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

Please go ahead, Vince..

Thank you, Annie. Good afternoon, everyone and thank you for joining us today to discuss Arrowhead's results for its fiscal 2024 first quarter ended December 31, 2023. With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter. We also welcome back Dr.

Bruce Given, who previously served as Arrowhead's Chief Operating Officer and Head of R&D, and who has rejoined the company n an interim basis as Chief Medical Scientist. Bruce will provide an update on our cardiometabolic pipeline. Dr.

James Hamilton, our Chief of Discovery & Translational Medicine will provide an update on our earlier stage programs; and Ken Myszkowski, our Chief Financial Officer will give a review of the financials. In addition, Patrick O'Brien, our Chief Operating Officer and General Counsel will be available during the Q&A portion of the call.

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

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.

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. I'd 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. Arrowhead has made a name for itself as a company capable of rapid innovation and development that is building a broad-based diverse business.

This is exemplified by our '20 and '25 initiatives, where we expect to grow our pipeline of RNAi Therapeutics to at least 20 clinical stage or marketed products by the year 2025.

This commitment to creating a large number of new medicines as quickly as we can, speaks to our dual mandate; to maximize number of patients, we can help and to maximize our ability to create durable value for our shareholders. These mandates can be entirely aligned during early development.

We decreased biology risk by focusing on well-validated targets, and our proven delivery platforms. At this stage, the cost of discovery and early development are relatively low, particularly when considering the potential value we can create with novel medicines.

In short, we can do many things at this stage without spending too much money and without building large teams with a deep therapeutic area of expertise.

However, as our pipeline grows, and we enter later stage, expensive and complex clinical studies requiring significant capital, deeper domain expertise, and ultimately commercial infrastructure, we need to prioritize what we do internally.

That is where we are now, and we are currently building out late stage development and commercial infrastructure to serve the cardiometabolic vertical. This is the primary engine of our near term value proposition.

We expect to follow that up and add a pulmonary vertical as our lung-targeted platform and candidates mature and we have the data we need to make a commitment to build out specialized commercial infrastructure. So does this mean that we will slow down or stop early development outside our focus areas? It does not.

We will continue to develop new candidates outside these verticals because A, we have confidence in our ability to find appropriate partners to continue development, and commercialize programs that are non-core for us. And B, we anticipate adding new verticals in the future.

Think of this part of our business as generating capital to support our internal programs, and as a farm system to create additional focus areas that could create long term value as platforms and candidates mature. Let's start with our cardiometabolic vertical.

Our lead program is plozasiran, which targets Apolipoprotein C-III, or APOC3 lipoprotein C3 or AOC. This is potentially a big year for plozasiran and for the cardiometabolic vertical broadly.

The PALISADE Phase 3 of plozasiran in patients with genetically or clinically confirmed familial chylomicronemia syndrome, or FCS, is on schedule for the last patient to have their last study visit in the second quarter of this year.

This would be the first complete Phase 3 dataset for Arrowhead that potentially would allow us to file our first NDA and launch our first commercial product. FCS is a severe disease in which patients have extraordinarily high triglyceride levels, often in the thousands of milligrams per deciliter.

Many of these patients experience painful and recurrent bouts of severe abdominal pain, pancreatitis and hospitalization. These patients have inadequate treatment options, and we believe that plozasiran could represent a significant leap forward. We see the data from the Phase 2 studies is compelling.

Plozasiran has been generally well-tolerated and consistently did what it was designed to do. We have a high degree of confidence that this will be a powerful drug for this patient population with very high unmet medical needs. We believe plozasiran could also help a broader population of patients.

Therefore we plan to initiate Phase 3 studies in patients with severe hypertriglyceridemia, or SHTG. These studies will likely begin next quarter and are aimed at addressing a larger patient population that we believe totals 3 million to 4 million in the U.S. alone.

As with the FCS population, our SHASTA-2 study gives us confidence that plozasiran will do exactly what it is designed to do. We believe it will be a powerful and welcomed leap forward for patients. Bruce will discuss study designs for SHTG in a moment.

We're still considering whether we also want to study plozasiran in the broader atherosclerotic cardiovascular disease or ASCVD population, but have not yet made a final decision on that. We will be completing our analysis this quarter, and we'll communicate our plans after they are finalized, and we have had some regulatory interactions.

If our cardiometabolic vertical represents the foundation of our value proposition, plozasiran is the bedrock of that foundation for the following reasons. The target APOC3 is well-validated across a variety of genetic studies.

Our data across hundreds of human subjects indicates consistent target engagement with deep and durable APOC3 silencing, triglyceride levels were deeply reduced in patients and healthy volunteers treated with plozasiran.

We know that elevated triglyceride levels in certain patient populations can lead to severe abdominal pain, acute pancreatitis, hospitalizations and other difficult downstream effects and even in rare cases, death.

There is currently no FDA-approved therapy that lowers triglycerides than more than 20% or 30% and plozasiran has been generally well-tolerated in prior studies. Together, these set up an attractive opportunity. We just need to get to market. We expect to launch plozasiran as early as next year in FCS.

We would hope to follow that relatively quickly by launching into larger SHTG market. And we will see if we follow that with the even larger ASCVD market. This brings me next to zodasiran, which targets angiopoietin-like protein 3, or ANGPTL3.

As we have discussed, we are assessing both zodasiran and plozasiran to determine which may be better suited for investment in a cardiovascular outcome study in patients with ASCVD.

