Full Year 2023 Arrowhead Pharmaceuticals Inc Earnings Call

Speaker 1: Number.

Yeah.

Speaker 2: Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals Conference call. Throughout today's recorded presentation, all participants will be in a listen-only mode. After the presentation, there will be an opportunity to ask questions. I will now hand the conference call over to Vince Anzaloni, vice president of Investor Relations for Arrowhead. Please go ahead, Vince.

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call throughout today's recorded presentation, all participants will be in a listen only mode. After the presentation there'll be an opportunity to ask questions. I will now hand, the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead.

Ben.

Speaker 3: Thank you, Justin. Good afternoon, and thank you for joining us today to discuss Arrowhead's results for its fiscal fourth quarter and year ended September 30th, 2023.

Thank you Justin good afternoon, and thank you for joining us today to discuss arrowheads results for its fiscal fourth quarter and year ended September 30th 'twenty to 'twenty three with US today from management are president and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter Dr. Javier San Martin <unk>, Our Chief Medical Officer, who will provide.

Speaker 3: With us today for management, our president and CEO , Dr. Chris Hanselini, who will provide an overview of the quarter Dr. Javier San Martín, our chief medical officer, who will provide an update on our mid and later stage clinical pipeline.

An update on our mid and later stage clinical pipeline, Dr. James Hamilton, our cheaper discovery and translational medicine, who will provide an update on our earlier stage programs and Ken Moskovsky, Our Chief Financial Officer, who will give a review of the financials.

Speaker 3: Dr. James Hamilton, our Chief of Discovery and Translational Medicine, who will provide an update on our earlier stage programs, and Ken Miskowski, our Chief Financial Officer, who will give a review-

Speaker 3: In addition, Tracy Oliver, our Chief Commercial Officer and Patrick O'Brien, our Chief Operating Officer and General Counsel, will be available during Q&A portion of the call.

In addition, Traci Oliver our Chief commercial Officer, and Patrick O'brien, Our Chief operating Officer, and General Counsel will be available during the Q&A portion of the call.

Speaker 3: Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the Meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than statements of historical fact are forward-looking statements.

Before we begin I would like to remind you that comments made during today's call contain certain forward looking statements within the meaning of section 27 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 our.

Speaker 3: and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements. For further details concerning these risks,

Subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward looking statements.

Further details concerning these risks and uncertainties. Please refer to our SEC filings, including our 10-K filed today and our quarterly reports on Form 10-Q.

Speaker 3: Please refer to our SEC filings, including our 10K file today, and our quarterly reports on form 10Q. Now, turn the call over to Chris Hansel-Honey, President and CEO of the company, Chris. Thanks, Ben.

Now like to turn the call over to Chris Anzalone, President and CEO of the company Chris.

Thanks Vince.

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

Speaker 3: Arrowhead made significant progress toward reaching our 20 and 25 goal to grow our pipeline of our N.I. therapeutics to a total of 20 clinical stage or marketed products by the year 2025.

Arrowhead made significant progress toward reaching our 2020 five goal to grow our pipeline of RNA therapeutics to a total of 20 clinical stage or marketed products by the year 2025.

Speaker 3: With yesterday's announcement that was CTI filing for ARODM1, our newest skeletal muscle-targeted program being evaluated as a treatment for type one myotonic dystrophy, we now have 15 clinical stage programs, 10 are wholly owned, and five are being developed with partners.

Well the yesterday's announcement of a Cta filing for Aero D. M. One our newest skeletal muscle targeted program being evaluated as a treatment for type one myoclonic dystrophy. We now have 15 clinical stage programs 10 are wholly owned and five are being developed with partners.

Speaker 3: We expect these 15 clinical programs to go to 16 over the next month with the addition of one more CTA this year.

We expect these 15 clinical programs to go to <unk> over the next month with the addition of one more Cta this year.

Speaker 3: This will complete an extraordinarily productive year on the development front. In 2023, we will have nominated nine new potential clinical candidates using our trim platform across four different issues. Libber, pulmonary, CNS, and skeletal muscle.

This will complete an extraordinarily productive year on the development front in 2023, we will have a nominated nine new potential clinical candidates using our <unk> platform across four different tissues liver.

Pulmonary CNS and skeletal muscle.

Speaker 3: In addition, we will have filed four CTAs for new clinical candidates during the calendar year. We believe this type of productivity is simply unmatched in our field. And it's particularly impressive, given the size and market capitalization of our company. Even so, we...

In addition, we will have filed four cpas for new clinical candidates during the calendar year. We believe this type of productivity is simply unmatched in our field and is particularly impressive given the size and market capitalization of our company.

So we expect more in 2024.

Speaker 3: To understand these 15 clinical programs now, the 20 we will shortly have, the new targets we are planning to address, and the new cell types we will target over the years, is to understand the magnitude of patients we expect to treat, and the value we can create over the long term.

To understand these 15 clinical programs now in 'twenty, we'll shortly have new targets, we are planning to address and the new cell types. We will target over the years is to understand the magnitude of patients we expect to treat the <unk>.

Value, we can create over the long term.

Speaker 3: Of course, there is too much there to discuss in this setting, so today we will focus on some of the accomplishments, events, and considerations that may derive and unlock value in the near term.

Of course, there is too much merit to discuss in this setting. So today, we will focus on some of the accomplishments events and considerations that may drive and unlock value in the near term.

I see three primary areas first we are de risking our pulmonary platform with knockdown and safety data in our clinical trials and toxicity data from our chronic Tox studies.

Speaker 3: First, we are de-risking our pulmonary platform with knockdown and safety data in our clinical trials and toxicity data from our chronic tox study.

Speaker 3: These enable us to move toward mid-stage studies addressing three main categories of chronic lung disease, inflammation, muclub destruction, and interstitial lung disease, each of which have unmet treatment needs.

Enable us to move toward mid stage studies addressing three main categories of chronic lung disease inflammation equal obstruction and interstitial lung disease, each of which have unmet treatment needs.

Second we are making good progress towards becoming a commercial company.

We expect our initial commercial product to be plus <unk>, formerly arrow Apoc III.

In the treatment of familial Carlo micro anemia syndrome for which we will complete a phase III study in Q2 2024, followed by our anticipated second indication for treating patients with severe hypercholesterolemia or S. H D. G and a later potential indication for treating a broad population of patients with mixed dyslipidemia and atheros.

Moronic cardiovascular disease.

Speaker 3: And lastly, we have directional guidance towards strengthening our balance sheet in a shareholder friendly way.

And lastly, we have directional guidance towards strengthening our balance sheet in a shareholder friendly way.

Let's start with the pulmonary platform.

We believe that Arrowhead is the first and only company to show clinically there Arnie I can be harnessed silencer gene expression in the human lung.

It is important and marks the accomplishment of our key long term goal, we set for ourselves several years ago.

Speaker 3: We've always thought that once we have human safety and activity proofing concept with one candidate, it will unlock value in the entire platform and provide confidence that other programs could work similarly, much like our current expectations for new liver programs. So let's talk about important derisking steps.

I always thought that once we have human safety and activity proof of concept with one candidate and will unlock value in the entire platform and provide confidence that other programs can work similarly, much like our current expectations for new liver programs. So.

Let's talk about important derisking steps.

Speaker 3: First, we think we have confirmation that we have adequately addressed the chronic GLP toxicology issues of our first generation, arrow enac canine.

First we think we have confirmation that we have adequately addressed the chronic GOP toxicology issues of our first generation <unk> candidates.

Speaker 3: In that program, we saw findings of a local lung inflammation in chronic rad and monkey toxicology.

That program, we saw finance local lung inflammation, and chronic rat and monkey toxicology studies. We determined that this result was consistent with macrophage overloads syndrome, and thus we needed to make next generation candidates with improved potency enhanced duration of effect. So we can stretch out the dosing interval and reduce exposure.

