Arrowhead Pharmaceuticals Inc (ARWR) 2023 Q2 法說會逐字稿

Ladies and gentlemen welcome to the Arrowhead Pharmaceuticals conference call. (Operator Instructions) I will now hand the conference call over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go-ahead Vince.

Good afternoon and thank you for joining us today to discuss Arrowhead's results for its fiscal 2023 second quarter ended March 31, 2023.With us today from management are president and CEO Dr. Christopher Anzalone, who will provide an overview of the quarter; Dr. Javier San Martin, our chief medical officer, who will provide an update on our mid and later stage clinical pipeline; Dr. James Hamilton, our Chief of Discovery & Translational Medicine, who will provide an update on our earlier stage programs; and Ken Myszkowski, our chief financial officer, who will give a review of the financials. In addition, Tracie 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.

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 Christopher Anzalone, President and CEO of the Company. Chris?

Thanks Vince. Good afternoon everyone and thank you for joining us today. In 2017, we introduced our proprietary TRiM platform. We believed then that it could become an industry-leading RNAi platform for hepatocyte-focused therapies and, importantly, one that could bring RNAi outside the liver. This was based entirely on our confidence in the potential of the science: at the time we had no clinical programs, a single partner, and our stock was trading for less than $2.

Six years later, we have 12 individual drug candidates in clinical studies targeting 2 different organ systems, 3 ongoing Phase 3 studies, 5 strong partners, a healthy balance sheet, and reason to believe that the next 6 years will be characterized by even more rapid growth.

We expect to have at least 14 drug candidates in clinical studies by the end of this year, targeting 3 different organ systems: liver, lung, and CNS. Skeletal muscle targeting programs could grow this to 16 individual drug candidates across 4 different organ systems in 2023, but partnering opportunities make that a bit more difficult to predict and I will touch on that later in the call. We are well on our way to reaching our "20 in 25" goal to grow our pipeline of RNAi therapeutics to a total of 20 clinical stage or marketed products in the year 2025. I do not believe there is a company on the planet that will match this.

We've made substantial progress over the past quarter and since our last call. Let's start with pulmonary.

We recently disclosed early topline data for ARO-RAGE in normal healthy volunteers. The data were very encouraging and indicated a high level of target gene knockdown with a long duration of effect, in a well-tolerated manner. James will talk about these data in a moment, but I want to put this into context. I believe that Arrowhead is the first company to ever show RNAi mediated target gene knockdown in the lung. Even more impressive was the magnitude of response. We didn't just get on the board, we saw up to 90% knockdown in serum after just 2 4 inhaled doses at the 4th of 5 planned dose levels. We do not yet have data from the highest single or multiple dose cohorts. It appears that the pulmonary platform is doing what it was designed to do and ARO-RAGE appears to be highly potent. I expect the durability to enable monthly or less frequent dosing.

We've often said that clinical validation of the lung platform could mark the beginning of a second rapid wave of growth for our company. Cells don't care what the sequence of an RNAi drug is. Once we find that reducing expression of a specific target gene can be done in a well-tolerated manner, we have a high degree of confidence we can replicate it with any number of new gene targets, much as we have done in the liver. That is where we may be with the pulmonary franchise. I think the data we reported and the additional data we expect to present at the R&D Day on June 1 represent the initial clinical validation we were hoping for. This is a big deal. I fully expect that in the near- to mid-term we will have several potentially important new drug candidates targeting the lung that could address grinding, unmet medical needs.

ARO-MUC5AC will be our next pulmonary data set, and I expect that we will have some normal healthy volunteer data by the R&D Day. These 2 programs continue to move forward and both have progressed into Part 2 of the Phase 1/2 studies where asthma patients are treated. We hope to have some data from the patient portion of the studies by the end of the year. Rounding out our current pulmonary pipeline is ARO-MMP7. During the last quarter, we initiated a Phase 1/2 study for the treatment of idiopathic pulmonary fibrosis, and we are currently dosing normal healthy volunteers.

So, where do we go next? The central nervous system. There are a number of untreatable and poorly treated CNS conditions and many genes that could serve as powerful targets for RNAi therapeutics. We have spent a substantial amount of time developing a CNS-focused TRiM platform and are just about ready to bring our first drug candidate to the clinic. As we announced a couple weeks back, ARO-SOD1 is our first CNS-targeted drug candidate to be nominated. It will be investigated as a potential treatment for patients with ALS caused by SOD1 mutations. We have already completed disease model work and CTA enabling toxicology studies and are now on track to file a CTA next quarter. You will hear more about the platform and candidate at the June 1st Analyst Day, and we see these as powerful tools for a new set of patients we seek to serve. Importantly, as with liver, pulmonary, and skeletal muscle delivery, we expect to follow AROSOD1 with several additional drug candidates.

In addition, we have made impressive progress on different modes of administration and while we are not quite there yet, we believe we are approaching the day where we may administer RNAi CNS drug candidates systemically that cross the blood brain barrier. This would be a truly disruptive leap forward and our data suggest that we are close.

