATEWAY and up to 16 subjects with homozygous familial, hypercholesterolemia, or HOFH.

We anticipate that this study will be fully enrolled by the end of the year, and we intend, to share the data in 2023 when possible.

End of the year and we intend to show that data in 2023 wind policy.

Moving on to AROH-APOC3, SAMHIT program of AROH-APOC3, our investigational medicine targeting, Apo-Lipoprotein C3 being studied in patients with various lipid disorders has three ongoing studies. Two phase two studies, SHASTA2 in patients with severe hypertriglyceridemia, or SHTG, or MUIR and MUIR in patients with mixed dyslipidemia, and the phase three PALACE study in patients with familial chelomeconemial syndrome, or FCS.

Moving onto <unk> family program or <unk>, our investigational medicine targeting apolipoprotein <unk> being studied in basically with various lipid disorders as three ongoing studies two phase II studies chest two in patients with severe hypercholesterolemia.

SHT CTG or mute.

Our new inpatient with mixed Dyslipidemia and the phase III palisade study in patients with familial <unk> syndrome or Fcs.

MUIR has now reached the total planned enrollment of 320 patients. We have a number of patients still in screening, so we will allow some additional patients, to join the study, but are not screening any new patients.

<unk> has now reached a total enrollment of 320 patients we have a number of patients seen in screening. So we will allow us some additional patients to join this study by that.

I've noticed any new patients chest that do have some grow over 80% of the planned number of patients and we anticipate full enrollment. This year. This will allow for both studies to be completed in 2020.

Shasta II has enrolled over 80% of the planned number of patients and we anticipate full enrollment, this year. This will allow for both studies to be completed in 2023.

Palisades is planned to enroll approximately 72 patients with SCS.

Let's face is planned to enroll approximately 72 patients with FCS we continue to open new clinical sites around the world and enroll new patients into the study.

We continue to open new clinical sites around the world and enroll new patients into the, study.

We are still on schedule and anticipate that Palisades will reach full enrollment in the, middle of 2023, which would allow for study completion in 2024.

Still on schedule and anticipate the Palisades will reach full enrollment in the middle of 'twenty two.

Which would allow for study completion in 2024.

I will now turn the call over to Dr. James Hamilton.

I will now turn the call over to vote or change coming from James.

James.

Thank you, Javier.

Thank you Javier.

Some updates on some of our earlier stage development programs.

Some updates on some of our earlier stage development programs.

Let's start with the pulmonary platform. As Chris mentioned, we hosted an R&D day on our emerging pipeline of pulmonary targeted, RNAi therapeutics and the technology platform that these candidates are built on. We have learned a great deal about the platform with details provided in the archived pulmonary, R&D day webcast available on our website. In summary, we believe that we now have improved siRNA triggers with longer pharmacodynamic, duration, allowing less frequent dose administration, which are less likely to overload lung clearance mechanisms and are less likely to induce pulmonary inflammation.

Start with the pulmonary platform.

Chris mentioned, we hosted an R&D day on our emerging pipeline of pulmonary targeted RNA therapeutics in this technology platform that these candidates are built upon.

We have learned a great deal about the platform with details provided in the archived pulmonary R&D day webcast available on our website.

In summary, we believe that we now have improved S irony triggers with longer pharmacodynamic duration, allowing less frequent dose administration, which are less likely to overload lung clearance mechanisms and are less likely to induce pulmonary inflammation.

This gives us increased confidence in the platform as we move forward with current and, planned future clinical studies and additional toxicology studies.

This gives us increased confidence in the platform as we move forward with current and planned future clinical studies and additional toxicology studies.

We also presented preclinical data on the development of our next generation pulmonary candidates Aero multiply they see an arrow rage, which has recently begun dosing in clinical studies and Aero MMP, seven which will be approaching clinical studies later this year.

We also presented preclinical data on the development of our next generation pulmonary, candidates, AeroMUK5AC and AeroRAGE, which have recently begun dosing in clinical studies and AeroMMP7, which will be approaching clinical studies later this year. AeroMUK5AC is the first investigational medicine to directly silence expression, of pathologic MUK5AC, a mucin protein with upregulated expression in the asthmatic airway and potentially address mucoobstructive disease characterized by mucus hypersecretion in a fundamentally different way than current therapies. Preclinical results have shown deep silencing of up to 70 to 90% of induced MUK5AC expression in mice and primates. In a sheep model of allergic asthma, AeroMUK5AC effectively preserved airway function.

Everyone must buy they see is the first investigational medicine to directly silence expression of pathologic multiply they see a mucin protein with up regulated expression in the asthmatic airway and potentially address nuclear obstructive disease characterized by mucus hyper secretion in a fundamentally different.

He then current therapies.

Preclinical results have shown deep silencing of up to 70% to 90% of induced marked by they see expression in mice and primates.

Sheep model of allergic asthma era.

He effectively preserve airway function.

Yeah.

<unk> is an investigational medicine designed to reduce expression the receptor for advanced location and products that aims to achieve broader anti inflammatory effects compared to current biologics and with a more convenient inhaled mode of administration.

AeroRAGE is an investigational medicine designed to reduce expression of the receptor, for advanced glycation end products that aims to achieve broader anti-inflammatory effects compared to current biologics and with a more convenient inhaled mode of administration. Preclinical studies have shown that single inhaled doses of AeroRAGE in rats, and primates led to reductions of greater than 90% in lung RAGE mRNA and in serum SRAGE protein, a circulating biomarker for RAGE target engagement in the lung.

Preclinical studies have shown that single inhaled doses of <unk>.

<unk> and rats, and primates led to reductions in greater than 90% in long rage mrna and then serum <unk> protein circulating biomarker, who reached target engagement in the lung.

Chromicodynamic response appears to be highly durable, enabling bimonthly or quarterly dosing.

Pharmacodynamic response appears to be highly durable, enabling bi monthly or quarterly dosing.

Earlier this month, we announced that we dosed the first subjects in.

Earlier this month, we announced that we had dosed the first subjects, in phase 1, 2A clinical trials of both AeroMUK5AC and AeroRAGE. We have since completed dosing the first cohort of healthy volunteers in both studies. Both studies have three parts consisting of single ascending and multiple ascending doses, in normal healthy volunteers and multiple dose cohorts in asthma patients with dose levels selected for patient cohorts based on data from normal healthy volunteer cohorts.

Phase <unk> clinical trials of both Aero.

And Aero Rich we have.

Since completed dosing the first cohort of healthy volunteers in both studies. Both studies have three parts consisting of single ascending and multiple ascending doses in normal healthy volunteers and multiple dose cohorts in asthma patients with dose level selected for patient cohorts based on data from normal healthy.

And to your goals.

The third pulmonary program we discussed at the R&D day is Arrow MMP7, our newest and, previously undisclosed candidate designed to reduce expression of matrix metalloprotein, A7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF. MMP7 plays multiple roles in IPF pathogenesis, including promoting inflammation and aberrant, epithelial repair in fibrosis, silencing MMP7 expression in a rat IPF model-reduced inflammatory cell infiltration, limited lung fibrosis, and preserved pulmonary function.

The third pulmonary program, we discussed at the R&D day is arrow MMP seven our newest and previously undisclosed candidate designed to reduce expression of matrix Matala protein 87 core MMP seven as a potential treatment for idiopathic pulmonary fibrosis or IPF.

MMP seven plays multiple roles in IPF, pathogenesis, including promoting inflammation and Abilene epithelioid repair and fibrosis.