The data we presented at AHA in November on zodasiran's ability to reduce remnant cholesterol which is believed to be a major contributor to the residual risk of ASCVD after LDL cholesterol is well controlled was very encouraging.

In fact, we have not seen any other therapy capable of the type of reductions seen after zodasiran treatment in the Phase 2 study. Just as available drugs have shown only modest lowering of triglycerides, available therapies have similarly produced only modest reductions in remnant cholesterol.

Zodasiran has also shown promising results in a Phase 2 study in patients with Homozygous Familial Hypercholesterolemia or HoFH. We're currently preparing materials for an end of Phase 2 meeting with the FDA and intend to begin a Phase 3 study in HoFH after we have regulatory feedback on our plans.

We could also expand into the much larger heterozygous or HeFH population. If we decide to conduct a Phase 3 study of zodasiran in ASCVD, the commercial plan will likely follow a similar path as plozasiran.

That plan is to launch in a rare population and continue to build out commercial infrastructure and capabilities to support larger patient populations, while the additional Phase 3 studies are being conducted.

For zodasiran, that could mean addressing the small HoFH population relatively quickly, then expanding into HeFH, and ultimately the very large ASCVD market as we get each approval. This path makes a lot of sense for us as an emerging commercial company, and will allow us to grow in a measured stepwise fashion.

We believe that plozasiran and zodasiran clearly warrant investment into cardiometabolic infrastructure -- I'm sorry, cardiometabolic commercial infrastructure. Those outlays become increasingly cost efficient, as we increase the number of drugs that infrastructure manages.

Therefore it makes sense to expand the cardiometabolic vertical to include additional complementary medicines in the portfolio, and we have several in mind. One is based on our adipose targeting TRiM platform, which has shown impressive preclinical data.

We have seen target gene silencing with this platform in excess of 90% after a single dose in animal models, with the activity that lasted over six months. Adipose tissue is the largest endocrine organ in the body, and there are multiple attractive metabolic targets that may be amenable to an RNAi-based knockdown strategy.

We are not prepared to disclose the first gene target we are addressing, but it is in the metabolic space. Another program we are adding to the cardiometabolic vertical is ARO-INHBE. This utilizes the liver targeted TRiM platform and targets the INHBE gene which encodes inhibin subunit beta e.

James will talk about the target in a moment, but the intention is to study this in an obesity and metabolic disease population. Both programs fit well in our cardiometabolic vertical, and are on schedule for CTA filings as early as the end of this year.

It is difficult to overstate the importance of our cardiometabolic vertical in driving our value proposition. We have near term commercial opportunities in plozasiran and zodasiran, a high expectation of success surrounding the programs and longer term opportunities with future drug candidates.

The next vertical we expect to invest in late stage clinical studies and commercialization is pulmonary. There are only about 16,000 pulmonologists in United States and we believe it's an attractive prospect to build a specialized commercial sales organization to support a growing pipeline of medicines that addresses various respiratory diseases.

We currently have three programs in clinical studies that collectively address three major components of chronic lung disease, inflammation, muco-obstruction and interstitial lung disease.

We also see the pulmonary space as a target-rich environment where we believe we can advance and ultimately bring to market a number of different drugs for various diseases treated by a relatively small number of physicians. We like the leverage this creates. The current programs -- in clinical studies are ARO-RAGE, ARO-MUC5AC and ARO-MMP7.

We expect to have multiple clinical readouts for these programs this year and intend to start at least one Phase 2 study in 2024. We also expect additional targets potentially this year. Cardiometabolic and pulmonary are where we are focusing a lot of our attention, and will represent quite a bit of our spend moving forward.

So what does that mean for the rest of our existing and future pipeline? As I mentioned, we are not slowing down our discovery organization and will not limit growth in our early stage pipeline. For example, in 2023, we nominated nine new clinical candidates and filed four new CTAs. These are promising programs.

So the question is, where do they fit strategically? And what role do each play in our business? I think there are three primary categories that the new programs can slot into. One, new candidates that fit into existing verticals. ARO-INHBE is a good example of this. It fits neatly into the cardiometabolic vertical.

Two, new candidates, that pending clinical proof-of-concept, could warrant an expansion into a new vertical. Our work in CNS is very early. But given the vast, unmet medical needs and the broad target-rich environment, this could be an area we build out, should clinical data support it.

And three, new candidates that are interesting, from a medical and commercial standpoint, but may not fit into one of our verticals. This is an important category for us and can serve as a substantial source of capital to fund the other two categories.

We brought in close to a $1 billion in partnering capital over the past seven years, and we anticipate this will be increasingly important piece of our financing plan going forward as existing partnerships mature, and we continue to do new deals.

Our partnership with Amgen on olpasiran, formerly ARO-LPA is a good example of what we can do after even a modest investment in discovery. In late 2016, when we partnered with Amgen, ARO-LPA was still an early preclinical program.

Since then, we have received around $362 [ph] million in cash and are still eligible to receive another $535 million in potential payments as certain clinical and commercial milestones are achieved.

In fact, we're eligible to receive $50 million when olpasiran Phase 3 study is fully enrolled, which Amgen recently publicly guided could be in the first half of this year. Business development is an important source of capital, but of course, not the only source we will rely on.

Last month we announced a $450 million equity financing, the first such deal we have done in approximately four years. That transaction was confidentially marketed to just a handful of funds and we were pleased with the result. It was substantially oversubscribed and saw a terrific participation from high quality investors.