Speaker 3: We determined that this result was consistent with macrophage overload syndrome, and thus we needed to make next generation candidates with improved potency and enhanced duration of effect so we could stretch out the dose and interval and reduce exposure. I think we are now over

I think we are now over that initial hurdle.

Speaker 3: We've received chronic toxicology results in both rodent and primate species for arrow rage and arrow MMP7. James will talk about the specifics, but the takeaway is that the NOAELs, or no observed adverse effect levels, suggests sufficient safety margins to move confidently into phase 2 study.

We've received chronic toxicology results in both the rodent and primate species for Aero Rage, and Aero MMP seven James will talk about the specifics, but the takeaway is that the <unk> or no observed adverse effect levels suggest sufficient safety margins to move confidently into phase III studies.

Speaker 3: These were welcome results. And I believe represent substantial de-risk for the entire pulmonary plaque.

Welcome ourselves and I believe represent substantial derisking for the entire pulmonary platform.

Speaker 3: Once we select a dose and dose interval for each candidate, we plan to interact with the regulatory authorities in 2024 to discuss all results to date, including toxicology, and our plans for further clinical development.

Once we select a dose and dose interval French cabinet.

And interact with the regulatory authorities in 2024 to discuss all results to date, including toxicology and our plans for further clinical development.

Speaker 3: Next, we want to ensure that clinical safety and tolerability are acceptable. We now have three pulmonary programs in first in human studies, and safety results have been consistent with no concerning safety signals across all three programs in 145 patients or healthy volunteers on active drugs.

Next we wanted to share the clinical safety and Tolerability are acceptable.

I have three pulmonary programs and first in human studies and safety results have been consistent with no concerning safety signals across all three programs and 145 patients or healthy volunteers on active drug.

Speaker 3: Third, we need to ensure that our pulmonary drug candidates are doing what they are intended to do.

Third we need to ensure that our pulmonary drug candidates are doing what they are intended to do with.

Speaker 3: There's still any patient data in Arrow NMP7 and Arrow Muck5AC to understand this. But Arrow Rage data has been very encouraged.

We still need patient data in <unk> and <unk> to understand this but arrow range data have been very encouraging.

Speaker 3: Normal healthy volunteers showed 89% mean max knockdown and 95% max knockdown of circulating S-Rage after two doses of 184 milligrams aerolase.

Normal healthy volunteers showed an 89% mean, Max knockdown and 95% Max knockdown of circulating S range. After two doses of 184 milligrams Aero range.

Speaker 3: At 92 milligrams, healthy volunteers showed a mean max knockdown of 80% and max knockdown of 90% after two days.

At 92 milligram is healthy volunteers showed a mean Max knockdown at the 80% and Max knockdown of 90% after two doses.

Speaker 3: We're still collecting data from asthma patients, but so far they are mapping on top of those from normal healthy volunteers, as we expect.

Collecting data from asthma patients, but so far they are mapping on top of those from a normal healthy volunteers as we expected.

Speaker 3: I believe these data are important for the Aero-Rage Program and more broadly serve to de-risk the entire pulmonary franchise. These data give us confidence that one, we have chronic talks, covers to move confidently into phase two studies for Aero-Rage and Aero-NV7.

Together I believe these data are important for the Aero range program and more broadly serve to derisk. The entire pulmonary franchise. These data give us confidence that one we have chronic tox coverage to move confidently into phase III studies for Aero Rage, and Arrow and <unk> seven.

Speaker 3: Two, the drug candidates have been generally well tolerated in humans. And three, we are seeing deep and durable knockdown in the Arrow-Raise clinical program that tracks with what we saw in animal study.

To the drug candidates have been generally well tolerated in humans and three we are seeing deep and durable knockdown in the Aero raised clinical program the tracks with what we saw in animal studies.

Speaker 3: The next step is to interrogate whether rage knockdown leads to a favorable clinical effect in patients.

The next step is to interrogate whether rage knockdown leads towards favorable clinical effect in patients.

Speaker 3: upstream of hard clinical outcomes or FEV1, but there are biomarkers that can inform on whether error range is engaging in inflammatory cow.

Dream of hard clinical outcomes, our FTB one.

There are biomarkers that can inform on whether arrow rage is engaging inflammatory pathways. We are approaching the time during the coming months, where we may have data on aero rage in asthma patients to make that assessment.

Speaker 3: We are approaching a time during the coming months where we may have data on oral rage and as a patient to make that assessment.

Speaker 3: We're currently dosing mild to moderate asthma patients and enrolling patients with high baseline pheno to potentially enrich for an anti-inflammatory signal. I believe that signal would represent a significant further de-risking event. So we are working quickly to get high pheno patients enrolling.

We're currently dosing mild to moderate asthma patients enrolling patients with high baseline.

To potentially enrich for an anti inflammatory signal.

I believe that signal would represent a significant further derisking event. So we are working quickly to get high female patients enrolled.

Speaker 3: The next area where I think we are creating substantial value is our progress toward becoming a commercial company.

The next area, where I think we are creating substantial value as our progress towards becoming a commercial company.

Speaker 3: Our phase three study of Plasasaran in patients with familial colomac kidney and biosendrome. This approaching completion, can we expect the last patient visit to be in the second quarter of 2024? That is a big step for development stage biotech.

Based on studying <unk> in patients with familial color Micronesia syndrome is approaching completion and we expect the last patient visit to be in the second quarter 2024.

It's a big step for development stage biotech company we are.

Speaker 3: We are carefully considering launch strategies for Plovaciran and look forward to speaking more about those soon.

Carefully considering launch strategies for both <unk> and look forward to speaking more about those soon.

So where do we go after Fcs.

Speaker 3: Data from Phase 2 studies of both Pudassaran and Zodassaran, formerly Arrow and Three, have been very compelling. In our presentations and webcast around the American Heart Meeting earlier this month were well received by physicians, industry, and the investment community.

Data from Phase II studies of both <unk> and <unk>, formerly arrow and three have been very compelling in our presentation and webcast around the American heart meeting earlier. This month were well received by physicians industry and investment community.

Speaker 3: For pleasacin, we see a clear opportunity to treat patients with severe hyperglyceridemia or SHTG.

For <unk>, we see a clear opportunity to treat patients with severe hypercholesterolemia or S. H T G.

Speaker 3: We believe there are three to four million people in the US with triglycerides over 500 milligrams per deciliter, with approximately one million of them with TG's greater than 880.

We believe there are three to 4 million people in the U S with triglycerides over 500 milligrams per deciliter with approximately $1 million of them with <unk> greater than 880.

There are very limited treatment options for these patients further we anticipate <unk> approval based upon studies, demonstrating a lowering of triglycerides during one year of treatment adequate safety profile.

Speaker 3: In phase two studies, podassaran reduced TGs, reduced TGs to lower than 500 virtually all patients, and many had TGs fall to normal levels.

And phase two studies, both Astro and reduce <unk> reduce <unk> to lower than 500 in virtually all patients and many had tg's call to normal levels.

Speaker 3: We are presented with a compelling set of facts. A large pool of patients without adequate treatment options, a clear and relatively short regulatory pathway, and a drug candidate that has been consistent and very effective in phase one and phase two studies with good tolerability.

We are presented with a compelling set of facts and large pool of patients without adequate treatment options are clear in a relatively short regulatory pathway and drug candidate that has been consistent and very effective in phase one and phase two studies with good tolerability.

Speaker 3: We've had productive interactions with FDA, including end-of-face-to-meeting, to discuss the design of a phase three clinical program in SHTG patients. We are finalizing planning, and I expect we will launch the studies early in 2024.

With that productive interactions with FDA, including end of phase two meeting to discuss the design of a phase III clinical program and S. HTC patients, we're finalizing planning and I expect we will launch the studies early in 2024.

Speaker 3: Beyond FCS and STG, we continue to see attractive opportunities to help a broader population of patients with plosas or N or with the zodiac...

Beyond <unk>, we continue to see attractive opportunities to help a broader population of patients with <unk> or with <unk>.