Silencing <unk> seven expression in a rat IPF model reduced inflammatory cell infiltration limited lung fibrosis and preserve pulmonary function.

We're conducting CTA-enabling work and preparation now, and we are on track to file this year, to initiate first-in-human clinical studies.

We are conducting Cta, enabling work and preparation now and we are on track to file this year to initiate first in human clinical studies.

Alaska early stage clinical program is <unk> three our investigational RNA therapeutic designed to reduce production of complement component three or <unk> three as a potential therapy for various complement mediated diseases.

Our last early-stage clinical program is Arrow C3, our investigational RNAi therapeutic, designed to reduce production of complement component 3, or C3, as a potential therapy for various complement-mediated diseases. We are approaching the final healthy volunteer cohort in Part 1 of a Phase 1-2 study. Data from Part 1 will inform dose selection for Part 2, which will include eligible subjects, with paroxysmal nocturnal hemoglobinuria, or PNH, and complement-mediated renal diseases, including IgA nephropathy and C3 glomerulopathy.

We are approaching the final healthy volunteer cohort in part one of our phase one two study.

From part one will inform dose selection for part two which will include eligible subjects with paroxysmal nocturnal hemoglobinuria or <unk> and complement mediated of renal diseases, including Iga nephropathy and C III commercial apathy.

We anticipate that Part 2 of the study will start before the end of the year.

Anticipate that part two of the study will start before the end of the year.

I will now turn the call over to Ken Muskowski.

I will now turn the call over to Ken Moskovsky Ken.

Ken?

Thank you, James, and good afternoon, everyone.

Thank you James and good afternoon, everyone.

As we reported today, our net loss for the three months ended June 30, 2022, with 72 million, or 68 cents per share, based on 105.8 million fully diluted weighted average shares outstanding. This compares with a net loss of 29.9 million, or 29 cents per share, based on 104.1 million fully diluted weighted average shares outstanding for the three months ended June 30, 2021.

As we reported today, our net loss for the three months ended June 32022 was 72 million or <unk> 68 per share based on 105 eight.

Fully diluted excuse me fully diluted weighted average shares outstanding.

This compares with a net loss of $29 9 million or <unk> 29 per share based on $104 1 million fully diluted weighted average shares outstanding for the three months ended June 32021.

Revenue for the quarter ended June 32022 was $32 4 million compared to $45 9 million for the quarter ended June 32021.

Revenue for the quarter ended June 30, 2022, was 32.4 million, compared to 45.9 million for the quarter ended June 30, 2021. Revenue in the current period primarily relates, to our collaboration agreements with Takeda and Horizon. Revenue will be recognized as we complete our performance obligations, which include managing the ongoing AAT Phase 2 clinical trials for Takeda, and delivering a Phase 1 ready candidate to Horizon. There remains 142.1 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate will be recognized over approximately two years. And there remains 13 million of revenue to be recognized for Horizon, which we anticipate will be recognized by the end of calendar 2022.

Revenue in the current period, primarily relates to our collaboration agreements with Takeda in horizon.

Revenue will be recognized as we complete our performance obligations, which include managing the ongoing a phase II clinical trials for Takeda and delivering a phase one ready candidates to horizon.

There remains $142 $1 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate will be recognized over approximately two years.

And there remains $13 million of revenue to be recognized for horizon, which we anticipate will be recognized by the end of calendar 2022.

Revenue in the prior period, primarily.

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 and Takeda.

Related to the recognition of a portion of the milestones received from our license and collaboration agreements with Janssen and Takeda.

Total operating expenses for the quarter ended June 32022, or $105 3 million compared to $77 8 million for the quarter ended June 32021.

Total operating expenses for the quarter ended June 30, 2022, were 105.3 million, compared to 77.8 million for the quarter ended June 30, 2021. This increase is driven by higher employee compensation expense, including stock compensation, expense, as well as higher R&D discovery expense.

This increase was driven by higher employee compensation expense, including stock compensation expense as well as higher R&D discovery expense.

Net cash used by operating activities. During the quarter ended June 32022 was $68 9 million compared with net cash used by operating activities of $29 6 million for the quarter ended June 32021.

Net cash used by operating activities during the quarter ended June 30, 2022, was $68.9, million, compared with net cash used by operating activities of $29.6 million for the quarter ended June 30, 2021.

The increase in cash used by operating activities is driven by higher expenses.

And research and development.

The increase in cash used by operating activities is driven by higher expenses in research and, development, and we expect our operating cash burn to be $70 to $80 million next quarter, and I will provide additional guidance during our year-end conference call.

And we expect our operating cash burn to be 70 to 80 million next quarter and I will provide additional guidance during our year end conference call.

Turning to our balance sheet, our cash and investments totaled $582.4 million at June, 30, 2022, compared to $613.4 million at September 30, 2021. The decrease in our cash and investments was primarily due to cash used for operating activities, mostly offset by cash inflows from GSK, and the cash investment in our joint venture Viserna.

Turning to our balance sheet, our cash and investments totaled $582 4 million at June 32022, compared to $613 4 million at September 32021.

The decrease in our cash and investments was primarily due to cash used for operating activities, mostly offset by cash inflows from GSK and the cash investment in our joint venture by Cerner.

Our common shares outstanding at June 30, 2022, were $105.8 million.

Our common shares outstanding at June 32020 to $105 8 million.

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

That's our brief overview.

I will now turn the call back to Chris.

Thanks, Ken.

Thanks, Ken.

We have a large and growing pipeline of clinical drug candidates, providing us with the opportunity, to help millions of patients and create a substantial amount of value.

We have a large and growing pipeline of clinical drug candidates, providing us with the opportunity to help millions of patients and create a substantial amount of value.

It also affords us the opportunity to regularly report clinical data so stakeholders can follow, our progress.

It also affords us the opportunity to irregular route reported clinical data so stakeholders can follow our progress however.

However, with the development of next-generation pulmonary candidates and timing of other studies, we have been in a bit of a data desert over the last several quarters.

However, with the development of next generation pulmonary candidates and timing of other studies, we have been in a bit of a data desert over the last several quarters. We are now emerging from that desert between.

We are now emerging from that desert.

Between now and the end of next year, I expect at least 12 clinical readouts between our, wholly-owned and partnered programs.

Between now and the end of next year I expect at least 12 clinical readouts between our wholly owned and partnered programs.

They include the following.

Include the following.

One, biopsy data from the Sequoia study in AAT with Viseran.

One biopsy data from the Sequoia study in <unk> with visits are in two phase one two data from <unk> three in healthy volunteers and different patient populations.

Two, phase 1-2 data from Aero C3 and Healthy Volunteers and different patient populations.

Three, phase 1-2 data from Aero RAGE and Healthy Volunteers and Patients.

<unk> phase one two data from Arrow rage in healthy volunteers and patients.

Four, phase 1-2 data from Aero MUC5AC and Healthy Volunteers and Patients.

For phase one two data from <unk> in healthy volunteers and patients.

Five, phase 2 data from Opasaran in Amgen's LP little a study.

<unk> phase II data from El Paso ran in Amgen's L. P Little a study.

Six, phase 2 data from the Aero ANG3 Arches 2 study in mixed dyslipidemia.

Six phase III data from the Arrow and three arches two study in mixed Dyslipidemia.

Seven, phase 2 data from the Aero ANG3 gateway study in HOFH.

<unk> phase II data from the Arrow Ams three gateway study in H O F H.

Eight, phase 2 data from the Aero APOC3 Muir study in mixed dyslipidemia.

Eight phase III data from the Arrow Apoc III Muir study in mixed Dyslipidemia.