We look forward to discussing this as well at the Analyst Day. We have said in the past that we are committed to bringing RNAi to where unmet medical need is, and that means constantly expanding TRiM. We believe we can address a new cell type every 18-24 months, and while our new CNS franchise meets this, it is not the only new organ system we are exploring. I believe we can now also deliver to adipose tissue and have demonstrated in non-human primates target gene silencing of greater than 90% with over 6 months of duration after a single subcutaneous injection, using what we believe are clinically relevant dose levels. Adipose tissue is the largest endocrine organ in the body, and we believe there are many targets to address and many potential patients to help. You will hear more about this new platform next month at the Analyst Day.

Let's now turn to our more established clinical programs. We've shared some early data from the Phase 1/2 study of ARO-C3 for complement mediated diseases, and they are compelling. We are seeing deep and durable knockdown in healthy volunteers and have progressed to the patient portion of the study. We also shared liver fat data that Janssen generated in a P1/2 study of ARO-PNPLA3 for NASH in patients with PNPLA3 mutations. Those too were quite encouraging and demonstrated deep reductions in liver fat after only a single dose of ARO-PNPLA3. We plan to move that into a multidose P2 study in NASH patients late this year.

Moving on to our later stage pipeline, we continued to enroll patients in the Phase 3 PALISADE study of ARO-APOC3 in patients with familial chylomicronemia syndrome, or FCS, and expect to meet our enrollment goal of 72 patients tomorrow. There are also some additional patients that have passed screening and who will likely be randomized over the next 2 weeks. At that point enrollment will be complete and I suspect that we will have closer to 80 patients in the study. We also received Fast Track designation from the FDA for ARO-APOC3 for reducing triglycerides in adult patients with FCS, which will be helpful as we advance the program rapidly.

Javier will talk about this in a moment, but I expect this to be our first drug to complete a Phase 3 study and, if efficacy and safety are established, could be the first NDA that we file. This could be next year, and it would represent an important step for us. Of course that is not the only population of patients we intend to treat with ARO-APOC3. Rather, I expect us to take steps toward pivotal studies in patients with severe hypertriglyceridemia and those with mixed dyslipidemia later this year.

The ARO-ANG3 P2 study in mixed dyslipidemia patients is complete as is the P2 study in patients with homozygous familial hypercholesterolemia, or HoFH. I expect that both of these will move toward P3 studies later this year. Both ARO-ANG3 and ARO-APOC3 appear to be potentially powerful drug candidates. We have included nearly 900 patients in the basket of P2 and P3 studies of ARO-ANG3 and ARO-APOC3 over the past couple of years and continue to be encouraged by the drug candidates' activity and safety profiles. I believe that both of these will ultimately be important drugs for many patients.

Also, during the quarter, we announced that our partner Takeda had treated the first patient in the Phase 3 REDWOOD study of fazirsiran being investigated as a potential treatment for alpha-1 antitrypsin deficiency liver disease. This is the third TRiM enabled candidate to reach a Phase 3 study, which earned Arrowhead a $40 million milestone payment.

We also received a $30 million milestone payment from GSK after the start of GSK's Phase 2b trial of GSK4532990, formerly called ARO-HSD, an investigational RNAi therapeutic for the treatment of patients with NASH. These milestone payments are helpful for our balance sheet but also represent 2 more important things. First, they are a confirmation that our strategy to have a healthy mix of both wholly owned and partnered programs is playing out as intended. Second, they indicate that important new medicines that Arrowhead discovered are getting closer to the patients that need them.

Before I hand off to Javier, let me say a few words about the skeletal muscle franchise and ARO-DUX4 specifically. We completed everything required for the CTA including regulatory filing preparation, acute and even chronic GLP toxicology studies. We are prepared to file the CTA and begin a P1/2 study but several companies have expressed interest in potentially partnering on the development of ARO-DUX4 and, potentially, our next skeletal muscle-targeted drug candidate, that will be CTA-ready in Q4. As such, we paused filing while we explore these options. Of course, I do not know if any of these will translate into license agreements and partnerships, but I expect we will either complete a deal or move forward with the ARO-DUX4 clinical program over the next couple months.

Arrowhead is executing at a very high level: our platform is expanding into new areas; our early pipeline is generating impressive results; our mid and later stage pipeline are giving us line of sight to when we may be able to make the transition into a commercial stage company; and our business development activities continue to bear fruit.

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

Javier?

Thank you, Chris, and good afternoon everyone. Before I go into the mid and late stage cardiometabolic studies, I want to quickly review the status of the fazirsiran, our investigational RNAi therapeutic being developed in partnership with Takeda for the treatment of liver disease associated with alpha-1 antitrypsin deficiency.

During the last quarter we reported data demonstrating that patients receiving 25, 100, or 200 mg of fazirsiran who had baseline fibrosis achieved a dose dependent mean reduction in serum Z-AAT concentration at week 48 of 74%, 89%, and 94%, respectively, leading to dramatic reductions in total liver Z-AAT and PAS-D globule burden, a histological measure of Z-AAT accumulation. In addition 42% of patients showed an improvement in portal inflammation and 50% of patients achieved an improvement in fibrosis of at least one point by METAVIR stage.

These data were very consistent with the prior data generated from the 2002 open label study. Subsequently, Takeda initiated and began dosing in the REDWOOD clinical study. It is a randomized, double-blind, placebo-controlled, Phase 3 trial to evaluate the efficacy and safety of fazirsiran in the treatment of AATD liver disease. Approximately 160 adult patients with METAVIR stage F2 to F4 fibrosis will be randomized 1:1 to receive fazirsiran or placebo. The primary endpoint of the study is a decrease from baseline of at least 1 stage of histologic fibrosis METAVIR staging in the centrally read liver biopsy done at Week 106 in patients with METAVIR stage F2 and F3 fibrosis. Additional information on the REDWOOD study can be found at www.theredwoodliverstudy.com. I also want to give a brief update on where we are with our cardiometabolic candidates, ARO-APOC3 and ARO-ANG3.