Speaker 3: Both candidates have shown a substantially, have shown two substantially reduced remnant cholesterol, increasingly appreciated risk factor of cardiovascular.

Both candidates have shown a substantially as shown to substantially reduce remnant cholesterol increasingly appreciated risk factor of cardiovascular disease I expect that we will conduct a cardiovascular outcome trial or Cmos that we will launch in and that we will launch it in the middle of 2024, we have been planning to run <unk>, but given the exciting data with <unk>.

Speaker 3: I expect that we will conduct a cardiovascular outcome trial or SEVOT that we will launch and end that we will launch it in the middle of 2024. We have been planning to run SEVOT with POSASRAN, but given the exciting data we presented at AHA in mixed-dislippin, in mixed-dislippinemia patients, we are now considering whether POSASRAN or ZodasRAN would be a better candidate.

Hey, Jay and mixed Dyslipidemia in mixed Dyslipidemia patients. We are now considering whether <unk> would be a better candidate.

Speaker 3: We expect to decide which is better suited for this patient population over the coming months. This is a good problem to have as both appear to be potentially powerful agents in this large market. And we simply want to try to ensure we are moving the best candidate forward in this space.

We expect to decide which is better suited for this patient population over the coming months. This is a good problem to have as both appear to be potentially powerful agents in this large market and we simply want to try to ensure we are moving the best candidate forward in this space.

Speaker 3: Also on the late stage side of our business, Takeda is enrolling patients in the phase three study of pazirceram. It is my understanding that they intend to open approximately 90 sites worldwide to help ensure the program moves quickly to an approvable endpoint that could be met after two years of pre-work.

Also on the late stage side of our business Takeda is enrolling patients in the phase III study of <unk>.

It is my understanding that they intend to open approximately 90 sites worldwide to help ensure the program moves quickly to an approvable endpoint that couldnt be met after two years of treatment.

Speaker 3: Our wholly owned programs, discovery engine, and burgeoning commercial presence are all exciting components of our business that we believe will create substantial value going forward.

Our wholly owned programs discovery engine and burgeoning commercial presence are all exciting components of our business that we believe will create substantial value going forward.

Speaker 3: They will also require significant capital over the coming years, and we are focused on building out our balance sheet to ensure that we can make these important best.

They will also require significant capital over the coming years, and we are focused on building out our balance sheet to ensure that we can make these important investments.

Speaker 3: To that end, we are actively working on opportunities to bring in capital in shareholder-friendly ways. And we believe there are several good options in front of us.

To that end, we are actively working on opportunities to bring in capital in shareholder friendly ways and we believe there are several good options in front of us.

Speaker 3: For instance, we are exploring specific product financing for the PlozacerN SHDG Phase III study and separately a possible C-Bot whether done with PlozacerN or Zodac.

For instance, we are exploring specific product financing for the <unk> phase III study and separately a possible <unk> when.

When they're done with <unk> or is that accurate. We believe we can source sufficient capital for those studies in return for limited royalties on those products.

Speaker 3: We believe we can source sufficient capital for those studies and return for limited royalties on those products.

Speaker 3: In addition, we have discussed business development in the past. We now have five different platforms that incorporate the design of high-quality RNA molecules that target five different cell types, hepatocytes, skeletal muscle, pulmonary, adipose, and CNF.

In addition, we have discussed business development in the past, we now have five different platforms that incorporate the design of high quality RNA molecules that target five different cell types.

Skeletal muscle pulmonary adipose and CNS.

Speaker 3: We believe this broad ability to deliver highly potent RNAi molecules to a variety of tissues is both scarce and valuable and could enable dozens of new drugs. We believe there is ample work, there's ample room to work with partners and also continue to build an extensive Holyoke pipeline.

We believe this broad ability to deliver a highly potent RNA molecules to a variety of tissues is both scarce and valuable and could enable dozens of new drugs. We believe there is ample work there is ample room to work with partners and also continue to build an extensive wholly owned pipeline.

Speaker 3: That is intended to continue to let artists go re-engined quickly while ensuring that one we focus on a more limited set of wholly owned assets to provide our commercial teams with the level of synergy and efficiency. Two, we continue to have access to necessary capital outside the capital market.

That is intended to continue continue to let our discovery engine quickly while ensuring that why don't we focus on on a more limited set of wholly owned assets to provide our commercial team with the level of synergy and efficiency.

We continue to have access to necessary capital outside of the capital markets.

Speaker 3: Three, we can continue to build more passive value as our partners invest in development and commercialization. And four, we can continue to serve patients.

Three we can continue to build more passive value as our partners invest in development and commercialization and for we can continue to serve patients.

Speaker 3: As we are able to provide better clarity related to the sources and magnitude of new capital, I believe a clear overhang in our stock may be removed. There is a lot of high quality work going on in the arrowhead and substantial potential value to be unlocked as we solidify our balance sheet. Stay tuned for details when we're able to talk more about it.

As we are able to provide better clarity related to the sources and magnitude of new capital I believe a clear overhanging our stock may be removed. There is a lot of high quality work on arrowhead and substantial potential value to be unlocked as we solidify our balance sheet stay tuned for details when we are able to talk more about it.

Speaker 3: I want to highlight one last event from the quarter that is ported. We announce the GSK reached an agreement with Jamsen to transfer exclusive worldwide rights to further develop and commercialize J&J 3989 to GSK.

I want to highlight one last events from the quarter that is important we.

We announced the GSK reached an agreement with Janssen to transfer exclusive worldwide rights to further develop and commercialize J&J $39 89 to GSK.

Speaker 3: If you recall, Genshin announced that they were just continuing Hepatized B research and later announced that they were winding down most of their Vex' disease and vaccine programs.

If you recall Janssen announced that they were discontinuing hepatitis B research and later announced that they were winding down most of their infectious disease and vaccine programs J&J.

Speaker 3: G&J 3989 was one of the discontinued programs of the Strategic Decision. That created uncertainty about.

J&J $39 89 was one of the discontinued programs of the strategic decision.

That created uncertainty about the future.

Speaker 3: Jansen was a good partner and we are confident the GSK will continue the diligent work the Jansen started

Janssen was a good partner and we are confident that GSK will continue the diligent work Janssen started.

Speaker 3: The transaction also builds on Arrowhead's relationship with GSK, which includes the 2021 exclusive license of GSK 453 to 990, formerly ArrowHSD, an investigational RNA-I therapeutic currently in a phase two study as a potential free with patients with alcohol related and non-alcohol-related liver diseases. We look forward to continuing our productive...

This transaction will also builds on arrowheads relationship with GSK, which includes a 2021 exclusive license of GSK for $5 three to 99 zero, formerly Arrow HST <unk>, an investigational <unk> therapeutic currently in a phase II study as a potential treatment for patients with alcohol related and non alcohol related liver diseases.

Look forward to continuing our productive relationship with GSK.

Speaker 3: With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier? Thank you, Chris, and good afternoon.

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

Thank you Kris and good afternoon, everyone.

Speaker 4: I want to focus on the significant progress we've made on Plussassiran, formerly Aero-Apositri, and Zovassiran, formerly Aero-Eng. This includes presentations at the American Heart Association meeting with phase two data on the New Year and Shasta II studies of Plussassiran and the Arches II study of Zovassiran.

Wanted to focus on the significant progress we made on <unk>, formerly <unk> and so thats <unk>, formerly <unk>.

This includes presentations at the American Heart Association meeting with Phase III data on the new year and set the two studies of <unk> and the <unk> two study so thats yet.

Speaker 4: a KOL webinar on the significance of this data and recent interactions we have had with the FDA on our plans for phase three.

<unk> webinar on the significance of this data and recent introductions.

With the FDA on our plans for the Phase III studies.

Speaker 4: Let's have a review of what the process is and then discuss the data presented at the AHA.

Let's start with a review of what <unk> is and then discuss the data presented at the AAN.

Speaker 4: Closer Cran is designed to reduce translation of apolipoprotene C3 or apoc3, a component of triglyceros-rich lipopropane or TRIO. And a key regulator of triglyceromnetavu.