Nine, phase 2 data from the Aero APOC3 Shasta 2 study in severe hypertriglyceridemia.

Nine phase III data from the Arrow Apoc III shaft, two study in severe hypertrophy glyceride email.

10, phase 1 data from Aero MMP7 and Healthy Volunteers and possibly IPF patients.

Ken Phase one data from Arrow MMP seven in healthy volunteers and possibly IPF patients.

11, phase 2 data from various Janssen studies of J&J 3989 in HPV patients.

11 phase II data from various Janssen studies of J&J 39, 89% in HBV patients and 12 phase one data from Janssen as Nash study with J&J zero 795.

And 12, phase 1 data from Janssen's NASH study with J&J 0795.

We are excited about these and other programs and look forward to updating you on our progress.

We are excited about these and other programs and look forward to updating you on our progress. Thank you for joining us today and I would now like to open the call to your questions operator.

Thank you for joining us today and I would now like to open the call to your questions.

Operator.

We will now begin question and answer.

We will now begin the question and answer session.

You May press Star then one on your telephone keypad.

You may press star then 1 on your telephone keypad.

If youre using a speakerphone, please pick up the handset before pressing the keys.

If you are using a speakerphone, please pick up the handset before pressing the keys.

To withdraw your question, please press star then 2.

To withdraw your question. Please press Star then two.

For each participant, please limit yourself to one question.

Core each participant please limit yourself to one question.

At this time, we will pause momentarily to assemble our roster.

At this time, we will pause momentarily to assemble our roster.

Our first question comes from Luca Issi with RBC.

Our first question comes from Luca <unk> with RBC. Please go ahead.

Please go ahead.

Oh, great.

Oh, great. Thanks, so much for taking my questions I have two quick ones, maybe one Javier I mean congrats.

Thanks so much for taking my questions.

I have two quick ones.

Maybe one, Javier.

I mean, congrats on publishing, obviously, the New England Journal of Medicine.

Congrats on publishing obviously, the new England Journal of Medicine, I think the 100 milligram dose in the 200 milligram dose have essentially high frame possible PD curves in the serum. However, it improvement in fibrosis only occurred in high dose and not in the low dose. So just wondering what's the best way to rationalize that difference and then maybe quickly on the cash position.

You know, I think the 100-milligram dose and the 200-milligram dose have essentially, hyperimposable PD curves in the serum.

However, the improvement in fibrosis only occurred in the high dose and not in the low dose.

So, just wondering what's the best way to rationalize that difference.

And then maybe quickly on the cash position, you're obviously still fairly well capitalized.

You're obviously still fairly well capitalized however, your opex and Capex are both going up so wondering how youre thinking about options to extend your runway. Thanks so much.

However, your OPEX and CAPEX are both going up.

So, wondering how you're thinking about options to extend your runway.

Thanks so much.

Thank you Luca for the question this is Javier.

Thank you, Luca, for the question.

This is Javier.

So if you think about the 2002 study we enrolled 12 patients in the 200 milligram dose photo staying with highly biopsies six months eight of them at 12 months.

So, if you think about the 2002 study, we enrolled 12 patients in the 200-milligram dose. Four of them had a biopsy at six months and eight of them at 12 months.

And we only enrolled four patients in the 100-milligram dose, and they all had a paired, biopsy in between at six months. With the caveat that one of the four patients in the 100-milligrams did not have the paired, biopsy, so we can't report in those patients. So, we only had three patients in the 100-milligrams that had very robust effect on Z-protein, ALTs, liver Z-protein, globules, and inflammation, but we didn't see a change in fibrosis at that early point in those three patients.

And we only enrolled four patients in the 100 milligram dose and they all have pay anybody else in between a six months.

With the caveat that one of the four patients in the 100 immediacy no paired.

Paired biopsies, so we can't reporting those patients. So we only had three patients in the 100 milligrams that has very robust effect on Z protein alp's leavers, he promoting global and inflammation, but we didn't see it changing fabulous said that at any point in those three patients. So I think it's a little bit.

So, I think it's a little bit about the small numbers.

The small numbers in contrast, as you said in the.

In contrast, as you said, in the 12 patients that received 200-milligrams, we saw all the, improvement in the different biomarkers and parameters, but we also saw 7 out of 12 improvement in fibrosis.

12 patients that received two have been made and we saw all the improvement in the different biomarkers. Some parameters about we also saw saving up to 12 improvement in fibrosis.

I think the reason here is likely to be the small sample size, the variability of reading, fibrosis, which is well known, and you're right that the magnitude of the PD effect is very consistent between the 100 and the 200 milligrams.

The reason that he had its likely to be the small sample size to buddy ability of leading fibrosis, which is well known and youre right that the PV effect is very consistent with the 102 hundred milligrams.

But we believe that way you pull all the data together absence of any.

But we believe that when you put all the data together, absence of any safety issue between, 100 and 200, very consistent suppression of Z-protein.

Safety should between 100 200, very consistent sufficient of the Z protein when you look at the PK and the PD.

When you look at the PK and the PD, there are small differences, but I think it favors, the 200-milligram dose.

Small differences, but I think he favor the 200 milligram dose. So I think when you put all the information together.

So, I think when you put all the information together, there is reasons to see the 200-milligrams, as the best dose to move forward, and as I said, the difference in fibrosis is likely to be variability in a small sample size.

Since two to see the 200 milligrams a S T.

At this dose to move forward and as I say the defense in fibrosis is likely to be buddy ability in a small sample size.

And look I can I'll take the cash question.

And Luca, I'll take the cash question.

So, I agree.

Uh huh.

I agree.

I feel comfortable with our cash position right now, in large part because we have right, now six partnerships with five different companies, important ammunition to do to the future deals.

We're comfortable with our with our cash position right now.

In large part because we have a right now six partnerships with five different companies.

Hum.

If I get if I have my math right and those partnerships are maturing I think that we have access to a substantial amount of capital across all of those partnerships over the next 12 to 24 months.

So we feel good about that inflow, but also as you know Luka you know, we're really good at and pushing.

New drug candidates into the clinic, we've got a pipeline clinical pipeline right now 10, or 11 candidates and I think that grows to 20 in the next few years.

And I think thats important ammunition to do future deals now I think we'll be pretty choosy about that and I think that ultimately.

Now, I think we'll be pretty choosy about that.

And I think that ultimately, you know, the majority of our pipeline will be wholly owned, we'll commercialize ourselves, but we will have access to, you know, to other non-core assets that we can partner.

The majority of our pipeline will be wholly owned we will commercialize ourselves, but we will have access to.

The other non core assets that we can partner I would expect on average.

I would expect, on average, of around a deal a year, a new deal a year to be about the right cadence. You know, that may change from year to year.

Around a deal a year, a new deal a year to be about the right cadence.

That may change from year to year, but I think on average that's probably the way to think about it and I just think that gives us access to as much capital.

But I think, on average, that's probably the way to think about it.

And I just think, that gives us access to as much capital, you know, as we need in the near term.

As we need in the near term.

Thank you so much.

Thank you so much.

Our next question comes from Maury Raycroft with Jefferies. Please go ahead.

Our next question comes from Mari Raycroft with Jefferies.

Please go ahead.

Hi, This is zane on for Marty. Thank you for taking our questions.

Can you set some expectations for the phase two a decent client data and fixed sizes you'd expect to achieve.

Hi, this is Farzin on for Mari.

Yeah, I don't think we're going to want to get into too.

Two to front running that we haven't seen those data yet but.