We view that as the first step in substantially increasing our balance sheet. We expect the second step to be a structured finance transaction that could be based around taking in capital in return for royalties on one of our future products that is capped at some return. This could also have a debt component to it.

We anticipate executing such a transaction in the coming months. We expect the third step to be one or more partnership transactions and while we cannot control the exact timing of these, our goal is to do one or more economically meaningful deals this year.

Together, we expect these multiple steps to provide a strong financial base on which we may continue to invest in our core programs, and new innovations. There's also a cost management side to creating a strong financial base.

As I discussed, we have reached the point where we need to be more strategic about the particular drug candidates we take into late stage studies and ultimately to commercialization. It is simply not economically feasible to do everything on our own past a certain stage of development.

That means looking more vigorously for partners and potentially pausing or even culling some programs that are outside our chosen verticals. To that end, we've recently conducted a portfolio review. We are moving forward with clinical studies for our complement programs, AROC3 and ARO-CFB, and our muscle targeted programs, ARO-DUX4 and ARO-DM1.

We're continuing to assess the clinical path and designing Phase 1b/2a studies for our NASH candidate, ARO-PNPLA3, the gout candidate, HZN-457, which was returned to us by Amgen after its Horizon acquisition, is being terminated and will not move forward. In addition, ARO-SOD1 our CNS candidate against SOD1 ALS will not move forward.

We are continuing to work on additional CNS programs and expect a new candidate against a different target to begin clinical studies later this year. It is more commercially attractive than ARO-SOD1, while still serving as a good proof-of-concept for the CNS platform. Our portfolio review also affected some undisclosed preclinical programs.

We have revised our budget to reflect an anticipated reduction in growth of our spend over this fiscal year and beyond. Ken will talk about specifics in a moment, but we're reducing our guidance on fiscal year operating burn by approximately $100 million.

We are achieving these estimates, while importantly, continuing to fully fund our core pulmonary and cardiometabolic verticals and innovative new technologies and programs.

Continuously assessing our anticipated uses and sources of capital, and ensuring they alive -- that they align with the overall goals of the business is of course a critical exercise. I think our revised budget puts us in a stronger position strategically, as well as financially. With that overview, I'd now like to turn the call over to Dr.

Bruce Given.

Bruce?.

Thank you, Chris, and good afternoon everyone. It's great to be back helping Arrowhead move forward in the most effective and efficient way possible. I've been doing a good amount of work getting up to speed with the cardiometabolic clinical development teams, which are operating at a very high level.

We are doing important design and analysis work to ensure our studies are world class. Shortly, we will be getting centers initiated so additional Phase 3 studies can get up and running rapidly. Chris mentioned that we are in the middle of a process to assess which program plozasiran or zodasiran, we want to take forward into an ASCVD population.

And we have nothing new to update on that front today. So I will focus my time today on where we are with plozasiran and the progress we've made. To review plozasiran is designed to reduce production of APOC3, a component of triglyceride-rich lipoproteins or TRLs, and a key regulator of triglyceride metabolism.

APOC3 increases plasma triglyceride levels by inhibiting breakdown of TRLs by lipid protein lipase, and uptake of TRL remnants by hepatic receptors in the liver. We've studied plozasiran in multiple clinical studies in different patient populations, with several hundred patients having been dosed.

We have been consistently encouraged by safety and tolerability results with treatment-emergent adverse events reported to-date that generally reflect the comorbidities and underlying conditions of each study population.

This is encouraging and consistent with our expectations of a properly designed RNAi therapeutic that leverages our proprietary TRiM platform. In addition, plozasiran has demonstrated a high level of pharmacodynamic activity with a mean maximum reduction in APOC3 of around 90%, give or take, regardless of the patient population studied.

This is also consistent with our expectations and speaks to the consistency of the RNAi mechanism. This was a hallmark of Arrowhead candidates in our earlier days in the HPV and AHE space and continues to be the case as we have developed new candidates targeting diverse genes.

So where is plozasiran going, and what has changed over the last couple months. First and most critically in the short term, we are making some changes to the proposed design of the suite of Phase 3 SHASTA studies for patients with SHTG. Our goal with these changes, which I will discuss in a moment is twofold.

First, we want to accelerate enrollment and enable regulatory filings in the U.S. and other key markets as quickly as possible.

And second, we want to maximize the probability to show an effect on severe abdominal pain and acute pancreatitis, which could be a significant differentiator from other triglyceride lowering therapies and could aid in value and access discussions with payers.

So what are we doing towards those ends? Our plan was to conduct two similar Phase 3 studies, SHASTA-3 and SHASTA-4 in approximately 700 patients with triglycerides greater than 500 milligrams per deciliter across the two studies combined with a primary endpoint of lowering triglycerides after one year of treatment.

This general design remains largely unchanged. But we have streamlined several features of the study to potentially speed up time to NDA submission in Europe and the U.S.

We also intended to include a predefined number of patients at higher risk of severe abdominal pain and acute pancreatitis events, with the goal of potentially characterizing an expected reduction in risk of these events in SHTG patients treated with plozasiran.

This remains an important goal but we believe the best way to assure ourselves of adequate power to show this effect is to run a separate study designed specifically for that purpose. This separate study will be called SHASTA-5. We will provide more details in the design, sizing and inclusion criteria when we initiate the study.

This separate study strategy could potentially do two things. It gives us the best chance of showing a reduction in events versus placebo. And second, removing the predefined number of high risk patients in SHASTA-3 and SHASTA-4 is expected to further speed enrollment for these studies.