I will start with ARO-APOC3, our investigational RNAi therapeutic being developed as a treatment for patients with mixed dyslipidemia, severe hypertriglyceridemia, and FCS. The SHASTA-2 Phase 2 study in 229 patients with severe hypertriglyceridemia and the MUIR Phase 2 study in 353 patients with mixed dyslipidemia are both on schedule for data readouts later this year. These data will enable us to request end of Phase 2 meetings with regulators to discuss and get feedback on our plans for Phase 3 studies.

The PALISADE Phase 3 study in 72 patients with FCS is ongoing. We have enrolled 70 of the planned 72 patients and we believe we will reach planned enrollment tomorrow. This is a 48 week study with a primary endpoint of percent change from baseline in fasting triglycerides. This puts us on schedule for study completion in Q2 of 2024, a data readout shortly after that, and then NDA preparation. I am also pleased to announce that during last quarter ARO-APOC3 was granted Fast Track designation by the US FDA for reducing triglycerides in adult patients with FCS. ARO-APOC3 was previously granted Orphan Drug designation by the FDA and the European Union for the same use.

Fast Track is a process designed to expedite the development and review of drugs to treat serious or life-threatening conditions and fulfill an unmet medical need. The purpose is to get important new drugs to patients earlier. This designation makes Arrowhead eligible for multiple potential benefits including more frequent interactions with FDA, eligibility for priority review, and eligibility for rolling review of the NDA. Once we have complete data from the Phase 3 PALISADE study in 2024, we intend to utilize all available mechanisms to get this potentially important drug to patients as quickly as possible. This would be the first Phase 3 readout for Arrowhead and our pipeline of RNAi therapeutics that utilize our proprietary TRiM platform. That represents a significant milestone for the company.

Moving on to the second wholly-owned cardiometabolic candidate ARO-ANG3, which is our investigational RNAi therapeutic being developed as a treatment for homozygous familial hypercholesterolemia, or HoFH, and heterozygous familial hypercholesterolemia, or HeFH. We have completed the ARCHES-2 Phase 2 study in 204 patients with mixed dyslipidemia and we are currently in the process of generating and analyzing study data, which we intend to report on later this year. The second Phase 2 study of ARO-ANG3 is the GATEWAY study in 18 patients with HoFH. This study is open label and was fully enrolled previously. I'm happy to report that the LDL-C reduction in this difficult to treat population with limited treatment options appears to be competitive with evinacumab, a monoclonal antibody that targets the same ANGPTL3 protein which is currently approved for HoFH patients. We will present interim data for the GATEWAY study at the 91st European Atherosclerosis Society Congress on May 23. These were welcome results, and thus we are currently working on a Phase 3 study design and plan for ARO-ANG3 in HoFH.

We will also talk in more detail about the unmet need in cardiovascular disease, the results from our cardiometabolic programs, our clinical development plans, and our commercial strategy at the upcoming R&D Day in June.

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

Thank you, Javier. We have demonstrated significant progress across discovery and early development. We continue to extend the reach of our TRiM platform to new tissue types and expand our pipeline into new disease areas in which patients have inadequate treatment options. We have also rapidly and efficiently advanced multiple early clinical stage programs and continue to generate highly encouraging data using various versions of the TRiM platform, each optimized for a different cell type.

I want to focus today on a few different areas: The pulmonary platform, with recent topline data announced for ARO-RAGE; ARO-C3, our candidate for complement mediated diseases; and, our emerging CNS platform, with the first candidate being ARO-SOD1.

Let's start with pulmonary. We have 3 candidates in the clinic now: ARORAGE, ARO-MUC5AC, and ARO-MMP7, which all use the same TRiM conjugate that targets the avß6 integrin for delivery to pulmonary epithelial cells. I will talk about each individually, but we think one of the benefits of gaining a RNAi therapeutic delivery platform with increasing validation is that learnings from each program can directly inform advancements in others. So, we view derisking events for one program, such as the data we saw with ARO-RAGE, as potentially de-risking to some extent to the others.

ARO-RAGE is our investigational RNAi therapeutic designed to reduce expression of the receptor for advanced glycation end products, or RAGE, as a potential treatment for inflammatory pulmonary diseases, such as asthma. We are currently conducting a Phase 1/2a, randomized, double-blinded, placebo-controlled study in normal healthy volunteers, which is Part 1, and in patients with mild-to-moderate asthma, which is Part 2. The single ascending dose portion of the study includes 5 sequentially enrolled NHV cohorts with escalating single-dose levels. The multiple ascending dose portion of the study includes 5 NHV cohorts and 3 asthma patient cohorts.

We have fully enrolled and dosed all SAD cohorts and the final MAD cohort is anticipated to be fully enrolled in the coming weeks. We have also opened the patient cohorts with enrollment of the first cohort nearly complete. We reported very encouraging topline results from 4 of the 5 SAD and MAD cohorts in NHVs. We do not yet have data from the 5th and highest dose level, but we plan to report on those results when they are available later this year.