We feel we are looking forward to seeing those data.

The data so far that we've seen have been consistent as Javier said.

We've seen we've seen a circulating <unk> levels and its consistent.

Across patients we've seen in a handful of patients in the open label study with good.

Logical response.

Six to 12 months.

So we expect we're looking forward to seeing those data.

I want to I don't want to put any expectations around them, but but.

I wouldn't expect the basic story to change and I just think my hope is that is that.

There's quite a data just reinforced the existing stores.

Thank you for taking our questions.

Okay. Thank you.

Okay.

Our next question comes from Ted <unk> with Piper Sandler.

Can you set some, expectations for the Phase II AAT sequelae data and the effect sizes you'd expect to achieve?

Yeah, I don't think we're going to want to get into, you know, to front-running that.

Thanks, Hi, everybody. Thanks, so much for taking my questions. So I guess picking up a little bit on the last question and again appreciating that.

We'll see what the data okay.

We haven't seen those data yet.

Walk us through sort of how you guys are seeing the potential paths forward. How you on ticket are sort of discussing it.

Look, we feel we are looking forward to seeing those data.

The data so far that we've seen have been consistent, as Javier said.

Following the data thank you for.

For it.

P T.

Hi.

Thanks, Ed.

So look I'm, a middle child, and and and and I like to give people what they want but I can't give you that we are we are in we are in.

Takeda is in is in discussions with the FDA and we're just going to have to wait to see to see where those go we feel we feel comfortable that that the FDA.

We are aligned with the FDA in and appreciating the importance of this disease and the fact that it.

There's no good treatment for it right now at Liberty is easily associated with <unk>, We've got I think the only thing.

You know, we've, seen circulating AAT levels, and it's consistent, you know, across patients.

In the in the clinic that really offers these patients hoping so my hope is that we can get to two alignment reasonably soon with the regulators, but I can't really give you an idea about about where that's going now that's quite data I think I think will be could be helpful. Because it because it just gives us more numbers and hopefully we see what we've been seeing.

You know, we've seen in a handful of patients in the open-label study, you know, a good histological response, you know, in six to 12 months.

And in the smaller open label study.

But that should.

My hope is that that will that will help the discussions along but we'll see how that goes.

Great. Thank you and what's important to us.

Okay. Thanks, guys.

Our next question comes from Ellie Merle with UBS. Please go ahead.

And so we expect, you know, we're looking forward to seeing those data.

Hey, guys. Thanks for taking the question just on the pulmonary franchise, if I heard correctly you completed that.

And the first cohort in healthy volunteers for my five AC and range I guess.

I don't want to put any expectations around them.

But, you know, I wouldn't expect the basic story to change.

I know that they were starting with sort of a single ascending dose here in healthy volunteers, but I guess, we're sort of that's circulating biomarkers or.

Measures of these protein levels.

Together in these healthy volunteers and any kind of a nutshell.

Data points in terms of target engagement, Yeah, and then I guess you know as you move into that multiple ascending dose as lives into patient that thing I mean, even I guess early on an even healthier than that I don't think could we potentially get some of these biomarkers as well just in terms of target engage Matt and I guess.

First if you're measuring yet, but then also thinking about from our perspective, where we sat that the timeframe underway potentially you're wondering about that thanks.

So James when you talk about what we're measuring and then Ahmed al.

I'll address the question about.

Information flow sure.

So both.

You're right we've completed the first cohort for both Aero multiply they see an arrow rage.

Since it's an ascending single ascending dose study and we start with the lowest dose of course and we measure.

In the multiply the deep C study we measure.

Sputum offer V C levels and then we will also in that study measure.

Suppression of marked by the sea.

Bronchial alveolar lavage fluid, so theres not a blood biomarker for multiply they see sputum and B a L based and.

Those have been drawn but we havent you know there is a lot.

We haven't seen any of that yet.

And similarly for Rage, there is a value.

Blood biomarker S rage, which is drawn all of the that'll be drawn in all of the healthy volunteer cohorts as well as in the patient cohorts. We will also look at sputum wage levels and.

Rage in the bulk fluid as well so there are several different biomarkers that we can look at it in both studies.

And regarding the data flow.

So my expectation is that certainly in 'twenty three.

We'll have results from those studies.

If we you know.

To be more granular.

Are there opportunities for us to to to release data earlier than when the entire studies are completed that's a possibility, but we just don't have any visibility on that right now because.

And I just think my hope is that, you know, the sequelae data just reinforced the existing story.

Yeah.

It is still ongoing and there are still fairly early in the studies. So so that's the best guidance I can give you that I do expect full data in 'twenty three.

Don't know about partial data upstream of that.

Got it but I guess in terms of internally for you guys.

Even if either healthy patients or healthy volunteers, you at least well from these markers maybe get a bit of a sense in terms of whether or not you're engaging the target.

Perhaps even in the near term.

Yes, I think Thats fair.

Think that the data from healthy volunteers will teach us a lot of as James said, we have taken we have we.

We have samples we haven't seen anything yet so we have no data at this point and of course. These are these at very low doses I believe so I don't even know if we would see any knockdown at least at these early doses, but but your point is a good one I think that we can learn something from the healthy volunteers.

Understood. Thanks.

Gotcha.

Okay.

Our next question comes from Joel Beatty with Baird.

Thank you.

Hi, Thanks for taking my question, but what's the outlook currently for your platform for oncology programs.

Yeah. So I think we learned a lot.

This year than last year with the with the Arrowhead II.

As we as we've said in the past I think the hit to market has changed a bit and so it didn't make sense for us to push that candidate forward.

I also think that that that that we learned a lot about about knockdown in oncology. The good news was I think we start.

And I think we can do better.

So it's.

We are looking to to continue to develop that platform. We have nothing in the near term I don't expect anything.

This year in oncology, but we will see where that goes going forward, it's not a it's not a.

It's not a real core of ours, but we do think there is value there and we do think that <unk> may play a role in oncology at some point and so so we're still working on them.

Okay. Thank you.

You're welcome.

Our next question comes from Madhu Kumar with Goldman Sachs.

Our next question comes from Ted Tennant with Piper Sandler.

Hey, Thanks for taking our questions. So one on <unk> and one on the pulmonary program. So on <unk> I guess kind of a question, we get a lot of people as well.

Great.

Hi, everybody.

Do you think it would be effective placebo rate of fibrosis improvement and do what he said do you think you can use the fraction of patients who had a worsening of fibrosis in the phase two open label extension study as an effective proxy for kind of sampling variability style placebo effects on kind of.

Thanks so much for taking my question.

Liver fibrosis improvement and worsening and then on the pulmonary programs you mentioned the idea of biomarker changes in healthy volunteers and in patients.

So, I guess, picking up a little, bit on the last question, and again, appreciating that, you know, there's – we'll see what the data has to say.

Walk us through sort of how you guys are seeing the potential paths forward, how you and Takeda are sort of discussing it, following the data.

The question, we get from people is when do you expect to see kind of assessments of clinical benefit in the multiply the AC and wage programs those kind of clinical proof of concept metrics for those pulmonary on AI programs.

Have you ever have my address.

Thank you for AAT.

Yes.

So as you know.

Thanks, Ted.

You know, I – so, look, I'm a middle child, and I like to give people, what they want, but I can't give you that.

You know, we are in – Takeda is in discussions with the FDA, and we're just going to have to wait to see where those go.

Neither biopsies he's policy, if anybody able to particularly the fibrosis quality students than you normally would require to our.