Thats it and if you think of.

With used per those April lipoproteins, CTV or apoc, III, a component of triglyceride, rich lipoproteins or <unk> and a key regulator of trade patterns, a paucity increases plasma DTE level, but.

Speaker 4: ApoC3 increases plasma teaching level by inhibiting breakdown of the cereals by lipocryptin and lipase and uptake of the cereals remand by hepatoreceptors in delivery.

Activity in breakdown of TRL, VI lipoprotein lipase, an uptake of TRL remnants by hepatic receptor in the liver.

Speaker 4: Presertion is developed as a treatment for patients with familiar calomotronymia syndrome, severe hyperpricusidemia and mixed misleptidemia. These are three distinct patient population with very different phenotypes.

Because that's the only thing develop as a treatment for patients with familial <unk> syndrome, Davita hypothetical three damia mixed dyslipidemia. These three distinct patient population with very different phenotypes.

Speaker 4: Family and Colombian Syngram or FCS is a severe and ultra-rear genetic disease characterized by extremely high TG levels, typically over 1,000 million per desiliter, leading to high risk of acute pancreatitis that usually requires hospitalizations and can be safe.

Hello, Nicole <unk> syndrome, or FCS is a severe rare genetic disease.

<unk>, Hi, DT level typically over 1000 milligrams per deciliter, leading to high risk of acute pancreatitis that usually pretty quiet hospitalizations and can be fatal.

Speaker 4: were contemplating the Palacese Phase 3 studies in 75 patients with FCA.

<unk> taken the team the palisade phase III study in 75 patients with Fcs.

Speaker 4: The primary aim for the study is percentage from baseline and fasting teaching.

Many input of the study is the same change from baseline in the <unk>.

Speaker 4: Palisade is a schedule to complete in Q2 of 2024.

<unk> is scheduled to complete in Q2 of 2024.

Speaker 4: Severe hyperfluidemia, or SHTG, is characterized by marked elevation in TG levels, typically over 500 milligrams per deciliter, which can also lead to increased risk of acute pancreatitis, as well as an increased risk for cardiovascular disease.

Hypothetically linear or SPT conducted by Merck elevation in DG levels typically over 500 milligrams per deciliter, which can also lead to increased risk of acute pancreatitis as well as an increase III for cardiovascular disease.

We conducted the phase II assessed the two study and reported data at AAN.

Speaker 4: We're also working on initial on phase three studies, just a three and just a four in early 2024. I will discuss the AHA data and phase three study design in a moment.

But also working on initiating phase III studies suggest that <unk> set the floor in Italy.

Thousand 24, I will discuss the AAJ Veda on Phase III study design in a moment.

Speaker 4: Lastly, mixed Lithuania is the presence of high-teaches and renman cholesterol often with low HDL cholesterol. Renman cholesterol is believed to be a major contribution to the residual risk of heteroclorosis cardiovascular disease after LDL is well controlled.

Okay Lastly, mixed dyslipidemia.

Is the business of <unk> and <unk>.

With low HDL cholesterol.

And cholesterol, if they need to be a major contribution to the receivable risk.

Carlos is kind of the left let me see asset LDL is well control.

Speaker 4: We conducted the phase two New Year study in patients with mixed sleep anemia and reported dose beta at AHA.

We conducted the phase II, new study in patients with mixed Dyslipidemia and reported those data at AAN.

Speaker 4: We're currently working on key features of the study design, including patient population selection for the potential phase three study in patients with ACVD and mixed sleep events. We presented data at AHA for these last two patients' population, SSTG, and mixed sleep events.

Hey.

But currently working on key features of the study design, including patient population selection for the potential phase III study in patients with HCV unmixed.

We presented data for.

These last two patient population.

<unk> and <unk>.

The phase II <unk> two study of <unk> in 226, <unk> <unk>, who has basically entities that eight of them 500 media servicing litter two doses of <unk> 25, or 50 milligrams. Assessing then once every 12 weeks.

Stg's to near normal levels and more than 90% of patients achieved <unk> levels below 500 media instead of this year.

Which is the risk which is at least official Ford acute onset diabetes.

<unk> achieved mean maximum dilution of up to 90% in April and 87% in <unk>.

At 24 weeks towards.

12 weeks after the second dose sit on a policy remains 79% below baseline ntt's was 74% and below baseline with reductions in glenmont collected of 63%.

HDL increase.

Increased 58% above baseline.

The phase III <unk> study of <unk> in 353 subjects with mixed Dyslipidemia.

Ntt's between <unk>, 50, and 499 milligrams per deciliter, and EBIT LDL cholesterol greater than 70 milligrams per deciliter.

Non HDL cholesterol greater than 100 million as the visit.

That's used in the study received two doses of $10 25, or 50 milligrams of necessity.

Based on <unk> at week 12.

So 50 million baseline and week 24.

So Seth you then treating subjects demonstrated a mean maximal dosing a paucity of up to 89% and robust reduction with net debt of Jimmy lipoproteins.

At 24 weeks, assessing and reduced <unk> by 54% Redmond cholesterol by 54% April by 19%.

Non HDL cholesterol by 27%, while increasing HDL cholesterol by 51%.

These were very encouraging results and they've received a lot of attention.

Okay.

After the presentations, we hosted a webcast featuring three expert in the treatment and management of lipid and lipoprotein disorders.

Danielle.

Professor of Medicine University, Montiel, who will discuss the <unk> in the context of the current treatment landscape for <unk>.

Hypothetically Dania.

To date, no discussed professor and Chief decisions, Copenhagen University Hospital University of Copenhagen, Denmark will discuss the merchant goal of friends around call. It 30 in cardiovascular disease.

Steven Nielsen Chief Academic officer for the heart and vascular Institute at the Cleveland Clinic, who discuss why the decreasing net debt attending proteins of settled with necessity then has the potential to Cleveland.

Okay.

A replay of that webcast is available on our website if you missed it.

My takeaway was that all the experts agree that processing that FSC unique profile and great potential in FCA SST and in patient with CBD and mixed Dyslipidemia in support of these notable experts us additional confidence as we embark on phase III.

Studies to further evaluate process yet.

So what would be assessed the <unk> phase III studies look like.

We had an end of phase II meeting with the FDA and our plan is to do two similar studies <unk> and therefore that together will be composed of approximately 70% of the patients all with DT is greater than 500 milligrams per deciliter.

The primary aim plenty slowing tg's. After one year. We will include a subset of patient that high at least with acute pancreatitis, who will provide more detail on that as we gave the studies initiated in early 2024.

We also have a third study that enrolled patients.

Moderately elevated TTS to add to our safety database.

We expect these studies to all be completed around the same time.

All in all our interactions with FDA have been productive unhelpful, we believe that we have incorporated their feedback and look forward to continued dialogue with the agency as we get closer to an NDA filing following completion of the palisade study in patients with FCS and as we move forward with additional <unk>.

<unk> and mixed Dyslipidemia.

We also presented data at AAN so.

Thats yen, which received a lot of attention. So that it is designed to reduce production of <unk> protein three or <unk>, TD LTE, which is.

Better say express regulator of lipid and lipoprotein metabolism looking multiple potential in multiple fashions, including inhibition of lipoprotein lipase.

And the quality of life.

And the phase two study.

A study of <unk> in 204 subjects with mixed Dyslipidemia, who had baseline <unk> between $1 50, and 499 million.

They're either LDL cholesterol greater than $70 million per distributor or non HDL cholesterol greater than 100 milligrams per deciliter, two doses of 50 milligrams 100 media. So 200 immediate answer so let's see them. Once every 12 weeks reduce expression of HPLC and decrease at the allogeneic <unk>.

Protein.

We've divested and resulted in substantial reductions of <unk> up to 74% which is.

Up to 63% LDL cholesterol or up to 20% rent mangala fill up to 82% in April would be up to.

22%.

Week 24.