Between these changes and a handful of others, we estimate that we can get the full enrollment for SHASTA-3 and SHASTA-4 more rapidly and potentially get to an NDA 6 to 10 months faster than the original plan. This is a significant advance if our projections are correct. We are actively working on getting these studies ready to go.

We estimate SHASTA-3 and SHASTA-4 will begin next quarter and SHASTA-5 shortly thereafter. Plus plozasiran has demonstrated best-in-class data at each prior step of the clinical development process. We're eager to move more rapidly through these Phase 3 studies.

The next important event for plozasiran is the completion and readout of the Phase 3 PALISADE study. This is in patients with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome, or FCS.

This is a severe disease of extremely high triglyceride levels that puts patients at high risk of episodes of severe abdominal pain, acute pancreatitis, hospitalization, and it can be fatal. There are no adequate treatment operating options for these patients.

PALISADE is a one year study with a primary endpoint of triglyceride lowering versus placebo. We enrolled 75 patients globally and the last patient is in -- is scheduled to have their last visit in May. After that visit, we will work quickly to complete sample analysis and data collection, preparation and analyze the data.

We intend to report top line results from the study in the third quarter and begin work towards filing Arrowhead's first NDA. That will likely be at the end of the year or into the first quarter of 2025. This is an exciting time, and I'm thrilled to be back and to be part of this next big milestone for Arrowhead. I'll now turn the call over to Dr.

James Hamilton.

James?.

A dose dependent reduction in serum C3 with 88% mean reduction at the highest dose tested; a dose dependent reduction in age 50, a marker of alternative complement pathway hemolytic activity, with 91% mean reduction at the highest dose tested and duration of pharmacologic effects supportive of quarterly or less frequent subcutaneous dose administration.

These results made us confident to move on to part two in patients with IgA nephropathy and C3 glomerulopathy. We are currently enrolling that part of the study and intend to present patient data around yearend 2024.

Lastly, the three clinical stage pulmonary programs continue to progress efficiently and are all on schedule for clinical readouts this year. These pulmonary programs are as follows. ARO-RAGE, which is designed to reduce expression of the receptor for Advanced Glycation End products or RAGE as a potential treatment for inflammatory pulmonary diseases.

For the Phase 1/2 study, we have fully enrolled and dosed all healthy volunteer cohorts, and the mild to moderate asthma patient cohorts as well. We should have additional PD data by the end of the first quarter for both of these.

We are also in the process of enrolling three cohorts of asthma patients with high baseline levels of fractional exhaled nitric oxide or FeNO which is a biomarker for IL-13 driven type two inflammation in the lung. We believe we will have initial results from these high FeNO cohorts in the third quarter of this year.

The biology of RAGE and where it sits in the inflammatory cascade, as well as our own preclinical studies have suggested that RAGE inhibition may provide potent anti-inflammatory effects with impacts on an array of cytokines including IL-13, IL-5, TSLP, IL-18, IL-33, IL-1B and IL-6.

In addition to FeNO, we're assessing other potential biomarkers of anti inflammatory effect including sputum and blood cytokines in the asthma patient cohorts.

The next two programs are ARO-MUC5AC which is designed to reduce production of Mucin 5AC or MUC5AC as a potential treatment for muco-obstructive pulmonary diseases and ARO-MMP7 which is designed to reduce expression of matrix metalloproteinase 7 or MMP7 as a potential treatment for idiopathic pulmonary fibrosis or IPF.

In both programs, we are conducting Phase 1/2 studies in healthy volunteers and then in patients. Both programs require patient data to assess PD, unlike ARO-RAGE, which has the benefit of a readily available and measurable PD biomarker in healthy volunteers.

Both ARO-MUC5AC and ARO-MMP7 have already enrolled and dosed healthy volunteers and we anticipate the patient cohorts will be enrolled and dosed in time to enable initial clinical readouts in the second half of the year. I will now turn the call over to Ken Myszkowski.

Ken?.

Thank you. James and good afternoon everyone. As we reported today, our net loss for the quarter ended December 31, 2023 was $132.9 million or $1.24 per share, based on $107.4 million fully diluted weighted average shares outstanding.

This compares with a net loss of $41.3 million or $0.39 per share, based on $106 million fully diluted weighted average shares outstanding for the quarter ended December 31, 2022. Revenue for the quarter ended December 31, 2023 was $3.6 million, compared to $62.5 million for the quarter ended December 31, 2022.

Revenue in the current period primarily relates to our collaboration agreements with GSK. Our revenue in the prior period primarily related to recognition of revenue from our licensing collaboration agreements with Takeda and Amgen. All upfront payments from existing agreements have now been fully recognized.

Total operating expenses for the quarter ended December 31, 2023 were $140.1 million, compared to $104.7 million for the quarter ended December 31, 2022. The key drivers of this change were increased candidate costs and salaries as the company's pipeline of clinical candidates has both increased and advanced into later stages of development.

Net cash used by operating activities during the quarter ended December 31, 2023 was $117.8 million, compared with $75.5 million for the quarter ended December 31, 2022. The increase in cash used by operating activities is driven primarily by higher research and development expenses and the lower cash revenue in the period.

We have reviewed our cash forecast and would like to provide additional guidance on our expected cash burn. For the next several quarters we expect operating burn to be $80 million to $100 million per quarter.