First, safety and tolerability assessments have been encouraging. Overall, there were no patterns of adverse changes in any clinical safety parameters, no reported serious or severe adverse events, and no dropouts related to drug or related to adverse events.

In addition to safety and tolerability, ARO-RAGE demonstrated a strong pharmacodynamic effect. The mean maximum reduction in soluble RAGE, or sRAGE, at the 92 mg dose as measured in serum after 2 doses on Day 1 and Day 29 was 80% with a maximum reduction of 90%. The lower doses of 10, 20, and 44 mg also showed a dose response ranging from 31% to 59%. Serum sRAGE was also reduced after a single dose, with a mean maximum reduction at the 92 mg dose of 56% and a maximum reduction of 68%. Reductions in sRAGE as measured in bronchoalveolar lavage fluid on Day 31 after a single dose were also observed, with a mean reduction at 92 mg of 75% and a maximum reduction of 92%. We have additional planned cohorts in which BALF will be collected at later timepoints to quantify the additional lung level knockdown after 2 doses.

Lastly, the duration of pharmacologic effect persisted for at least 6 weeks after the second administration of the 92 mg dose. This is the last timepoint currently available and additional follow up is ongoing. This suggests that monthly, bimonthly, or less frequent dosing may be possible with ARO-RAGE. All in all, we believe these data show good translation of preclinical results to humans. Moving on to ARO-MUC5AC, our investigational RNAi therapeutic designed to reduce production of mucin 5AC, or MUC5AC, as a potential treatment for various muco-obstructive pulmonary diseases. We are currently conducting a Phase 1/2a study, similar in design to the ARO-RAGE study and we have begun enrollment of the asthma patient cohorts.

Sample processing and analysis for the NHV cohorts is ongoing and we intend to report on initial data when available. The third pulmonary program in the clinic is ARO-MMP7, which is designed to reduce expression of matrix metalloproteinase 7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF. During the last quarter we initiated a Phase 1/2a single ascending dose and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-MMP7 in healthy volunteers and patients with IPF. Dose escalation in this study is ongoing.

Now let's discuss initial results with ARO-C3, our investigational RNAi therapeutic targeting hepatic C3 expression as a potential treatment for complement mediated hematologic and renal diseases. Substantial unmet medical need remains in the treatment of multiple complement mediated diseases, including IgA nephropathy, C3 glomerulopathy, and additional renal and hematologic indications.

We are conducting a Phase 1/2, placebo controlled, dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-C3 in adult healthy volunteers and patients with complement-mediated renal disease. We originally planned to also include patients with PNH in this study, but we have since decided to eliminate these cohorts. We may decide to study PNH patients in the future, but we believe we can generate the data we need in the other populations. During the quarter we reported topline interim data and presented additional data at the 7th Complement UK Training Course and Symposium in April. In Part 1 of the study in NHVs, ARO-C3 demonstrated a dose-dependent reduction in serum C3, with 88% mean reduction after 2 doses at highest dose tested. A dose-dependent reduction in AH50, a marker of alternative complement pathway hemolytic activity, was also observed with a 91% mean reduction at highest dose tested. ARO-C3 had a long duration of pharmacologic effect, and we think this suggests quarterly or less frequent subcutaneous dose administration is possible.

Lastly, I want to briefly mention our announcement that CNS is the next area of focus for the TRiM platform. We have been working on CNS delivery for some time but have not discussed these efforts publicly until now. Our TRiM platform now includes a construct optimized for intrathecal administration to the central nervous system with good distribution throughout the brain and in all relevant brain cell types.

ARO-SOD1, the first program to use this new delivery platform, is designed to reduce expression of superoxide dismutase 1, or SOD1, in the CNS as a potential treatment for patients with amyotrophic lateral sclerosis, or ALS, caused by SOD1 mutations. ARO-SOD1 was highly active against its target with a long duration of effect in multiple preclinical models that we believe suggests it may be administered quarterly or less frequently. In preclinical studies, ARO-SOD1 achieved 95% spinal cord tissue mRNA knockdown after a single intrathecal dose in SOD1 transgenic rats and maintained greater than 80% spinal cord tissue mRNA knockdown 3 months after a single intrathecal dose in non-human primates.

ARO-SOD1, is on track for a CTA filing in the third quarter of 2023. We will talk more about our CNS platform and about ARO-SOD1 at the R&D Day in June, but I wanted to introduce the program because we are very excited about the potential for siRNA in the CNS.

I will now turn the call over to Ken Myszkowski. Ken?

Ken Myszkowski Thank you, James, and good afternoon, everyone. As we reported today, our net income for the quarter ended March 31, 2023 was $48.7 million or $0.45 per share based on 108.1 million fully-diluted weighted average shares outstanding. This compares with net income of $44.4 million or $0.41 per share based on 107.9 million fully-diluted weighted average shares outstanding, for the quarter ended March 31, 2022. Revenue for the quarter ended March 31, 2023 was 146.3 million, compared to 151.8 million for the quarter ended March 31, 2022. Revenue in the current period primarily relates to our collaboration agreements with Takeda and GSK.