So that's the that was also associated with relative that obviously liver fat fraction at week 24, with no adverse events related to leave a finishing this changes reported today.

<unk> continued to show a favorable safety profiles treatment emergent adverse events reported today reflect the comorbidities that underlying conditions of the study population.

As I mentioned before were currently considering multiple phase III studies in science, and making decisions on patient population selection for mixed dyslipidemia in patients with cardiovascular disease, who will talk more about that in 2024. After we have further interactions with FDA about <unk> proposed plan.

I will now turn the call over to Delta change comment on James.

Thank you Javier.

I believe the productivity of our discovery organization is unrivaled. This is partly due to the efficiency and scalability of SA RNA therapeutics, and specifically of our proprietary trim platform, but more importantly.

<unk> of the culture of speed and innovation at Arrowhead.

We continue to find ways to outperform others and the RNA therapeutic space highly productive and lean organization.

In 2023 alone, we completed discovery and optimization work across five different delivery platforms and nominated nine clinical candidates.

Each then may go on to the IMD, enabling phase, including GOP toxicology studies.

Cynical supply manufacturing as well as preparation and submission of regulatory filings.

We are also working on a discovery pipeline of similar size for 2024.

This high level of productivity is how we intend to reach our 2020 five development goal.

Our discovery stage pipeline is for the most part kept confidential until until we are approaching a cta.

At times until we file a cta.

So you will likely start hearing more about the newly nominated clinical candidates over the coming quarters.

For example, yesterday, we announced that we filed the Cta for Aro <unk>, our clinical candidate for the treatment of patients with type one my atomic dystrophy, or <unk> and our second clinical program using the trim platform for delivery to skeletal muscle.

The phase one two a dose escalating study will evaluate the safety Tolerability and PK PD profile of single and multiple ascending doses of <unk> compared to placebo and up to 48 patients with <unk>.

<unk> is designed to reduce expression of the dis <unk> my attack a protein kinase or DNP caging.

<unk> is the most common adult onset muscular dystrophy and there is currently no approved disease modifying therapies.

Treatments are focused on symptomatic management, including physical therapy exercise ankle foot orthosis wheelchairs and other assistive devices.

<unk> represents a novel approach to treat <unk> worn by silencing accurately transcribed GMT, K mrna, which could lead to improvements in multiple symptoms, including muscle strength and function.

We have several exciting early stage clinical programs that target genes expressed in the liver lung muscle in CNS each of which is moving towards proof of concept data.

However, I will focus on the three pulmonary programs specifically.

Specifically I would like to review safety and Tolerability data to date.

Recent chronic toxicology results that I think help derisk, the pulmonary platform broadly as well as some new PD data that further support our plans to rapidly move all programs forward.

To review, our three clinical stage pulmonary programs are the following.

Aero Rage is designed to reduce expression of the receptor for advanced application and products or rage as a potential treatment for inflammatory pulmonary diseases.

<unk> is designed to reduce production of newsome, five AC or modify they see as a potential treatment for musical obstructive pulmonary diseases.

Aero MMP seven is designed.

To reduce expression of matrix metallo protein, a seven or MMP seven as a potential treatment for idiopathic pulmonary fibrosis or IPF.

All three of these programs are in phase <unk> clinical trials evaluating single and multiple doses in normal healthy volunteers and in patients.

Across the three programs of 145 total subjects, both normal healthy volunteers and patients have received active drug via inhalation with another 31, receiving error rates via the subcutaneous Ralph.

There have been no serious adverse events deemed to be related to drug.

There have been no patterns of drug related adverse events pulmonary adverse events, such as call for shortness of breath or adverse changes in laboratory around the three values.

There has also been no evidence of local lung inflammation based on Bell cell count evaluation in our chest X rays have been read as normal.

These safety and Tolerability results have largely been consistent across the three programs that are highly encouraging for the pulmonary platform.

Next I'd like to cover the chronic toxicology results for Aero Rage in Aero MMP, seven, which we recently received.

These results are also highly encouraging and suggest that we have sufficient safety margins to proceed confidently to phase II.

Specifically for Aero Rage, no observed adverse effect level of noise.

And the six month Rat study was the mid dose and in the nine month Monkey study. It was the highest dose study.

For Aero MMP seven the retina oel was the highest dose in the monkey in Ohio was the mid dose.

Keep in mind with dose level selected for GOP toxicology studies are high multiples of the desired clinical dose. So some findings toxicology study are expected.

The results for both Aero Rage in Arab MFC seven suggests that the learnings and improvements we have made since our first generation pulmonary candidate arrow enact have improved the therapy therapeutic index for our inhaled <unk> programs.

And the feedback from regulatory authorities, we are confident that he will have the required safety margins to begin phase III studies.

This is an important step for the pulmonary platform at an important time as we look to design and initiate phase two studies in 2024.

Now moving onto the new Pharmacodynamic data.

<unk> continues to yield promising dose dependent target engagement results with.

We previously reported impressive reductions in soluble rage protein or S rage in serum and in Bronchoalveolar lavage fluid for balanced and healthy volunteers.

Previously reported at our June analyst R&D day. After two doses of <unk> 92 milligrams given on days, one and 2009 serum <unk> mean maximum reduction was 80% with a maximum reduction of 90%.

After a single dose of 184 milligrams, we observed a mean reduction of 90% and maximal reduction of 95% in Belfast Rage with mean maximum serum <unk> reduction of 76% and Maxwell reduction of 91%.

We have since received additional <unk> data after two doses of 184 milligrams in healthy volunteers.

After a second dose of 184 milligrams serum <unk> mean maximum reduction was 89% with a maximal knockdown of 96%.

Additionally reduction of serum rage, <unk> with similar in healthy volunteers and in patients with asthma at the 44 milligram dose level.

So what are the next data points that we're watching.

Currently enrolling the top dose cohort in the mild to moderate asthma patients and have initiated a cohort of asthma patients with high baseline levels of fractional exhaled nitric oxide or <unk>.

Which is a biomarker for the degree of IL <unk> 13, driven type two inflammation in the lung.

These are both important to watch if we continue to see consistency of PD effect in asthma patients that would be encouraging.

Also it would be highly encouraging if rates slow knockdown.

<unk> two an anti inflammatory effect via the female biomarker and either the mild to moderate asthma patient cohorts or more likely in the high <unk> cohort.

The former should have data available during the coming months and the latter will have the data around Q3 of 2024.

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

Thank you James and good afternoon, everyone.

As we reported today, our net loss for fiscal 2023 was $205 3 million.

For $1 92 per share based on $106 8 million fully diluted weighted average shares outstanding.

This compares with a net loss of $176 1 million or $1 67 per share based on $105 4 million fully diluted weighted average shares outstanding for 2022.

Revenue for fiscal 2023 was $240 7 million compared to $243 2 million for 2022.

Revenue in the current period, primarily relates to our collaboration agreements with Takeda GSK and Amgen.

Revenue is recognized as we complete our performance obligations or key development milestones are reached for Takeda revenues recognized commensurate with our performance obligation, which includes managing the ongoing <unk> phase III clinical trials.

866000 of revenue to be recognized associated with the Takeda collaboration which will be recognized in the next fiscal quarter.

Revenue in the prior period, primarily related to the recognition of payments received from our license and collaboration agreements with GSK and a portion of the payments received from our license and collaboration agreements with Takeda in horizon.

Total operating expenses for fiscal 2023 were $445 7 million compared to $421 7 million.

Please remain on the line and your conference will resume shortly.

Again, please remain on the line your conference will resume shortly.

Please remain on the line your conference will resume shortly.

We are currently experiencing technical difficulties and we are trying to get back online please bear with us.

Yeah.

We are currently having technical difficulties and were trying to get back online please standby and.

And thank you for your patience.

Hello.

Yes.

Okay.

Hello.

Yes, you are now back online.

Yes.

Sorry, Bulks, we lost our Internet connection.

We're calling it out as a cell phone will continue where I think we are left off.

Total operating expenses for fiscal 2023, or $445 7 million compared to 421.7 million for 2022.