You know, we feel comfortable that the FDA – you know, we are aligned with the FDA in appreciating the importance of this disease and the fact that there's no good treatment for it right now, liver disease, at least, associated with AAT.

We've got, I think, the only thing in the clinic that really offers these patients hope, and so my hope is that we can get to, you know, to alignment reasonably soon with the regulators, but I can't really give you an idea about where that's going.

Our policy is leading the biopsies have been in that Chile came through which is what we did in both 2002.

Sequoia studies.

So it is so based on this.

Interesting viability and the data from <unk>.

Natural history studies is about 20% of people may have add rig ratio without any treatment in about 20% or 30% can have progression in about two to CES time, that's that's at least one relatively small studies shows.

When you look at not just the numbers that are kind of similar you see a 20% decrease without seeing them and thats why sometimes its difficult to power those studies.

I think the second part of your question had to do with how many people have an increased score in the 2002 study and two of the 16 patients had an increase of one.

One point both of them have a very significant reduction in seat rotating they leave the global burden actually both of them went to zero one of which started with nine which is the highest scores. So they don't see it.

Step two was designed to do across the board those patient decrease in inflammation and yet they have at one point progression in surplus and so I think that speaks to the reality.

<unk>, which is leading to liver biopsies is challenging and the consequence of that that you need to do that study with the appropriate methodology for us is it.

Policy and that's what we're doing.

And then on the pulmonary from Singapore Mach five AC.

If you look at the the levels of moths or they see expression in patients and he has matic versus expression in.

The healthy volunteer you probably need significant knockdown.

To start to see it.

Change in phenotype, and based on where they see knockdown, you're probably looking at.

70% plus knockdown.

<unk> is not dissimilar correlate rage based on our animal data in two different rodent models again, you need to achieve significant knockdown.

Good magnitude of Knockdowns, so probably better than 70% to 75% knockdown, but I think the more is better.

For both of those.

My question's more on timing like when can we expect data to test things like forced vital capacity and things.

He asked in trials in the Kingdom.

You've got sort of allergic disease trials.

Of course, we will look at that in our current study, but that's not the focus of the current studies are really more focused on biomarkers.

So.

I don't know if you can talk timing.

Timing on AR.

Functional readouts like that yes.

We have not.

Our expectation is that is it is there to really look at those functional changes you have to rely on on the phase two studies and so I don't think you'll as Jim said, we'll be looking for those things, but my expectation is that is that we're not we don't really see those until phase two.

Yes, thank you very much guys.

Our next question comes from Patrick Trujillo with H C Wainwright.

Now, the sequoia data, I think, will be – you know, could be helpful because it just gives us more numbers, and hopefully we see what we've, Our next question comes from Ellie Merrill with UPS, please go ahead.

Thanks, Hi, good afternoon, and congrats on all the progress I have a couple of follow up questions. So first is on <unk> to the top line data is expected in the first half of next year I'm wondering if you can discuss what you'd be looking for in this data and discuss the anticipated differentiation.

Hey guys, thanks for taking the question.

Just on the Pulmonary Franchise, if I heard correctly, you completed those things in the first cohort in Healthy Volunteers for MUCS 5AC and RAGE.

I guess I know that we're starting with sort of single ascending dose here in Healthy Volunteers, but I guess we're sort of the circulating biomarkers or measures of these protein levels taken in these Healthy Volunteers and any kind of initial data points in terms of target engagement here.

And then I guess, you know, as we move into the multiple ascending dose, as well as into patient dosing, I mean, even I guess early on, and even just healthy and MAD dosing, could we potentially get some of these biomarkers as well, just in terms of target engagement?

And I guess first, if you're measuring it, but then also thinking about, you know, from our perspective, where we set the timeframe under which we could potentially learn about this.

Thanks.

So James, why don't you talk about what we're measuring, and then I'll address the question about information flow.

<unk> III from Bupa Nordson, and why why we should not expect our industry to have a similar outcome that came from that phase two b translate trial.

Sure.

So the first part of your question, Yes, we stated that they thought the first half of next year.

Yeah, so both, you're right, we've completed the first cohort for both arrow MUCS 5AC and arrow RAGE.

Since it's an ascending, single ascending dose study, we start with the lowest dose, of course, and we measure in the MUCS 5AC study, we measure sputum, MUCS 5AC levels.

That means we are tied to work on the next step.

And then we will also, in that study, measure expression of MUCS 5AC in bronchial alveolar lavage fluid. So there's not a blood biomarker for MUCS 5AC, but it's sputum and BAL based.

And those have been drawn, but we haven't, you know, there's a lag, we haven't seen any of that yet.

And similarly for RAGE, there is a value, a blood biomarker, SRAGE, which is drawn in all the, that'll be drawn in all the healthy volunteer cohorts, as well as in the patient cohorts.

We will also look at sputum RAGE levels and RAGE in the BAL fluid as well.

The phase III. So this will enable a phase III study, so I think I want to emphasize the relevance of these fatal.

So there's several different biomarkers that we can look at in both studies.

That's a possibility, but we just don't have any visibility on that right now because, you know, these are still ongoing and they're still fairly early in the studies.

The first half of next year.

Well so the comparison that I I don't think he is also with two different folks to different technologies, we haven't seen in our phase one study any of this finding the no.

Very clear yet reported from from them. So.

At this point, we have no concern with regards to seen any unexpected.

Safety finding.

With no doubt very soon.

So that's the best guidance I can give you, that I do expect full data in 23.

Got it and then just with the with the Gateway program with HOS H. This study is fully enrolled with the data to follow in 2023 I'm wondering if you can discuss the anticipated path to approval and interest rates and what you would need to demonstrate in this gateway program from a safety and efficacy perspective and is there.

And I just don't know about partial data upstream of that.

Got it.

But I guess in terms of internally for you guys, even if these are healthy patients or healthy volunteers, you at least will, from these markers, maybe get a bit of a sense in terms of whether or not you're engaging the target, perhaps even in the near future.

I think that's fair.

There are potential for an accelerated review.

I think that the data from Healthy Volunteers will teach us a lot.

As James said, we have samples.

And finally, you know what what would the potential commercialization looked like in this patient population would you know what would you look to launch this on your own or with a partner.

Just just lastly, I guess, how how large of an indication could ultimately be.

Well, so H H.

A condition that is a drug approved.

Similar pathway with the same powerful with an antibody a widely in our first proof of concept of course that will be at what point of reference how we compare with the antibody to HPT L. Three we know that we do have in Atlanta in Atlanta to try that.

We haven't seen anything yet, so we have no data at this point. And of course, these are very low doses, I believe.

I don't even know if we would see any knockdown at these early doses.

But your point is a good one.

I think that we can learn something from the Healthy Volunteers.

Way, because the dosing will be feel.

Understood.

Six months, who knows subcutaneously. So we do have an advantage there. So we need to see and we will compare that data with them and say are we competitive to the antibody instead more efficacy safety.

Thanks so much.

Our next question comes from Joel Beattie with Baird.

Hi.

Total liability those rates and so forth so.

Thanks for taking the question.

We'll see we're going to look at that data.

What's the outlook currently for your platform for oncology programs?

Yeah, so I think we learned a lot this year and last year with the Arrowhead 2.

As you know the market is relatively small it would be competition against the antibody and I think if we feel that we havent very good profile to compete against them what kind of move forward that development process. A program for this indication is well established.

As we said in the past, I think the HIF-2 market has changed a bit, and so it didn't make sense for us to push that candidate forward.

I also think that we learned a lot about knockdown in oncology.

We have nothing in the near term.