Our footprint expansion is mostly complete with the final payments to be made over the next several months totaling about $70 million, after which we expect capital expenditures to be nominal. Breaking the operating burn a bit further, our cash burn related to G&A has been about 10% of costs.

So think of that as about $10 million G&A each quarter, which is expected to grow slowly going forward as we continue to advance commercialization efforts. We expect quarterly R&D expenditures to be about $80 million this year, increasing modestly next year as our registrational studies advance.

Turning to our balance sheet, our cash and investments totaled $220.3 million at December 31, 2023. Pro forma cash and investments accounting for the recent capital raise would be approximately $649 million.

Our common shares outstanding at December 31, 2023 were 107.5 million and pro forma shares outstanding accounting for the capital raise would be 123.8 million. With that overview, I will now turn the call back to Chris..

Thanks, Ken. This is an important year for Arrowhead in five primary areas. First, we expect a lot of activity within our cardiometabolic vertical. We will have our first Phase 3 readout for plozasiran and plan to file our first NDA.

We plan to initiate several additional Phase 3 studies in patient populations including HoFH, HeFH, FHTG and potentially ASCVD across two different drug candidates, plozasiran and zodasiran. We also intend to expand the cardiometabolic vertical to include two additional candidates, ARO-INHBE, and an undisclosed adipose targeted candidate.

Second, we plan to have multiple clinical readouts in our pulmonary vertical across three different drug candidates and initiate at least one Phase 1 study. Third, we intend to continue to strengthen our balance sheet with a structured finance transaction and one or more business development transactions.

Fourth, our other clinical programs continue to move forward. These include continuing enrollment of the plozasiran Phase 3 study with Takeda.

Amgen potentially completing enrollment of its Phase 3 study of olpasiran, progress in Phase 2 studies in HBV, with GSK, progress in Phase 2 studies of GSK 4532990 in NASH, planning for Phase 2 studies in ARO-PNPLA3, progress in Phase 1 studies for our neuromuscular candidates, ARO-DUX4 and ARO-DM1, and progress in Phase 1 studies of our complement base candidates ARO-C3 and ARO-CFB.

And fifth, we are not done innovating. As I mentioned, we expect to bring our first adipose targeted candidate to the clinic and initiate clinical studies for an undisclosed CNS candidate this year. Thanks for joining us today. And I would now like to open the call to your questions.

Operator?.

[Operator Instructions] And our first question comes from Luca Issi with RBC Capital. Your line is open..

Oh, great. Thanks so much for taking my question. Two quick one here, maybe James, first on FeNO. I know that data for the high FeNO cohort is in the third quarter. However, I was under the impression that you were planning to show us the FeNO data from the mild to moderate patients potentially ahead of that.

Is that no longer the plan? And if so, what drove that decision? And then maybe second, either Chris or Ken? I think this is the first time I'm hearing you directly talk to you about potentially using debt.

Given the broader macroeconomic environment and where the rates are, why do you think that adding debt is the right strategic decision at this point? Thanks so much..

Sure, Luca, thanks for the question. I'll take the first one. In the mild to moderate asthma patient cohorts, we didn't have a FeNO cut off. So it was sort of an all comers asthma series of cohorts. And we just don't have the numbers.

I think in the top dose cohort we have one patient with high FeNO, so just not enough to make a call based on present data based on -- that's why we're waiting for the high FeNO cohorts..

So even though interest rates are higher than they have been historically, the cost of debt is certainly lower than our cost of equity capital. And it's we think an important part of non-dilutive financing. So that's why we're looking at that possibility..

And I think that we're at stage of this company where we can consider that. We are close enough to commercialization that it makes sense, I think to start exploring those options..

Got it? Thanks so much. .

You're welcome. .

One moment for our next question. And our next question comes from Ted Tenthoff with Piper Sandler. Your line is open..

Great, thank you very much, and thanks for the thorough uptake on a really exciting year.

As you're getting ready for PALISADE data, and again fingers crossed, assuming success based on the mechanism and dedication in the past, how do you start to think about the commercial buildout for that indication, especially in the U.S., obviously? I know, it's not a huge indication, but it would be the company's first commercial buildout.

And then you discussed partnerships. Is it something where you would envision seeking distribution partners overseas? Or what's sort of the thinking OUS? Thanks a ton..

Thanks, Ted. Yeah, boy, we're really excited to make this transition. We're excited about seeing those data. The Phase 2 data were compelling. And so we are optimistic that those data are going to continue to look good. Look, we like the way, the way this transition into a commercial company is panning out. We're not a commercial company right now.

And so it can be jarring. One could imagine going from zero to a very large market that could be a bit diffused. And so we get to take this baby step, if you will, in FCS. The way I sort of segregate the triglyceride market is there are those genetically defined FCS patients, those patients are known. The physicians who treat them know where they are.

They're relatively easy to address. You take one step down, if you will, say patients who are not genetically FCS but have triglycerides over 880 and history of pancreatitis. Again those patients are relatively well known and relatively easy to address. It is those populations that we will be addressing initially.

And so it's a nice entry, if you will, into commercial. As we grow, and as we continue the other phase study, the other Phase 3 studies we will be increasing our ability to go after those harder to find patients, those on triglyceride side, those patients, who have triglycerides above 500 and who may not have history of pancreatitis.

That's a very large number, we believe, but will take some education of the market and will take some digging, of course. And so we've got extra time to develop our ability to do that. So that's domestically. Internationally, we feel like we can handle the FCS market, in certain ex-U.S. markets and so we intend to do that.