This increase is driven primarily by increased candidates specific and discovery R&D costs as a companys pipeline of clinical candidates have both increased and advanced into later stages of development.

Net cash used by operating activities during fiscal 2023 was $153 9 million compared with net cash used by operating activities of $136 1 million during 2022.

The increase in cash used by operating activities is primarily driven by higher research and development expenses.

We expect our operating cash burn to be $110 million to $130 million per quarter in fiscal 2024.

And we expect full year capital expenditures of approximately 150 million as we near completion of our GMP manufacturing facility.

Turning to our balance sheet, our cash and investments totaled $403 6 million at September 32023.

Compared to $482 3 million at September 32022.

The decrease in our cash and investments was primarily due to cash used for operating activities and capital expenditures, partially offset by cash inflows from financing activities.

Our common shares outstanding at September 32023 for $107 3 million.

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

Okay.

Okay.

Thanks, Ken.

<unk> had another productive quarter and we.

We see wide open space to accelerate our growth over the coming year.

We expect 2024 to be a data and event rich year with many expected opportunities to create value, including readout of the blood ASUR and FCS phase III.

Filing our first NDA.

Launching a phase three four S. H T G with pedestrian launching a phase III seaboard with either of those as ran orange in Odessa ran.

[noise] readout in various patient populations with <unk> three.

Initial CNS data in patients with Aerostar one.

Aero Rage, Pheno and knockdown data in asthma patients.

Aero MMP seven knockdown data in IPF patients.

Aero Mach five AC knockdown data in asthma, and COPD patients and initiation of first in human studies with our first adipose targeting candidates.

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

As a reminder to ask a question. Please press star one on your telephone and wait for your name to be announced to withdraw. Your question. Please press star one one again please.

Please standby, while we compile the Q&A roster and we ask that you limit yourself to one question.

And one moment by first question.

And our first question comes from Edward <unk> from Piper Sandler Your line is now open.

Credit. Thank you very much. Thanks particular classroom I'm excited about all the progress on the cardiovascular side I wanted to ask about the idea one filing today.

Because now with this I think you guys also recently may be followed on doctors for if I'm remembering correctly. So this was really a franchise you're starting to build in muscle is this going to be a core area or could this be one of the areas for potential partnerships that you were highlighting.

Thanks.

Hey, Ken Thanks, very much and again, we're really sorry for the technical problems here.

I think you're right you know, we view Scott our muscle as as potentially another vertical another franchise.

We think both the M. One and Ducks four are good targets. We think if these are these are you know.

Two large numbers of patients who desperately need treatment options and so we're excited about these we.

We are we are looking at add some additional targets as well and so and so we'll see if this can grow to be something as large as we foresee a pulmonary being for instance, I at this point, it's a little bit too early to tell but but but I would agree that right now it appears to be pretty interesting burgeoning.

Franchise for us.

Great. Thank you book, Nevada, Mr Muramoto.

Thank you Ted.

And thank you.

And one moment for our next question.

And our next question comes from Ellie Merle from UBS. Your line is now open.

Thanks, so much for taking that question.

The color on that timeline and asked for the pulmonary program.

Maybe just in terms of understanding the biology of range, particularly in the high seen alcohol cohort I guess, what are you looking to see that and what would you view as clinically meaningful thanks.

Okay.

I'd like to start this year.

The objective in ticket.

And it shows.

We would expect to see at the reductions in you know primarily based on our animal data.

The work we did in the Alternaria model showed steep reductions in IL 13, we can't measure schiano in rats.

A large reduction in IL 13 should translate into a reduction in pheno.

And in terms of what would be clinically meaningful based on what we're seeing with <unk> or is excellent I think something in the 30% or so range and would would put us.

It in the range of what those other molecules have been able to show.

And again.

Davis.

Yes.

Great. Thanks.

And thank you.

Okay.

And one moment our next question.

And our next question comes from Maury Raycroft from Jefferies. Your line is now open.

Hi, Thanks for taking my question.

I was going to ask one on Aero rage too.

You mentioned that in patients.

The data is mapping with what you observed in healthy volunteer data can you elaborate on whether you're seeing this for your 92 and 184 Meg asthma patients egg could you have the F&B one data from these non fino patients.

Potentially even by year end or first quarter of next year I guess, maybe.

If you provide more granularity on the timeline there and also you met you talked a little bit about the sub Q Arrow rage data.

Can you remind what are can you talk about what youre seeing there and remind what the purposes of a resetting that route of administration.

Sure So I'll take those in reverse order since some.

Some sub Q.

We're still about halfway through.

That study the study is fully enrolled but.

With healthy volunteers over just collecting the data from some of the earlier cohorts.

We're not ready to share the S range data from those studies, yet the and the idea there is that based on the animal work. We've done we were able to see significant levels of knockdown.

In the in both rodents and in monkeys with subdue administration. So we wanted to do.

Viewed that as a potential additional option with an optional route of administration it could be different from an inhaled route of administration.

Then the next question I think was on F&B, one and that we see.

<unk> seen those data as they come in.

It's primarily in there as a safety end point and the cohort sizes are very small we have not analyzed those data in the.

The patient cohort that we have.

At this time and so I think it's too early for us to say anything about F&B, one changes suffice it to say that the cohort sizes or single digits and PD one can be a noisy metric and then the first question was.

With mapping of.

Additions that's right if we only have the S antigen data.

S rates reduction data from a 44 milligram dose level in the patients. So we've not seen the S range reduction data from 92 milligrams or 184 milligrams.

Got it okay and for MTV one at baseline is that something you can comment on for <unk> for the asthma cohorts the higher dose cohorts.

Yeah, again, I think we.

We don't have all of that the aggregated data as of yet.

Big cohort supposedly aggrieved savvy Whitehall mild.

Asthma patients. So it just takes it could have been a more model based on inputs as well.

Got it on the most patient for the Hino cohorts.

<unk> program by the day rates asthma, they had a mild patient by definition.

Got it so more mild patients in and the expectations for those two higher dose cohorts.

Okay. Thanks for taking my question.

Thanks Laurie.

And thank you.

And one moment for our next question.

Sure.

And our next question comes from Manny <unk> from Leerink Partners. Your line is now open.

Thanks for taking the question.

Yes, I'm gonna do out on strike and ultimately more macro and philosophical question.

You talked about.

Or monetize.

Some type of synthetic royalty or royalty sale monetization you talked about a couple of different approaches to finance the ongoing cbot.

In my mind raise of two questions. One that is by definition anything that's royalties.

Fairly high duration.

Financing instrument and then it's essentially a form synthetic debt.

How do you think about timing.

Our royalty or I guess convert any type of that type of rate dependent transaction, given how volatile the funding rates of anyone who would be buying a royalty from here would be to do or wait until they come down to see if you could potentially get a tighter spread et cetera is just how do you think of that from a purely financial CFO macro perspective.

And then secondarily.

Going to stop I'll ask my follow up afterwards.

Sure.

So that.

The short answer is no. We are we are we would not.

Wafer macro environments to change that you know who knows what.

Who knows where those are going to go.

There are there are there are.

Several thunders multiple vendors that do this kind of work.

And we have been we have we've been chatting with some of them.

For a bit now and and and and we believe that there are that could be attractive opportunities there.

That are not dependent upon.

Fundamental changes in the macro environment. So so we feel comfortable that there that there are there is capital there at <unk>.

At a reasonable range for us to finance these and this kind of manner.

Will we ultimately pull that lever we have we haven't made that decision, but we just wanted to make clear that that is a lever and potentially attractive lever that we could call as as part of an overall financing strategy.

Great and I guess my follow up is if youre going to be selling part of the economics of an asset, but youre going into our Cdos Hugh hop, but how do you think about that versus partnering the asset entirely rather than G by yourself.

Zuma via large pharma partner.

Woods water scribed, a lower a lower operational discount.

They're only carrying out of a CDO G versus you guys doing their first cbot.