The good news was I think we saw it, and I think we can do better.

Don't expect anything this year in oncology, but we'll see where that goes going forward.

And so we are looking to continue to develop that platform.

It's not a real core of ours, but we do think there is value there, and we do think that RNAi may play a role in oncology at some point.

So it would be a relatively small study placebo control and we like I say the profile is as good as we expected competitive to the to the regenerative antibody then.

Hum.

Move forward, because we think that there is a very unmet medical need and this can offer.

And more of a friendly approach to these treatments.

And also I want to say that.

It is not fully enrolled so we said we were enrolling efficiently, but it is not yet fully enrolled.

So we're still working on it.

Thank you by the end of the year.

Got it okay. That's helpful. Thank you very much.

Our next question comes from Kane Mckay Sheridan. Please go ahead.

Great.

Yes. Thank you.

Thank you.

You're welcome.

Question about palisade.

Our next question comes from Madhu Kumar with Goldman Sachs.

Last quarter, you talked about some trouble with some of the plant sites in Eastern Europe . Just wondering now you know what the outlook is in terms of how you're set up to it.

Hey, thanks for taking our questions.

So one on AAT and one on the pulmonary program.

Enroll these patients.

Given how difficult don't really declined.

[noise] Palisades.

Oh perfect.

So we are the only reason that we didn't have any travel in Europe . Other than this is a phase III study with no phase II study, so regulatory agencies and some <unk>.

<unk> dot consenting and say well how do you know that maybe got some data to move from where you are to a phase III study and we address all of those comments and questions and I think letting them pretty good shape now getting.

Many countries around the world are proved to run to run this study.

And it's important to recognize and we said that two regulatory agencies by the time that the phase III Palisade study will be done well then I have two relatively large phase two studies that would be part of that regulatory process. So.

I think the good news is yes, we do.

Got some pushback from regulatory agencies and all of them so far.

Understood.

And the study is getting the approvals around the world, including Japan, but we have several meetings with them.

The study is now approving final.

Negotiation with the size and ready to start enrollment in Japan within a month or so so.

And no no any unexpected delay other than more regulatory work too.

Justify that we werent ready for the Phase III study and I just wanted to say to your point about about sites.

Eastern Europe look our clinical and regulatory teams have done incredible work here, we had a number of sites that we're planning for Belarus, Ukraine, and Russia and.

And in one fell swoop, we lost all of those of course.

But they've done a great job finding additional sites and we are on track with all of those studies thanks to their good work.

So on AAT, I guess kind of a question we get a lot from people is what do you think is the effective placebo rate of fibrosis improvement?

Okay. Thanks.

Our next question comes from Manny <unk> with <unk> Securities. Please go ahead.

And do you think you can use the fraction of patients who had a, quote, worsening of fibrosis in the Phase II open-label extension study as an effective proxy for kind of sampling variability-style placebo effects, on kind of liver fibrosis improvement and worsening?

And then on the pulmonary programs, you mentioned the idea of biomarker changes in healthy volunteers and in patients.

Hey, Thanks for taking the question.

I wanted to revisit the topic with somewhat of a couple of times around the pulmonary platform.

Clarity general macrophage overload is really helpful.

As you pursue more effective more potent approaches to allow a lower absolute dose.

What metrics will you be tracking and what will your Barbie.

I guess one question we get from people is when do you expect to see kind of assessments of clinical benefit in the MUC5AC and RAGE programs, those kind of clinical proof of concept metrics for those pulmonary RNAi programs?

To disclose further evidence of macrophage activation any additional toxicology soon.

Signals the pop up as you track, how effectively earn effectively your threading the needle on <unk>.

<unk> delivered dose and macrophage activation.

Yeah I think.

We will.

Ron I think we've already discussed the acute tox results at the analyst.

Javier, you want to address AAT?

They are a while back and and as a reminder.

IND, enabling or Cta, enabling studies at the top dose was was the new proposal five AC per rage, and there were no adverse findings neither of those Tox studies and then we will in the near future.

Initiate chronic tox studies.

As also described during the analyst day event, I think we can really spread the doses out.

And those those chronic tox studies so just.

Overall less exposure.

Those studies compared to what we did in <unk>.

And then in terms of results of those studies.

No.

I don't know if we've guided on timing to disclose chronic tox study results.

And if not or if not generally are we generally don't don't disclose it.

<unk> results.

But as those come in.

We will know.

We'll know more about them about whats for Ti to expect but.

We had we had I think some good slides in the in the analyst in the pulmonary R&D day.

Where where we showed what we believe now is sort of a threshold above which we don't want to go for for.

In terms of in terms of volume of material.

We feel good that MMP seven month, five AC enrage are substantially below that line. If you look if you compare what our expected dosing is for for instance, mucking enrage, which are in the clinic now as you know compare that to two <unk>. So not only are we are we are we providing less drug but we're also providing it.

Less frequently that was that was three consecutive days every two weeks and now we're looking at it at one dose every month or less frequently and a lower dose on top of that so we feel good.

That we can thread this needle.

And frankly, I don't think I don't think I that needle is terribly terribly narrow.

But look we'll know more as we as we start to see knockdown.

And as we see chronic tox data.

Thanks, guys I was really clear.

Our next question comes from my Young Moms, Tommy with B Riley FBR.

Good afternoon. Thanks for taking our question. So just a strategy question for auto and street, the new rate for the Gateway study the dogs before.

Dominic next steps for <unk> and three on the Dyslipidemia indication based on <unk> and the reason I ask is that.

He has a similar study like Liz.

<unk> clinical drives dot Gov that good.

It of any competitive situation now.

Funds like the antibody or to do less.

Steve.

Without it'd be has cleared out so just curious when you laid out for you that joke, which is that.

Yes.

Yes.

We have some ideas about about.

What phase three will look like but of course.

We need to see what those data look like before we before we design those studies.

We feel with respect to the competitive question, we feel good about where we sit competitively.

In terms of our of our lead.

With RNA eye and certainly over over antisense.

As well as antibody competitors.

But anyway I guess the short answer is yes, we have we have a lot of ideas about what a phase III is going to look like but but we're not going to make any real decisions until we until we can sift through the data.

My expectation is that is that just too probably too strong a word we're curious to see if if if pockets populations.

Present themselves.

As a result of this you know do we do we find certain populations that respond better than others.

Yeah.

There's just no substitute for data so we'll wait to see that.

I would add also that we're not we wouldn't have we're not going to have to wait for gateway, So gateway and arches should read out right around the same time. So gateway is an open label study arches, two is fully enrolled and it'll complete right around the end of the year. So we should have both of those available at the same time.

Got it thank you and then on.

<unk> you.

Disclose those neighborhoods youre going up during the <unk>.

Because you said the end lower than that but I don't know how that guy put draws absolute dose level and frequency.

I think we've disclosed.

The actual dose levels yet.

And Dan.

At the analyst day, we put in the study design so.

Sure.

There was a slide that showed kind of the magnitude of the dose levels in the Tox studies, but I don't think there was the exact doses weren't disclosed.

Any case.

Frequency is certainly less than what we were doing with ebay.

Yes, remember what they wanted to three every two weeks.

And here is just one day.

Two or four weeks right either.

<unk> single dose.

Day, One day 29 29 so.

Very different.

Okay. Thank you and then my final question just curious.

About the milestone payment structure would be I'm doing that literally is there anything specific new structure around them initiating or along the way of executing our CV outcome studies, there and any milestones associated with it.

Unfortunately, we can't give you any guidance on on magnitude milestones are.

Or individual triggers.