Revenue is recognized as we complete our performance obligations, which include managing the ongoing AAT Phase 2 clinical trials for Takeda. There remains $31 million of revenue to be recognized associated with the Takeda collaboration which we anticipate will be recognized over the next year. Additionally in the quarter ended March 31, 2023, Takeda dosed the first patient in its Phase 3 REDWOOD clinical study of fazirsiran, triggering a $40.0 million milestone payment, and GSK dosed the first patient in its Phase 2b trial of GSK4532990, formerly known as ARO-HSD, in March, triggering a $30.0 million milestone payment. Both milestone payments are expected to be paid in the third quarter of fiscal 2023.

Revenue in the prior period primarily related to the recognition of the $120.0 million associated with the upfront payment received from GSK in addition to a portion of the payments received from our license and collaboration agreements with Takeda and Horizon. Total operating expenses for the quarter ended March 31, 2023 were $98.1 million, compared to $110.3 million for the quarter ended March 31, 2022. The key driver of this change was decreased candidate costs and lower stock compensation expense. The decreased candidate costs were primarily due to the reduction in outsourced manufacturing and toxicity study costs related to our cardiometabolic studies as the Company's pipeline of candidates progressed through clinical trials in 2022.

Net cash used by operating activities during the quarter ended March 31, 2023 was $107.2 million, compared with net cash provided by operating activities of $1.4 million for the quarter ended March 31, 2022. The prior period includes $120 million cash inflow from the GSK licensing and collaboration agreement. We expect our operating cash burn to be at the lower range of $70 to $90 million per quarter in fiscal 2023. We expect capital expenditures of approximately $90 million in the second half of fiscal 2023 as we near completion on our footprint expansion projects, including GMP manufacturing.

Turning to our balance sheet, our cash and investments totaled 559.8 million at March 31, 2023, compared to $482.3 million at September 30, 2022. The increase in our cash and investments was primarily related to the $250.0 million payment from Royalty Pharma, offset by our operating cash burn along with continuing capital projects. Our common shares outstanding at March 31, 2023, were 106.9 million. With that brief overview, I will now turn the call back to Chris.

Thanks Ken. We have already had a busy 2023 and have made a great deal of progress on many fronts. However, we anticipate that the middle and into the second half of the year will be even busier and offer even more opportunities to demonstrate what our pipeline can bring to patients.

We have always been clear that we believe for RNAi to reach its full potential as a revolutionary therapeutic modality, it needs to be able to address gene targets wherever they are. That no longer feels like a long-term goal. Between the liver franchise, the pulmonary franchise, the skeletal muscle franchise, the CNS franchise, and the adipose franchise, we have the opportunity to help a lot of people and create a substantial amount of value. But this is just the start. I expect us to blow through 20 in '25 and build a uniquely large and diverse pipeline of important medicines across multiple therapeutic areas. I have never been more excited about our near-term prospects or more proud of this amazing team. When you combine a technology that works with talented innovators who are aligned as to mission and empowered to make decisions and push science, incredible things can follow. We hope you can all join us on June 1 at our R&D Day to hear more. Thank you for joining us today and I would now like to open the call to your questions. Operator?

(Operator Instructions)

I also want to just remind analysts that we – in the interest of time, we like to limit the questions to one question and one follow-up.

Our first question comes from the line of Maury Raycroft with Jefferies.

I was going to ask if you can provide some additional detail on what new data we see at the R&D day from the cardiometabolic and pulmonary program specifically? And as follow-up for the Phase 3 PALISADE study, you mentioned readout in second quarter 2024, I'm just wondering if you will report on patient baseline characteristics at the R&D day or potentially at a medical meeting this year?

Thanks, Maury. So there's – I think, there's different questions there. What are we going to be talking about the R&D day? We'll be overviewing the pulmonary programs of course and we'll give you what data we will have at the time. We expect, as I mentioned in the prepared remarks, we expect to have some early non-healthy volunteer data from MUC5AC. I don't expect that we'll have MMB7 data, but we'll – we'll also likely have a bit more of ARO-RAGE.

We also – we will talk about those indications or those targets, as well as the indications. On the cardiometabolic side, it'll be a good chance for us to talk broadly about how we see ARO-ANG3 and ARO-APOC3 fitting into treatment paradigms. We'll talk a bit about a more recent data as well. We'll talk about the new CNS platform. We'll probably go into a little bit of the adipose platform a bit. We'll talk about SOD1, we'll talk about the portion of ALS that we'll be addressing with SOD1.

I'm sure I'm forgetting some things. It will be a bit of a busy day. We have a lot going on as you know, Maury, and we hope to touch on most of what we're doing.

And anything additional you could say about the PALISADE study, sounds like that's moving along and you'll have that readout second quarter of next year. Will you provide more on the types of patients that you've enrolled into this study, is that something we can learn more about this year?

Sure. I think we will review the entry criteria, and that would give you a really good idea, but I don't think we're going to look at the baseline (inaudible) and report that ahead of the end of the studies. This is a Phase 3 registration study. It is going really well. So, I will review the key inclusion criteria so you get a sense of the patient population.

For our next caller, we have Eliana Merle with UBS.

Congrats on the recent pulmonary data. Maybe just in terms of the patient cohorts that we can expect later this year. I guess, how should we think about what endpoints in particular you'll be reporting out, I guess, between, like, Feno FeV1, and what you'll be looking to see in some of that early data? Thanks.

James, do you want to address that?