Implying more are more attractive and can be if they were to acquire the asset from you in our partnerships.

100% purchase royalty 50, 50 any of them under any terms.

By definition, the economics of a partnership would be better doing raising capital doing yourselves, so but how do you. So is there a reason why you see retaining it and then raising at an implied higher cost of capital.

The better strategy rather than.

Selling it at an implied lower of partnering at an implied lower cost of capital and eliminating the operating risk of having to do with Cvs to yourselves.

The outlook look those are all things that we consider as we as we we look at the array of funding opportunities ahead of us.

Okay.

Uh huh.

Pain, some mineral royalties on these is relatively cheap for us because we're not stacking royalties. We don't we don't owe royalties on any of these assets and so and presumably also those worlds recapped, presumably that would not go.

Indefinitely.

But but youre right as we look at all these and all of these opportunities.

Need to take all those things into consideration.

We see ourselves as a commercial company. We think we can create a lot of value as a commercial company and so and so assuming that that are.

The relative cost of capital.

While holding on to these assets is reasonable then that's something that we would do.

Alright, Thanks, guys that's really helpful.

You're welcome.

And thank you.

And one moment.

Our next question.

And our next question comes from David Leibowitz from Citi. Your line is now open.

Thank you very much for taking my question just piggybacking on the last question.

As far as any licensing agreements here looking at our U.

Planning to wait until after the pivotal data and also what activity level are you intending to really take within the partnership is this something where you're going to be very active licensing to kind of a one of these royalty companies or would this be something more specific where you're basically gaining control of the asset.

Two a larger pharmaceutical player.

Yes.

The answer that it just depends on the asset of course, you know we have done and will continue to do asset licenses like we do in HST, our HBV or AEG Argos Ags will be different because we definitely have to capture there, but but but or <unk>. There we.

We'll do those going forward.

Depending upon the asset.

Look our RV.

Here's uncle.

We have a very large pipeline and it's and it's only going to get larger and so we've got plenty of room to license out some some individual assets. What we wanted to beat what we want to end up with is a series of verticals, where we can concentrate commercial.

Build out.

And and we can give our commercial team.

Several drugs to hold in the bag to to sell into various channels.

I think we can do that given our franchises with pulmonary muscle.

Cardio metabolic.

Yes.

CNS et cetera, adipose et cetera.

So I think we can do that and.

And as we look at how the cluster of those.

We will find that there are some outliers if you will some that may not fit well.

Into a commercial strategy and those would be the easy ones those with easy ones to two to license out. We also have the opportunity to do platform deals. We've talked about this in the past I like that a lot and we now have five platforms five different cell types that we can that we can address them I like the idea of working with partners, who can bring in targets to us and we can help too.

To create drugs for those partners.

That for me is bound value as long as those have those.

As targets or not we're working on right now and so maybe it's an unsatisfying answer because because we'll be doing a number of different things, but that's the way we see the the waterfront and again, we are one or two.

Asset company, then the answer would be much simpler, but we are we are a 20 plus asset companies.

And so so we have the ability to infrastructure a number of different.

Our partnerships and go to market strategies for ourselves.

Thanks for taking my question.

Welcome.

Thank you.

And one moment for our next question.

And our next question comes from Luca I see from RBC capital. Your line is now open.

Oh, great. Thanks, So much thing a question congrats on the farmers have a quick one maybe Javier if I may.

And then the impression that you were planning a cardiovascular outcome trial with apoc three while it sounds to me that you are now planning cardiovascular Concord, either with apoc, three or <unk> three assuming that that is correct.

What drove the change in strategy was different for by conversations with the FDA and is this related in many saw former shape with the numerical worsening English Simi control that we've seen for April secret any color there much appreciate it thanks so much.

Thank you for that question has been really really important and I think this.

Highlight how dynamic is.

Those development today, and how fast science change in advance.

If we go but I would say six to nine months when we're ready we're thinking and working on a sequel play on design for <unk>.

Adjusted annual Halo Apoc III.

Focus wounds triglycerides and the field was focusing today gives us a key component of the receivable base.

The last six months.

I think that focus change and I'm, saying in the last six months take aside the node you call into the Kols webinar.

The American Heart Association.

<unk> showed a slide where you see the number of publications and remnant cholesterol as a company of that receivable risk in the last 10 years, which was <unk> 28 per C versus count them in the last one yet that means the change of this deal is happening as we speak.

And the understanding that it's not just D. G. By these redman cholesterol and the totality of the Atherogenic Lipoproteins is there no development and frankly six months ago nine months ago. It was in a key component of our decision, making and it is now and it's been in the last three months.

So now when you look at the tool.

Molecules and you focus on the concept of totality affected attending lack of protest no T. G. R. <unk> D. G only because remember for D. G. A perceived has built an efficacy there.

Agency that when you look at the totality of had been attending led the protein.

It'll age three to reduce LDL cholesterol by 20 plus percent previous remnant cholesterol by 80%.

So it is substantially different.

The population that we should address it may now be exactly the same and that's something that we're seeing.

<unk> thinking and talking to experts right now.

So I think we're like changing following the science.

We did have conversations with some expenses, we did not have any conversation about these with the FDA yet and.

And within the next month or so we'll go next to.

Close to to make a decision on offense will be find out what next steps from a regulatory perspective from the clinical trial design perspective.

And I don't think this was I don't think you're you're getting towards that but let me just say it.

Our our increase in interests in and three of.

Doesn't reflect a lack of confidence in equals three.

We were moving forward to that at your forward on that as you point out for CEVA, but as that as the science has been moving up.

As Javier said over the last six months, we've had this growing wait a minute moment, where we're.

Where we should be looking also at Ns III just to ensure that we are pushing that.

The the best candidate that we can into into a specific type of <unk>. We are we still.

We are still moving as quickly as we can obviously with FCS where he will be finished with that phase III I think in the second quarter will.

We will be starting the <unk> phase III early 2024, and now we've got a little bit of time to figure out where we're going to place a bet with the C box.

Alright, thanks, so much guys.

Welcome and thank you.

And one moment our next question.

And our next question comes from Brendan Smith from TD Cowen. Your line is now open.

Great hire thanks for taking my questions Congrats on the progress.

Just a couple quick ones if I could.

<unk> had a follow up just on the timing to pulmonary and it is it is it fair to say, we'll see the high dose range data in asthma patients by Q2 of next year.

With the high Pheno data in Q3, and then really just any color you can give us on Macquarie 8-K M 87.

Maybe when we might see some of that data next year would be great.

And then quickly I just wanted to see if there's any update on the aerospace three program and if there's any plan to put out any data from that next year either.

Sure Jay.

Yeah.

Sure Yeah, the intention would be to really.

Lease V S rate data from the asthma cohorts.

When it becomes available tourists.

Probably.

Yes.

The middle of the first half of next year I think for the the asthma the high dose.

Asthma estrange data.

And then in terms of snow.

In the the ico cohorts to be able to hit Q3 or half of D&O data in those.

And those patients and then Marc why they see Ed has been in a little more challenging to enrol speed.

Some protocol requirements and they're in a requirement.

Of those patients being severe asthmatic.

But.

Likely towards the middle of the year for four months, they see data, who still need to enroll in the highest dose cohort of those patients.

In terms of suite three we are in the process of enrolling.

Patient cohorts, the Iga nephropathy patients as well as the Super gene patients so probably the second half of 2024 four.

Rosemary O data.

Alright, great. Thanks, very much appreciate it.

Thank you.

And one moment our next question.

And our next question comes from ink, Montana from B Riley Securities. Your line is now open.

Good afternoon, thanks for taking our questions. So maybe James if you could dive a.

The deep layer on the safety margin difference that you've seen between must buy versus raised in the recent preclinical data that we receive them and if you are able to Colin Dunn, our venmo as doses four month five correlate the tacos, that's being tested in the clinic and and and maybe at a high level question on like what.

Four months five would be.

Human proof of concept like be like investors to think about.