Longer term, I would expect for us to find good local partners for FHTG. We'll see where we are with ASCVD, with AGFH and the like, but at least for FHTG, it would probably make some sense for us to find the right local partners in other countries..

Right, thanks for the update. .

You're welcome..

One moment for our next question. And our next question comes from Mayank Mamtani with B. Riley Securities. Your line is open..

Hey, team. Thanks for taking our questions and good to have Bruce back on the call.

So on the outcome trial consideration and deliberations for zodasiran, Bruce, could you point to any meta analysis informing correlation of DRL [ph] percent reduction or cumulative lowering that informs event rate with outcomes? I believe you and possibly another peer might be doing a similar exercise in coming months.

And like you said, there might be additional external partners involved as you look to do a structured financing process. Would love to hear your thoughts and I have a quick follow up after that..

Well, yeah, there's a lot of interest in the remnant cholesterol concept. A lot of Mendelian randomization data and other data pointing to these remnant cholesterols being highly atherogenic. In some of these analyses are even more atherogenic than you know, ApoB and LDL on a milligram per milligram basis.

It is yet unproven in clinical trials because frankly, there just haven't been good enough drugs for treating these and so it has been untestable. They were waiting for the good drug to come along that you could you could test this remnant cholesterol hypothesis.

Both zodasiran and plozasiran are really incredibly good drugs from a pharmacologic perspective. So they offer that opportunity, and it's not actually an easy choice between the two, because they're both equivalent in a lot of ways with respect to their ability to address that particular question.

So I think it's -- there's plenty of paper out there, plenty of genetic studies that point us this way, that give us reason to be hopeful, as a field but alone as a company. But ultimately, we have to prove it. We have to do the old fashioned thing, we have to actually do the clinical trials and prove it..

Got it. And then on the FeNO high cohort James, I heard sputum and blood biomarker data will also be part of the 3Q analysis.

Could you just maybe talk to the significance of that and broadly in your pulmonary pipeline for MUC5 and other patient cohorts are you also assessing that? And what's the relevance of that, as you look to make some go, no-go decisions this year? Thanks for taking our questions. .

Sure, right. So the additional biomarker data, specifically the cytokines I mentioned, I think that those are an important piece of the readouts that we'll have this year in addition to FeNO.

We are not assessing those in the level of detail that we're doing in the RAGE cohorts with the other pulmonary programs like MUC5AC or MMP7, just not as relevant. We do measure cell counts on belts [ph] for all the pulmonary programs, just to get an indication of if we're seeing any kind of pro-inflammatory effect.

And we've not seen such an effect to-date in the belts for any of those three programs..

Got it. Thanks for taking your question..

One moment for our next question. And our next question comes from Jason Gerberry with Bank of America. Your line is open..

Hi, guys, thanks for taking my question. One for me, on RAGE.

Can you just remind us, what your cutoff is for high FeNO? And will there -- the placebo patients that you're actually comparing against -- with that date update in 3Q and what I'm trying to get at is thinking about your competence, you can derive from about 25 patients of data here with respect to like FeNO variability as a measure.

And just lastly, do you think there's a chance that ARO-RAGE could achieve, higher than this 30% to 40% bogey set by biologics on the FeNO measure, just given it targets, multiple interleukins involved in the type two inflammatory pathway?.

Thanks. Sure, yeah, I can't really comment on the magnitude question of what will we expect to -- we think we can have a higher FeNO reduction compared to the biologics. The FeNO cut off is 35. And there are, I think 38 total patients across the high FeNO cohort. So we should have a pretty good number and that includes placebo patients.

So we'll be able to compare the active treatment arm to a placebo group..

Got it. Okay, thank you..

One moment for our next question. And our next question comes from Patrick Trucchio with H.C. Wainwright. Your line is open. .

Thanks. So I've a couple of follow up questions.

The first is just on the CMO role if you can maybe discuss the reasoning behind the decentralizing the Chief Medical Officer function and what impact this is expected to have as well as potential advantages of this decentralized approach? And then secondly, just on the CNS platform, can you talk a bit more about what went wrong with ARO-SOD1 more specifically? Was it a decision based on market potential or with the SRA or something else? Maybe just give us an idea of how you expect the platform to build out going forward..

Sure, so with the slight restructuring of R&D, look we just thought that we needed, good leaders with deep expertise in our chosen verticals. So far that's going to be cardiometabolic. We expect pulmonary to be the next vertical. We just need a deep expertise there.

We expect those not to be the last verticals that we're going to create, we're probably going to have several others going forward. And they just needed their own leaders and so for us, it made sense to restructure towards that. Regarding SOD1, look, there is nothing within ARO-SOD1 that pushed us off it to be honest.

We liked ARO-SOD1, we liked the opportunity because it gave us a good chance to interrogate the platform. It was going to give us a good, we thought proof-of-concept the platform is working or is not working. The problem with SOD1 is that it was becoming -- it was appearing to be increasingly commercially unviable.

So the good news is we can see what's working, the bad news is it didn't make economic sense to develop that drug we thought. And we a fast follower, at least one that we think, at once gives us the ability to interrogate the platform. It gives us good proof-of-concept of platform, but also will be a more commercially viable drug.

So it just made sense to allocate resources to it and to others. And so it was less of SOD1 failing than a lack of confidence in the SOD1 ALS market..

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

You're welcome..

One moment for our next question. And our next question comes from Mani Foroohar with Leerink Partners. Your line is open..