Uh huh.

Although.

I think it would it would.

It would.

I think it's it's quite common that there is a milestone payment for our four phase III initiations.

Got it looking forward to learning more about that thanks again for taking our questions.

Sure. Thank you.

Our next question comes from per car and Guam with Cantor.

Hi, Thanks for taking my question. So I had two first a clarification on A&P.

Is the biopsy sampling underwriting protocols between two two and phase two Sequoia trial, similar or are there any changes that we should be aware of.

So as you know, liver biopsies, the histology is very variable, particularly the fibrosis core systems, and you normally require two pathologies within the biopsies and then an adjudicator, which is what we did in both 2002 and Sequoia studies.

So based on this intrinsic variability and the data from some natural history studies, about 20 percent of people may have a regression without any treatment, and about 20 percent could have or 30 percent can have progression in about two to three years' time.

That's what at least one relatively small study showed.

When you look at NASH, the numbers are kind of similar.

You see a 20 percent decrease without treatment.

That's why sometimes it's difficult to follow those studies.

I think the second part of your question had to do with how many people have an increased, score in the 2002 study, and two of the 16 patients had an increase of one point.

Actually both of them went to zero, one of which started with nine, which is the highest, score.

Both of them have a very significant reduction in C-protein in the liver, global burden.

So the extractable was designed to do across the board, those patients decreased in inflammation, and yet they have a one point progression in fibrosis.

Second on the long term strategy for the CV portfolio, Chris recent CV launches continue to be slow even for companies with strong existing infrastructure in this space.

35 million in sales in first half I'm no why does it still working through some of the logistical hurdles.

How much of these are the exclusive launch of shaping your view about keeping the different assets in house versus looking for partners, who already have the infrastructure. Thank you.

So would the AAC program they buy up C assessment is identical for both studies instead to pathology thought were trading train together to read this if they agree that the end of the process. If they disagree there is a third pathology the decided which one of you to read it.

So I think that speaks to a reality fact, which is reason liver biopsies is challenging, and the consequence of that, but you need to do appropriate study with the appropriate methodology to assess histology, and that's what we're doing.

And then on the pulmonary front, I think for MUC5AC, if you look at the levels of MUC5AC, expression in patients in the asthmatic versus expression in a healthy volunteer, you probably need significant knockdown.

So to start to see a change in phenotype based on MUC5AC knockdown, you're probably looking, at 70% plus knockdown, and there's not the similar correlate for rage based on our animal data in the two different rodent models.

Again, you need to achieve significant knockdown, a good magnitude of knockdown, so probably, better than 70 to 75% knockdown, but I think the more is better for both of those.

My question is more on timing.

When can we expect data to test things like force vital capacity and things in the asthma, trials and the kind of mucocellular disease trials?

Of course, we'll look at that in our current study, but that's not the focus of the current, study.

These are really more focused on biomarkers.

So I don't know, we've talked timing on functional readouts like that.

Yeah, we have not.

My expectation is that to really look at those functional changes, you'd have to rely on, the phase two studies, and so I don't think you'll, as James said, you know, we'll be looking for those things, but my expectation is that we won't really see those until phase two.

It's the one that is considered the final green. So that's that's a procedure that the process is exactly the same.

Yeah, thank you very much, guys.

Policy side are the same so I expected it consistent output out of this study.

Our next question comes from Patrick Crucio with HC Wainwright.

Regarding our.

Our competence or a willingness to commercialize our CV assets on our own.

Thanks.

That hasnt changed for us.

We think these are these are we think these are drugs.

The data have been consistent they've been good.

Hi.

I think that there are clear places for both of these for both of these drug candidates if you will.

Good afternoon, and congrats on all the progress.

Look it at triglycerides.

Look I think there's increasing evidence that that elevated triglycerides at least for some patients are going to affect outcomes and there historically hasnt been a way to to modulate triglycerides you very much.

I have a couple of follow-up questions.

The first is on ARCHES-2, the top-line data is expected in the first half of next year.

I'm wondering if you can discuss what you'd be looking for in this data and discuss the, anticipated differentiation from ANG-3 from buprenorphine and why we should not expect, ANG-3 to have a similar outcome that came from that phase two V-translate trial.

So the first part of the question, yes, we are expecting to have the data the first half, of next year.

That means that we are starting to work on the next step, the end of phase two, so this, will enable a phase three study.

So I think I want to emphasize the relevance of this data, you know, in the first half, of next year.

And finally, you know, what would the potential commercialization look like in this patient, population?

Well, so the comparison, I don't think it's possible, two different drugs, two different, technologies.

Would you look to launch this on your own or with a partner?

We haven't seen in our phase one study any of these findings that are not very clear, yet reported from them.

So at this point, we have no concern with regard to seeing any unexpected safety findings, and we'll know that very soon.

And then just with the gateway program, with HOFH, the study is fully enrolled with the, data to follow in 2023.

I'm wondering if you can discuss the anticipated path to approval in HOFH and what you would, need to demonstrate in this gateway program from a safety and efficacy perspective.

And is there a potential for an accelerated review?

And just lastly, I guess, how large of an indication could this ultimately be?

If you look at fish oils, maybe 18 to maybe 30% reduction will you compare that to for instance April three where we're seeing reductions as high as 90%, sometimes even more than that where we really move the needle I think these are big opportunities for us and I think that that debt.

Well, so HOFH is a rare condition that is a drug approved with a similar pathway or, the same pathway with an antibody.

And we're doing our first study, proof of concept.

Of course, that will be our point of reference, how we compare with the antibody to HPTL3.

We know that we do have an advantage right away because the dosing will be every three, or six months, who knows, subcutaneously.

So we do have an advantage there.

So we need to see and we will compare that data with them and say, are we competitive, to the antibody in terms of efficacy, safety, and tolerability, dose rating, and so forth.

So we'll see.

You'll have a lot of patients and so we are we are is as his willingness as ever to commercialize these on our own.

Thank you.

Okay.

We're going to look at that data.

As you know, the market is relatively small.

It will be competition against the antibody.

This concludes the question and answer session.

And I think if we feel that we have a very good profile to compete against them, we're, going to move forward.

The development process or program for this indication is well established.

So, you know, it would be a relatively small study, placebo control.

And if we, you know, like I say, if the profile is as good as we expected and competitive, to the regenerative antibody, then we're going to move forward because we think that there is a very medical need and this can offer a more friendly approach to this treatment.

I would like to turn the conference back over to Chris Anzalone for closing remarks.

And also, I want to say the gateway is not fully enrolled.

So we said we were enrolling efficiently, but it's not yet fully enrolled.

Thank you, by the end of the year.

Got it.

Our next question comes from Mani Foroohar with SBB Securities.

Okay.

Please go ahead.

That's helpful.

Thanks, everyone for joining today and we look forward to talking to you again next quarter.

Thank you very much.

Our next question comes from Kay McKay with Shardham.

Please go ahead.

Yes, thank you.

Thanks for taking the question.

A question about palatate.

I want to revisit a topic that's been brought up a couple of times around the pulmonary, platform.

You know, last quarter, you talked about some trouble with some of the plant sites in Eastern, Europe.

The clarity you've given around the macrophage overload is really helpful.

Just wondering now, you know, what the outlook is in terms of how you're set up to enroll, these patients?

As you pursue more effective, more potent approaches to allow a lower absolute dose, what metrics will you be tracking and what will your bar be to disclose further evidence of macrophage activation, any additional toxicology signals that pop up as you track how effectively or ineffectively you're threading the needle on delivered dose and macrophage activation?