Sure. Yes. So for RAGE, we're enrolling patients with mild-to-moderate asthma and I think these are relatively small cohorts. So, they're not powered for FeV1, although we will be measuring FeV1. Some of the key biomarkers that I think could be indicative of pathway engagement that knocking down a RAGE is affecting the inflammatory pathways are things like Feno, which is an IL-13 driven parameter, where we're also measuring blood and sputum eosinophils. I think that will be interesting as well. And Periostin is also IL-13 driven. And then as you mentioned, FeV1 and spirometry.

Just a quick follow-up. I mean, maybe just what your latest thinking around what the clinically meaningful level of target not found, I'd be left to sort of select to go forward doses and how this could differ between RAGE and MUC5AC?

Yes. So that's a really good question, that's one that we just can't answer. No one has been able to reduce expression of MUC5AC or RAGE in the past or MMP7 for that matter. And so there's just – we don't have a good biomarker for what that [bogey] could be. We will say however though for RAGE, for instance, we were seeing Mean max knocked down after 2 doses. In the serum at least at around 80%. In the animal models that we have studied, that was more than enough to affect phenotype.

These are severe models. And so that gives us some confidence. But again, they're just models. And so, we really have to wait to see in humans on what this looks like. We are excited about that level of knockdown. It's a good deep knockdown and it appears to be durable. And so, we are optimistic that that will be – that we are on the board for RAGE and for MUC and for MMP7, as well as for future targets.

We believe that because this is a target rich environment, it is – it feels likely to us that if you can knock a gene product down by 80% or so that you're going to affect disease states in at least some of these targets.

Our next question comes from the line of Joel Beatty with Baird.

First one is, how could the profile of ARO-SOD1 potentially compare with Tofersen? And then second question is, can you provide a little more color on why I think eliminating the study of some of the PNH patients from the ARO-C3 study?

So with regards to SOD1, I think that we will be competitive and likely better in terms of depth of gene target knockdown. And extremely, importantly for this route of administration for intrathecal part of the administration duration, which is key if we can do intrathecal administration every 3 or even every 6 months, I think that it would be much preferable for patients compared to every 2 weeks or every month dosing with Tofersen.

And then with regards to PNH, it was really a matter of competition that PNH is a small market that's reasonably well addressed with a lot of ongoing competing clinical trials and competing marketed – pursuing to be marketed therapeutics. So, we thought that we have limited resources and best to put those resources to work elsewhere.

Our next question comes from the line of Mani Foroohar with SVB.

So, I want to dive in a little bit on some of the modeling impact financially, the updates you've given us. Obviously, you've got your NASH program back in your hand out of the HPVs remains in the J&J's hands. You've talked about moving a number of other assets forward, CNS. How should we think about what this means for the tempo of CapEx and OpEx going forward from here? And to what extent is that already contemplated in the commentary you gave us last quarter and prior around ramping CapEx and OpEx spend to drive growth?

Sure. I don't – this was already factored into our plans over the next few years. I don't think anything that's happened over the last couple of quarters has materially changed change those things. We are growing so fast now, Mani, as you know. And we've got 12 clinical programs, 7 of them are wholly-owned. I think we'll have 14 to 16 clinical programs by the end of this year. We have an awful lot of opportunity to partner judiciously. That's – as you know, that's an important part of our model.

I believe that we are going to have 20 clinical programs or marketed products by 2025 and no company, I don't think certainly not a company our size can commercialize all of those. And so we have an awful lot of ammunition to find good partners. To bring in non-dilutive capital and that continues to be an important part of our ongoing financial planning. I think that that job gets even easier as we expand these platforms to include CNS to include skeletal muscle, pulmonary adipose.

We've got an awful lot of opportunity to find good partners, but while still holding on to a very large number of, we think potentially important medicines to drive value for us.

Our next question comes from Mayank Mamtani with B. Riley Securities.

Just maybe on MUC5 and ARO-RAGE, just can you clarify how long or is the chronic tox data available from that – from the preclinical study standpoint? And then at a high level, like the differences between the candidate design delivery, I know the PD market is clear for – clearer for RAGE, but is there anything that we can glean from the different programs that help us think about the de-risking that is underway for the pulmonary delivery? And then I have a quick follow-up.

Sure. The chronic tox is not complete – those are ongoing. And then the next question is what is de-risking events? Well, James, do you want to address?

Want to address more data through this year. We'll have – we will look at – we will have more data on knockdown healthy volunteers shortly. We'll have patient data late this year, and then we'll have the chronic tax data. I guess all of those are somewhat – are incrementally de-risking. We feel really good about the changes we've made in ARO-RAGE, ARO-MUC5AC, ARO-MMP7, compared to ARO-ENAC a year ago. These are substantially more potent constructs.

We're using in broad terms, and James correct me if I'm wrong here. Around 1 mg per kg is at this fourth dose that we reported on. A little less than 1 mg per kg. And as you may recall, Mayank, in the pulmonary day a year plus ago, around a year ago, I guess, we graphed the various top studies and where we started to see local lung inflammation and over 6 months. And the cumulative the cumulative doses around 100 mgs per kg where we started to see that inflammation. And so, we feel like we are in good shape here that we should be substantially underneath that for RAGE.

We'll see where we are with MMP7 and with MUC, but at least so far the data we've seen it's encouraging to us that we have something that's extraordinarily more potent than ARO-ENAC. And again remember, I mean again, I know you will recall this. Our dosing for ARO-ENAC was with 3 daily doses every 2 weeks.