Part of the eight are at an age and download Pinot hiring asthma patients like you just commented COVID-19 asthmatic patients, but what sort of biological.

Signal would be irrelevant given obviously this is more downstream physiology to IL four efficacy.

Yeah, I think on the last question, Mr fifth tough to pin down what's clinically relevant in terms of markdown. They see knockdown since there's not a great correlate out there from.

From other drugs.

So I can't give you an exact number on that.

In terms of the safety margins.

Comparing.

MMP, seven or or wage we would enact I guess it depends on the dose level, we use a low mid and high dose level four for all of those chronic tox studies in rats.

If you compare with cumulative dose given over a six month rat study.

At a.

The high dose level four.

For wage we had there was a seven fold difference between the high dose level.

Used in and enact and in Enrage bin of four to five fold difference for MMC.

<unk> seven and the <unk>, so it's a significant difference between.

The total cumulative doses that were administered in in those two with those two different molecules.

Got it. Thank you and then just on the muscular targeting programs <unk> Liang widened could could you just remind us the targeting receptor ligand approach here and as obviously you guys know.

Active field there are the native antibody asphalt brilinta is maybe how does sort of your preclinical data in farm.

What <unk> seen.

And maybe related to that is the key.

<unk> secured non dilutive capital for that no longer a near double then Chris are you just going to be opportunistic.

And recognizing that there might be some organic or data coming in from these targets from any of your peers.

I'm, sorry, I misunderstood the debt what kind of capital it's in say that again.

Yeah, I think you had plans for non dilutive capital at some point, which delayed the ducks, Florida programs on I'm just curious if you had no longer.

Going to do anything strategically there are for the muscle in the near term.

Right Yep Yep that ran its course for now.

We are happy to have to run the <unk>.

To run the ducks for as well as being one.

Our clinical programs and an end.

Which does not mean that we will never partner them, but but.

We were exploring as you as you know we are exploring potential partnering drugstore and it just made sense to us too.

To start those discussions and we're moving ourselves right now of James Wang Sure and then on the comparison with the other muscle targeting platforms that are out there.

The B M, one and <unk>.

We've looked at.

At knockdown in the Chenault and have achieved.

Parity similar knockdown with similar duration of effect with whats been published or for example, the transfer targeted platforms. We.

We used the <unk>.

Peptide carrying the alpha beta six inch.

Integrin sorts of differently in a different way of getting the S RNA into the shell.

I think we in terms of total drug.

Dosage or dosages should be much lower compared to that with the transferring conjugates, which of course conjugate MSR on a tour that a monoclonal antibody.

And then I would also anticipated.

We would not expect to see some of the transferring related safe.

Safety issues that have been out there of course, but time will tell on the data will tell us, but it's something we did not anticipate.

Okay. Thanks for taking our questions.

You're welcome thank you.

And one moment our next question.

And our next question comes from Patrick <unk> from H C. Wainwright <unk> Company. Your line is now open.

Thanks, Good evening, just regarding the 2020 five targeting goals can you give us a sense of from which platforms to 'twenty drug candidates are expected to emerge from understanding several have been announced this year and if along with CNS pulmonary liver adipose and muscle up additional tissues may be targeted with trim.

But I don't have any guidance. It would tell you on additional cell types other than the fact that we will be in new cell types.

We've said publicly that we think we can get into as a new cell type every 18 to 24 months I think that continues.

Look I expect I expect by the year 2025, we will we will have new.

Our additional candidates and every one of those those are <unk>.

Articles.

Got it and then just a few follow ups on the pulmonary compounds just first regarding initial chronic tox results to the Aero Ray Janiero M. P. Seven I'm wondering if you can tell us if for one further chronic tox data is expected in the level of confidence that data should continue to support advancement of those programs and when you.

Have similar data for Aramark five ASC in 2024, and just to follow up on Aero reach if you can discuss the targeting mechanism of the sub Q administration.

And advantages that would be expected for this route relative to the inhaled route.

Yeah sure Shane in terms of with chronic rat or the chronic tox data for the pulmonary programs that that's it I mean, that's the that's the final.

Yeah. The vessel from the final report so there's there's no more expectations.

We won't be getting any more data around chronic tox for MMP seven or rage.

For multi they see it we're still planning the chronic Tox study, we wanted to and to get some biomarker data from the clinical study to better inform on.

And the dose frequency for the chronic Tox studies since frequency of administration seems to be really important to avoid entering into a.

Dose levels, where we see toxicity, we really wanted to nail down dose frequency. So we need to get that duration of effect from the clinical studies.

Before we finalize the chronic tox studies from our policy.

And regarding regardless of Q.

Our thinking there was twofold, one there there could be other targets and other indications where sub Q administration is just.

Preferred to inhaled.

And second it could that could potentially also broaden widen out our therapeutic index.

Great. Thank you very much.

Welcome and thank you.

And one moment for our next question.

And our next question comes from Frank Cor Agro law from Cantor Fitzgerald. Your line is now open.

Hi, Thanks for taking my questions and congrats on the progress. So on your Aero X D. Edge program that was partnered with horizon. It seems that Amgen has decided to terminate this agreement.

Was there any data generated by exchange program or was it just part of the recent strategic or all by Amgen After horizon is close.

And what are your plans for this asset now develop internally or will you be looking for a partner again. Thank you.

So it's it's early to say on that we haven't seen data.

I don't know that we will but at least at least so far we haven't seen any any of the clinical data and so and when we and we've not been told.

Why that was being discontinued whether a strategic or something else.

We have some theories.

James you want to talk about the <unk>.

Island program for instance, we procure yet.

Another company at a Mezz Fahrenheit exiting the same team with XT eight there was also a discontinued.

Who lack.

Decline in your gas it in the blood.

Even if you mapped out all of the SBA in.

In the liver there are still static sources, so liver knockdown might not have been enough.

Thank you.

Yes.

Thank you.

Okay.

And one moment for our next question.

And our next.

Comes from Mike <unk> from Morgan Stanley. Your line is now open.

Hey, guys. Thanks for taking the question maybe just a quick one on Aero reach just in terms of timing of a potential phase two study there.

Now that the clinical the chronic tox.

Studies are done for Aero rates do you have enough data to now start to engage with the FDA or is the plan more to wait for some of the other cohort data like the asthma patients are high fino before you start to do that thanks.

But we're thinking about.

In phase two.

2024, pursuant Theres already work going into that that we design patient population.

Election of CIO. So we are already planning as the data is coming in it would help us to decide the dose of the dose frequency.

We are already planning on the next stage development sort of hurdle rates.

Okay. Thank you.

Okay.

And thank you.

And one moment our next question.

And our next question comes from William Pickering from Bernstein. Your line is now open.

Hi, Thanks, so much for squeezing me in I had a few follow ups on the D. M. One announcements how is the drug designed to get your SA RNA inside the nucleus, where the mrna is accumulating and maybe can you share any more color on what endpoints, you'll be measuring that could suggest early signs of efficacy for example, spicing assessment or any function.

All end points. Thank you.

Sure Yeah. So we will look at some of the same endpoints that other companies have looked at and will look at.

Total D M P J knockdown.

Changes in Spice apathy and we'll also look at the video and opening time as well as some of the other functional endpoints.

And so your other question on.

Knocking down S irony in the nucleus.

We've done some work in animals, we haven't published the scatter shared it publicly.

A poster presentation.

We've shown at <unk>.

Okay.

Doses similar to what we plan on administering in the clinic that we are able to get a level of knockdown of Av.

Nuclear RNA.

And that translates into improvements in supply Sofie. So that was the impetus for US moving this program into the clinic.

Could get even with.

Modest levels of nuclear RNA knockdown, we could get improvements in spice opportunity.

Great. Thanks, so much and congrats on the progress.

Thanks.

Thank you.

Yeah.

And I would now like to turn the call back over to Chris Anzalone.

For closing remarks.

Thanks, everyone and thanks, very much everyone for joining us today and I wish you all a <unk>.

The holiday season.

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

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