Again, how difficult are they to find?

I think we will run.

Oh, perfect.

I think we've already discussed the acute tox results at the analyst day a while back. And as a reminder, in the acute IND-enabling or CTA-enabling studies that the top dose, was the no AEL for both MUC5AC and for RAGE. And there were no adverse findings in either of those tox studies.

The conference has now concluded. Thank you for attending today's presentation you may now disconnect.

So we, the only reason that we didn't have any trouble in Europe other than this is a, phase three study with no phase two study.

And then we will, in the near future, initiate chronic tox studies as also described during, the analyst day event.

So regulatory agencies and some ERBs raised that concern and said, well, how do you know, that there may be gaps in data to move from where you are to a phase three study?

I think we can really spread the doses out in those chronic tox studies.

And we addressed all those comments and questions, and I think we're in very good shape now, getting many countries around the world approved to run this study.

So just overall less exposure, those studies compared to what we did in ENAC.

And, you know, it's important to recognize, and we said that to regulatory agencies, that, by the time that the phase three study, the palatate study, will be done, we're going to have two relatively large phase two studies that will be part of that regulatory process.

And then in terms of results of those studies, you know, I don't know if we've guided on, timing to disclose chronic tox study results, but we, and it's not our, it's not generally our, we generally don't disclose tox results.

So I think the good news is, yes, we got some pushback from regulatory agencies, and all, of them so far accepted and understood the plan and the studies getting approved around the world, including Japan.

But, you know, as those come in, you know, we'll know, we will know more about, you know, what sort of, you know, TI to expect.

You may, now disconnect.

We have several meetings with them, and the study is now approved in final negotiation, with the sites and ready to start enrollment in Japan within a month or so. So not any unexpected delay other than more regulatory work to justify that we were ready, for the phase three study.

But, you know, we had, I think, some good slides in the pulmonary R&D day where we showed, what we believe now is sort of the threshold, you know, above which we don't want to go for, in terms of volume of material. And we feel good that MMP7, MUC5AC, and RAGE are substantially below that line.

And I just want to say, to your point about sites in Eastern Europe, look, our clinical, and regulatory teams have done incredible work here.

You know, if you look, if you compare, you know, what our expected dosing is for, for, instance, MUC and RAGE, which are in the clinic now, as you know, compare that to AeroENAC, you know, not only are we providing less drug, but we're also providing it, you know, less frequently.

We had a number of sites that were planned for Belarus, Ukraine, and Russia, and in, one fell swoop, we lost all those, of course.

That was three consecutive days every two weeks, and now we're looking at one dose every, month or less frequently, and a lower dose on top of that. So we feel good that we can thread this needle.

But they've done a great job finding additional sites, and we are on track with all of those, studies, you know, thanks to their good work.

And frankly, I don't think, I don't think the eye of that needle is terribly, terribly, narrow.

But, you know, look, we'll know more as we, as we start to see knockdown, and as we, you, know, see chronic toxins.

Data.

Thanks, guys.

That was really clear.

Our next question comes from Mayank Mamtani, with B Reilly FBR.

Good afternoon.

Thanks for taking our question.

So just a strategy question for Arrow Anstrey.

So will you wait for the gateway study results before determining next steps for Anstrey on the dyslipidemia indication based on Archie's?

And the reason I ask is that Lily has a similar study like Archie's listed on clinicaltrials.gov that, could make it a very competitive situation now that earlier forms like the antibody or the less safe modality has cleared out.

So just curious, will you wait out for your HOFH results?

Yes.

We have some ideas about what phase three will look like.

But of course, we need to see what those data look like before we design those studies.

We feel, with respect to the competitive question, we feel good about where we sit competitively in terms of our lead with RNAi and certainly over antisense as well as antibody competitors.

But anyway, I guess the short answer is yes, we have a lot of ideas about what a phase, three is going to look like.

But we're not going to make any real decisions until we can sift through the data.

My expectation is that, well, expectation is probably too strong a word.

We're curious to see if populations, you know, present themselves as a result of this.

You know, do we find certain populations that respond better than others?

You know, there's just no substitute for data.

So we'll wait to see that.

And I would add also that we're not, we wouldn't have, we're not going to have to wait for gateway.

So gateway and Arches should read out right around the same time.

So gateway is an open label study.

Arches, too is fully enrolled and it'll complete right around the end of the year.

So we should have both of those available at the same time.

Got it.

Thank you.

And then on error age, have you disclosed the specific dose levels, you're going up to in the MAD?

Because you say three times lower than ENAG, but I don't know how that cuts across absolute dose level and frequency.

I don't think we've disclosed the actual dose levels yet.

And the, we put in the study design, so.

It showed, there was a, there was a slide that showed kind of the magnitude of dose, levels in the tox studies, but I don't think there was the exact doses weren't disclosed.

In any case, the dose frequency is certainly less than what we were doing with ENAG.

Yeah.

Remember ENAG was day one, two, three, every two weeks.

And here it's just one day, every two or four weeks, right? Yeah.

Either day, single dose or day one, day 29.

Day 29.

So very different.

Okay.

Thank you.

And then my final question, just curious about the milestone payment structure, with the Amgen Lp-a.

Is there anything specifically structured around them initiating or, you know, along the way of executing a CV outcome study?

Is there any milestone associated there?

We, you know, unfortunately, we can't give you any guidance on magnitude of milestones, or individual triggers, you know, although, you know, I think it would, it would, it would, I think it's quite common that there is a milestone payment for, for phase three initiations.

Got it.

Looking forward to learning more about that.

Thanks, team, for taking our questions.

Sure.

Thank you.

Our next question comes from Prakhar Agrawal with Cantor.

Hi.

Thanks for taking my question.

So I had two.

First, a clarification on AAT.

Is the, biopsy sampling and the reading protocol between 202 and phase two sequoia trial similar, or are there any changes that we should be aware of?

And second, on the long-term strategy for the CV portfolio, recent CV launches continue to be slow, even for companies with strong existing infrastructure in this space. Inclusiran had 35 million in sales in first half and Novartis is still working through some of the logistical hurdles.

So how much of these, are these slow CV launches shaping your view about keeping the different assets in-house versus for looking for partners who already have the infrastructure?

Thank you.

So with the AAT program, the biopsy assessment is identical for both studies.

It's the two, pathologists that were trained together to read this.

If they agree, that's the end of the process.

If they disagree, there is a third pathologist that decided which one of the two reads is the one that is considered the final read.

So that's the procedure.

The process is exactly the same.

The pathologists are the same.

So I expect a consistent output out of this study.

And regarding our confidence or our willingness to commercialize our CV assets on our own, that hasn't changed for us.

We think these are drugs.

The data have been consistent.

They've been good.

I think that there are clear places for both of these drug candidates.

If you look at triglycerides, look, I think there's increasing evidence that elevated triglycerides, at least for some patients, are going to affect outcomes.

And there historically hasn't been a way to modulate triglycerides very much. If you, look at fish oils, maybe 18 to maybe 30% reduction.

We'll compare that to, for instance, ApoC3, where we're seeing reductions as high as 90%, sometimes even more than that, where we really move the needle.

I think these are big opportunities for us.

And I think that these will help a lot of patients.

And so we are as willing as ever to commercialize these on our own.

Thank you.

You're welcome.

This concludes the question and answer session.

I would like to turn the conference back over, to Chris Anzalone for closing remarks.

Thanks, everyone, for joining today.

We look forward to talking to you again next quarter.

The conference is now concluded.

Thank you for attending today's presentation.