For ARO-RAGE we are once a month and as James pointed out, we have data out through 6 weeks and we are still seeing a deep knockdown. And so this may not be once a month dosing, maybe once every 2 months dosing and then maybe once every 3 months dosing. So, we feel like we're in good shape here.

Look forward to seeing more of the R&D day. And then just another high level question. As you've decided on DUX4 muscle, for externalization and not maybe on SOD1 and CNS. So, I mean how are you thinking about which muscle types to go forward with internally versus externally? And for DUX4 muscle, skeletal muscle, are they like kind of deal analogs that exist out there for the kind of value you might be looking for?

Sure. So, let me be clear. We've not made a decision on partnering in ARO-DUX4. We were gearing up to file CTA. We are ready to go. If we even had chronic tox (inaudible), as I mentioned, and we had substantial interest from several companies and we decided to press pause and see where those go. And so that's where we are right now. We'll see if those – if any of those turn into an actual deal, if they do, that's great.

We know hopefully we'll find the right partner for that. If not, that's great too because we believe in the drug, we believe in the platform, and we'd be happy to push that into the clinic ourselves. It just made sense for us to wait a couple of months to see where these things go. We are in a good spot I think for not only ARO-DUX4, but also the follow-on clinical candidate. But as I mentioned, we think we'll be CTA ready in the fourth quarter.

We're in a good spot where we are almost agnostic. I'm happy to bring both those to clinic ourselves, but also I'm happy to listen to offers and if there are good companies who can – who have experience in these types of – in developing these types of drugs and come up with proper value than we have we're happy to talk about that as well.

(Operator Instructions) Our next question comes from Patrick Trucchio with H.C. Wainwright & Company.

Just a follow-up question on the CNS platform. I'm wondering if you can discuss the preclinical data that's been generated to date and the level of confidence in the safety profile of these sRNA constructs and delivery methods as you transition to human trials? And then secondly, I'm wondering if there's an update on the HBV program and what that collaboration may look like going forward?

I'm sure – so let me – I'll give you the high level answer to the CNS question and then and James can give you more granular answer if necessary. So, we have done the [GLP] tox studies and we feel comfortable about safety margins there. We've done exhaustive non-GLP tox studies with ARO-SOD1, as well as other potential candidates and we feel good about what we're seeing.

With respect to HBV, I don't have anything to update you on now. I believe that Janssen is running their process and so I don't have any information on where that's going to be over the next several quarters.

Yes. I think I would just add on the CNS platform, we'll share more of the specific data at the Analyst Day in June. But we're seeing 80% to 90% reduction in various brain regions in both rodents and non-human primates with good duration that should support at least Q3 month dose administration and we'll share more really next month.

Our next question comes from the line of Keay Nakae with Chardan.

Question on top. Anything you have learned from Biogen's development to first and that you think you might be able to learn from and benefit from as you proceed into the clinics? Yes. I mean, it's very helpful to have another asset out there that's hitting the same gene target that's kind of gone through the whole process. And I think learned a lot from what they did in their early clinical studies their Phase 1/2 design and then they're pivotal as well?

Yes. And I'd like to add that the regulatory person is very, very important. And the accelerated approval based on the validated biomarker for a disease like this, I think it's huge for the field. It's really important for our program. Will enable us to go a lot faster. I think in this condition and thanks to their work, there is a very good data over the natural history of this SOD1 ALS patient looks like and also was a benchmark for efficacy both in neurofilament and also clinically. So, I think this success program opened the door for advanced – our program even faster.

And our next question comes from Prakhar Agrawal with Cantor Fitzgerald.

The first question is on asthma for targets such as RAGE, given you're testing it in a broad population, how much benefit on lung function endpoint such as FeV1, you think you need to show to give you confidence on moving it into later phase trials trying to better understand what benchmarks are you looking at? And I had a quick follow-up.

Yes. So, James already made the point that we're not looking at efficacy data in this Phase 1 study. So, this program will require a proper Phase 2 study to show efficacy and probably FeV1. If you look at the benchmark with the biologics that are already approved with the (inaudible), we are looking about 100 milliliters improvement, approximate FeV1. So that's the benchmark, I think, for a Phase 2 study. And that's also something that we will discuss at the Analyst Day in June 1st.

And just curious as to the broader long-term strategy in asthma, given you have 2 targets, is the plan to continue developing both assets into Phase 2, Phase 3 or you could make a decision to prioritize one over the other at a certain time and what drives that decision?

Data. It's – as with ANG3 and APOC3, look, these are 2 targets that are interesting. And they will – and they'll be addressing asthma in 2 different ways. And so we look forward to seeing how they – how patients respond to each of them. It could be that there are populations of patients who respond better to one than the other, it could be that one is superior in all patient populations. We're just going to have to wait and see.

It's a good problem to have because we think we have a good opportunity for both of them to be important medicines. And so, let's just see what the data of the data show over the next couple of years.

Yes. And the other thing I would say is, MUC5AC is a very new constructive type of drug and there are other new construction diseases that are very prevalent and their memory can be very significant. So, please say we will evaluate total indications such as COPD or bronchiectasis, as well as we go along.

Our next question comes from Luca Issi with RBC Capital.