Hey, thanks for taking the questions. A couple of quick ones. We talked about $100 million step down in operating expenses, which obviously buys a lot of wiggle room for the company and allows you to maximize return on investment.

Could you give us any sort of color on the tempo at which we'll see that flow into OpEx over the course of this year just for our own modeling? And then I've got a couple of quick pipeline questions to follow..

So I think you should expect those results immediately. If you look at what our burn was in the current quarter, it was high compared to previous quarters, but we think it will go back to a normalized spend, like I had mentioned before of about $80 million to $100 million, and you can expect that beginning the second fiscal quarter..

Okay, and hopping over to the pipeline, for ARO-INHBE or INHBI, how are we going to pronounce it? That's a target for which we've seen some evidence in non-human population studies etc., for a change in adipose phenotypes, into the distribution into the hip to waist ratio, even after one accounts for BMI? So should we be thinking of that as a place where we're going to eventually see data that targets weight loss, adipose distribution? Like what are the endpoints we should be thinking about in humans? And then what are the endpoints we should be thinking about in earlier stage studies as we sort of-- as this asset gets progressively de-risked?.

Yeah, sure. I think all of the above for at least in terms of our initial clinical study, we'll look at all of that and investigate not just changes in body weight loss, but we'll evaluate body composition, loss of lean mass distribution of adipose tissue. They are the visceral fat stores shrinking, what happens to lean mass.

And we're also interested in what happens to measures of glycemic control like A1C, or oral glucose tolerance testing. So I think there are quite a few endpoints that we can study in even a Phase 1 study and learn a lot about our drug and about that particular target..

Great, and as a follow-up, is there an opportunity in initial human dataset to see this asset tested both in patients who are on and off with GLP1, given how broadly they're taken amongst the population of the U.S. and other places where you guys have done clinical trials. .

Yeah, I think so. I think that would be -- we're still a little ways away from the clinic. But would anticipate a study design that first starts in obese patients that are not on those drugs. And then also investigates the combination of the GLP1 agonist with INHBE knockdown and see how the combination plays out..

Right, I'm going to hop off, I know a couple of others are still waiting on the queue. Thanks, guys..

One moment for our next question. And our next question comes from Brendan Smith with TD Cowen. Your line is open. .

Hi, this is Jenna on for Brendan. Thanks for taking our question. I just want to ask, which of your non [technical difficulty] relation partnership and which would be the highest priority. Thank you..

Yeah, sorry. You're breaking up.

Can you repeat that?.

Of your non-core pipeline programs would you consider for a development commercialization partnership and which of these would be the highest priority for you?.

Yeah, so unfortunately, we don't do that entirely. We need a counterparty that's going to be interested as well. Look, there are -- we would certainly be happy to talk about C3 for instance. We'd be happy to talk about the muscle assets. We think those are all good assets. But at least right now, don't fit neatly into a planned vertical.

One would think that muscle would be a natural vertical for us. And it could morph into that. But right now, we are happy to talk to the right partner about one or both of those assets. PNPLA3, potentially, could be something that that we are interested in. NASH is a bit in flux right now.

But that's something that we that we could consider discussing as we partner HSE to GSK, we can talk about that as well. That's sort of what it feels like right now in our existing clinical pipeline. .

All right. Thank you so much. .

You're welcome..

One moment for our next question. And our next question comes from Mike Ulz with Morgan Stanley. Your line is open..

Hey, guys, thanks for taking the question. And maybe just a quick follow-up here in terms of BD. You mentioned maybe one or two potential deals this year. Could they potentially include the core areas like cardiometabolic and pulmonary? Or are those going to be excluded from potential royalty deals? Thanks..

Let's deal with those separately. So cardiometabolic, we are full speed ahead with zodasiran and plozasiran right now. And so we are not actively looking to partner those. On the pulmonary side, we are not actively seeking the partners for our three clinical assets.

We could be -- we would be happy to discuss with a potential partner, a platform partnership whereby somebody would bring in a target, one that we may not be working on for us to together build a drug candidate. But at least right now, we are not looking at partnering those existing clinical assets. .

That's helpful. Thank you..

You're welcome..

One moment for our next question. And our next question comes from Ellie Merle with UBS. Your line is open..

Hey, guys. Thanks for squeezing me in. Just in the past, on RAGE, you had mentioned a subcu program, I guess just what's the latest on the status and timelines there, and just the focus of that program.

And then just on a related note, as you think about planning a larger Phase 1 study in asthma, what are the considerations there and the design and what you're looking to see in the high FeNO cohort later this year, and just what everything from the subcu program, perhaps the plans and some of the considerations and the design? Thanks..

Sure, so the subcu programs we said we were seeing not -- we are seeing RAGE knockdown. That's the good news. We just weren't seeing as deep a knockdown as we've seen with the inhaled. And so we are really focusing our future development on the inhaled. But again, but it did work. It just was not as strong as the inhaled version.

James, you want to…?.

I don't have anything to add to that. I don't think it will play into our Phase 2 plans though. .

So what's the second question about asthma again? Can you repeat that one?.

Yeah, just the timeline for the Phase 2 start and the design considerations. And like what you're looking to see from the high FeNO cohort, and how that might inform some of the design decisions. Thanks..

Yeah, so we're tossing around and thinking about a lot of different designs right now. I think with the design we would certainly want to be able to study both the high type two and the non-type two patients in a single design. And I think that the FeNO readout, Q3 may inform on which patient population, we want to favor one more than the other.

But I think we'll want to -- plan to study both. .