I have a few, maybe Chris now that you have proof of concept here, I would say for targeting agent, I should say, in lung, how are you thinking about business development? Is this a good time to find a partner? Are you hoping to further the risk of platform before you entertain BD discussions? Or are you planning to keep pulmonary in-house full stop? Any thoughts there would be much appreciated. And maybe on SOD1 ALS, can you just talk about why going after this indication? Obviously, you're a few years behind Biogen, there are only 200 to 300 patients in the United States. So, why not going after other targets with bigger TAMs like maybe (inaudible). So again, any thoughts there appreciated it. And then last one quickly on CapEx, if I recall it correctly, last time you mentioned that you were expecting to invest up to $200 million in CapEx to build the facility in Verona, Wisconsin, however, I think the 10-Q suggests that the number is now between 200 and 260, so wondering if you can clarify that?

Sure. Thanks, Luca. Ken, you want to address the last first?

Sure. The 200 that we mentioned was the amount that we thought we were going to spend this year. The total project was anticipated to be $280 million, $290 million in total. We have spent less than the $200 million this year. We expect to spend probably around $90 million more in the second half and probably about $100 million toward that in fiscal 2024.

Okay. So the other 2 questions. The first one was around pulmonary partnering. So, look, we aren't rushing to partner the current 3 assets anytime soon or frankly even the broader platform right now. We want to learn more, we want additional data. I don't think that we should be in a hurry to do that. This is an important space for us. As we've said in the past, we don't see 2 or 3 or 4 drugs here. We see 8 or 9 or 10 drugs coming out of the pulmonary platform.

There's 16,000 or so pulmonologist in the U.S. we like the idea of building a commercial infrastructure to address that market with several drugs in our own bag. Having said that, it's probably not going to be 10, 11, 12 drugs. So, there will be partnering within this platform, I think at some point, I don't think it makes sense to spend too much time on it at this point because we're still early days. But this is a good opportunity for us. Again internally to create value and to serve patients ourselves, but also to find additional partners in order to really extract proper value from this part of the TRiM platform.

The second question I do with SOD1, why are you going after SOD1 instead of something else? Well, I'll tell you. We are also going after something else. We're an and company. We're not an or company. It just so happened that SOD1 popped first and we think it's a good place for us to be. We think we'll stack up well against to a first and as we talked about, it's nice to learn from somebody and accelerate our pathway because somebody went ahead of us, and then if we have a better drug for those patients, then so much better.

And so, we believe in SOD1, we believe in helping those patients who need it. But that's just the first of we think many, like the pulmonary space, CNS is a target rich environment and there's no shortage of important targets that we will be going after.

Our last question is coming from the line of Madhu Kumar with Goldman Sachs.

So, one kind of science question and then one big strategy question. So, the science question is, what do you think is the fundamental floor for sRAGE and the serum from extrapulmonary resources? Basically, how far do you think serum sRAGE can potentially get to, if you really were to just wipe it out in the lung ?

And then conversely, what is the floor in the lung, I said in bronchoalveolar lavage for sRAGE as well. And then kind of the big picture strategy question is, kind of related to Luca's question. Effectively, like what would you need to see to really reposition the company to focus on these 8, 9 or 10 lung indications relative to the kind of current menagerie of liver directed drugs?

Sure. Yes. So the floor of sRAGE, maybe the second part of question is key here. I think measuring – if you assume that the valve sRAGE is exclusively coming from the lung, I mean the floor would be close to zero that you maybe get a small amount of sRAGE coming from endothelium or some of the other cell types, but really the most of the sRAGE in the [bowel] should be coming from the type 2 alveolar epithelial cells.

Now, that doesn't mean that we'd be able to get 99.9% knockdown. I think even with our best triggers in the liver, we're getting 95% plus knockdown, so that's just not the way RNAi tends to work. In the serum, I don't think we know the answer to that really. I think the best indication are the data that we've shared so far that you can achieve 90% reduction in the blood. It's not entirely clear how much sRAGE in the blood is coming from extra pulmonary sources.

Although I think it is clear that most of it is coming from the lung. So that number may vary from person-to-person or either in between healthy volunteers and asthma patients. So, I think we're still trying to sort that out, what's the floor in sRAGE in the blood. It was one of the reasons why we added an additional dose level to this healthy volunteer study.

I think we're getting very close because we already seen 90%. If you look at APOC3, AAT, that's what you see, 80%, 85%. So, I think we're getting very close to the floor. Almost complete addition.

And so, and Madhu, I'll address the second question. So, I'm just curious. So, when you talk to a J&J and Pfizer and others, do you refer to their large pipeline as menagerie of drugs? So, look, we're not going to refocus this company to be a pulmonary company. I think there's no reason to do that. We actually like this strategy of having a broad pipeline across therapeutic areas.

I think we can do it in part, but I think we can do it because we are relying on well validated targets and hopefully we stay disciplined and we continue to do that. And so, ultimately I think that we can create the most value by being a relatively diversified company. Pulmonary is a (inaudible). And so that is a place I think that where we will have several or more of our wholly-owned drugs, but that won't be the only one.

I would now like to turn it back to Chris Anzalone for our closing remarks.

Thanks very much for joining us today, and we look forward to speaking with you on June 1.

Goodbye. Alright. Making sure you all can you hear me. Thank you for your participation in today's conference. This does conclude the program. You all may now disconnect if you haven't already.