Yeah, and keep in mind, with the FeNO, data, look, we're looking forward to seeing that, of course, but it really only reflects moving a single pathway. As James mentioned in his prepared remarks, RAGE, we expect RAGE to move a number of different cytokines and FeNOs, only really detecting movement of one of those.

And so while it's helpful, it's certainly not the only important data point..

Got it? Thanks. That's helpful. .

One moment for our next question. And our next question comes from Maury Raycroft with Jefferies. Your line is open..

Hi, thanks for taking my questions. I was going to ask one about RAGE too. So for the higher dose PD asthma patient data that you're collecting, can you clarify if you'll do a public update on that at the end of this quarter on those data? And will that only include knockdown? Or will that include cytokine and other PD biomarkers as well..

So it will include knockdown for sure. And I'm not sure if there's going to be a good venue in the near term to report those. I can tell you that, that what we've seen so far, it's still an incomplete data set.

What we've seen so far is consistent to what we said in the past, which is what we're seeing in knockdown in patients is really mapping on top of what we have seen the knockdown profile in healthy volunteers. And so that continues. Once we have a full dataset, given that again, I expect that to continue.

I don't know that we'll rush out and have a press release based on that. I think we'll probably have that as part of some presentation that -- at a conference or what have you. But to be honest, we really haven't put much thought into how we're going to disseminate those data.

Because again, we expect the knockdown in patients to be quite similar to healthy volunteers. That's we've seen so far.

Jim do you have anything else to add?.

No..

Got it. Okay, that's helpful.

And then maybe one follow up just for DUX4, or DM1, could you potentially have data updates from either of those programs this year?.

Yeah, I think that's depending on how enrollment goes. We could have some early data by end of the year, but very enrollment contingent. .

Got it? Okay. Thanks for taking my questions..

Thanks, Maury. .

One moment for our next question. And our next question comes from Prakhar Agrawal with Cantor Fitzgerald. Your line is open..

Hi, thanks for taking my question. So number one on INHBE. Preclinically how does your candidates profile differ versus some of our competitors Alnylam and [indiscernible] in terms of the level of knockdown you're seeing? I think you had mentioned 20% weight loss in DIO [ph] models.

So maybe if you can compare and contrast that? And then I had a follow up?.

Sure. Yeah. I think that that level of differential in weight gain between the control animals and the animals receiving drug is similar to what others have reported. And in that study, we were seeing 90-plus, I think 96% knockdown in that that obesity mouse model, which is I believe, more than what others have reported.

I think that's probably the best I can tell you..

Got it.

And on the CV side, what are the key questions do you need answers from the FDA to make a decision on which CV asset to move forward into the outcomes trial for the broader population or is it just mostly an internal decision at this point?.

Yeah, I mean we haven't gone to the -- it's Bruce Given again. We haven't gone to the FDA at this point on that. At some point, we will of course go to the FDA. We can't start a trial like that without their input. But we're not at the point yet that we've engaged them in the discussion..

Okay. Thank you for taking the questions..

Sure. .

One moment for our next question. And our next question comes from David Lebovitz with Citi. Your line is open. David Lebovitz, your line is open..

Hi.

Can you hear me now?.

Yes, we can. .

Hi. This is Vibhanjana [ph] on for David. Thanks for taking our questions. So maybe it's regarding the FPS readouts of last year. And you mentioned that the last patient is scheduled for the visit in second quarter. We were wondering if you could give us a little more color in terms of the data readout timeline.

And maybe what data points can we expect to see at the readout?.

Well, I think, we would again be looking to present, I would think in a meeting. I actually haven't spoken with Chris on this. Maybe we would top line in some way, once we did that, but we'd want to do that in such a way to not present a fulsome presentation in a in an academic meeting at some point.

I think it's kind of the same sort of question -- the same answer we had before. At this point, it's hard to predict, you know, what meaning that would be and when that would occur. But yeah, I suspect we would, in some way, get some top line information. But most of the fulsome data would come out later, I would expect..

Thank you. And just one follow up.

Assuming that zodasiran and plozasiran are both approved, how do you think clinicians would choose between the two therapies?.

It's hard to answer that question in a setting where actually we don't have the comparative results of the two agents at this point on either efficacy or safety in the SES population. So it'd be wildly speculative at this point to try to make a call on that. .

Yeah, I don't think we I don't think that we've seen triglycerides levels in, from that Phase 3 yet. When we look at the available data from their Phase 2 versus our Phase 2s, we are comfortable that our dosing interval will be longer.

And it appears at least according to the Phase 2 data appears that our APOC3 knockdown is greater and our triglyceride lowering is greater. But again, as Bruce says, we don't know what the Phase 3 looks like on their side or on our side, frankly..

Thank you. That's helpful..

And our final question comes from the line of William Pickering with Bernstein. Your line is open..

Hi, good evening. Thank you for taking my question. You've estimated the addressable FCS population at 70,000 to 100,000, which sounds like a pretty large population to get approved based on a single 75 persons study.

So can you just remind us of your agreement with the FDA on the exact definition of that FCS population for which they agreed to accept just a single trial? Thank you..

In that, in that Phase 3 study we are studying people with genetically confirmed FCS and those patients with clinical STS, if you will, which is patients with the triglycerides above 880 and history of pancreatitis. That population we are studying..

Thank you. .

You're welcome..

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

Thanks very much for tuning in. today. We look forward to speaking with you over the next quarter. And those of you who are in Southern California hope you stay dry..

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