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

Please go ahead, Vince..

Thank you, Justin. Good afternoon, everyone, and thank you for joining us today to discuss Arrowhead's results for its fiscal 2022 fiscal year ended December 30, 2022. 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 Senior Vice President of Discovery and Translational Medicine, who will provide an update on our earlier stage programs; and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials.

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

Before we begin, I would like to remind you 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. With that said, I'd like to turn the call over to Chris Anzalone, President and CEO of the company.

Chris?.

one, develop and commercialize some drugs ourselves; and two, substantially increase our market capitalization so we can do more of number one. That is the prize we need to keep our eye on, so every decision we consider should be made by asking ourselves if it gets us closer to or farther from that goal.

In my mind, the decision to sell these future royalties clearly gets us closer to that goal. With that overview, I’d now like to turn the call over to Dr. Javier San Martin.

Javier?.

dose and interval; patient population selection; length of study; modeling to estimate event rates and effect size; registrational path and Phase 3 design; and where and how to execute the studies. We essentially gave ourselves a six-month head start on all of that work.

This is critical since we plan on having multiple end-of-Phase 2 meetings and moving forward with multiple Phase 3 studies over the next 12 months. Next, I want to highlight some of the key results from the Phase 2 studies that we presented at the American Heart Association and our webcast event.

ARO-APOC3, ARO-ANG3, and olpasiran were all highly active at silencing their respective gene targets, which resulted in encouraging changes in multiple relevant lipid and lipoprotein levels.

In the SHASTA-2 study in subjects with severe hypertriglyceridemia who had baseline triglycerides, or TGs, greater than 500 mg/dL, treatment with ARO-APOC3 at doses of 10 mg, 25 mg, and 50 mg all durably decreased APOC3 up to 87%, TGs up to 86%, non-HDL up to 45%, and increased HDL cholesterol up to 99% through the week 16 time point.

ARO-APOC3 has been well tolerated with treatment emergent adverse events reported to date that reflect the underlying comorbidities and conditions of the population under study.

In the MUIR study in subjects with mixed dyslipidemia who had baseline average TGs of 220 mg/dL, non-HDL of 150, LDL cholesterol of 110, and ApoB of 95, remnant cholesterol of 46, and HDL cholesterol of 42mg/dL, treatment with ARO-APOC3 at doses of 10 mg, 25 mg, and 50 mg resulted in substantial reductions of APOC3 of 80%, TGs of 65%, non-HDL cholesterol of 25%, LDL-C of 20%, and ApoB of 20%, remnant cholesterol decreased by 60%, and an increase in HDL cholesterol increased by 50%.

We believe these changes all represent key reductions in residual cardiovascular disease at risk.

In the ARCHES-2 study in subjects with mixed dyslipidemia who had baseline median TGs of 226 mg/dL, treatment with ARO-ANG3 at doses of 50 mg, 100 mg, or 200 mg resulted in substantial reductions of ANGPTL3 up to 71% at week 8, TGs up to 59% at week 16, and LDL cholesterol up to 32% at week 16.

ARO-ANG3 was also associated with median relative reduction in liver fat fraction at week 24 of 28% for the 100 mg and 200 mg dose, with no adverse events related to liver function test changes reported to date.

ARO-ANG3 has been well tolerated with treatment emergent adverse events reported to date consistent with those expected in this patient population and with associated underlying comorbidities.

Amgen also presented end-of-treatment data from its Phase 2 OCEAN(a)-DOSE study of olpasiran in adults with elevated lipoprotein(a) levels of greater than 150 nmol/L and a history of atherosclerotic cardiovascular disease. These data were also published in the New England Journal of Medicine.

Placebo-adjusted mean percent reductions of LP(a) were at 70.5% for patients receiving 10 mg every 12 weeks, 97.4% for patients receiving 75 mg every 12 weeks, 101.1% for patients receiving 225 mg every 12 weeks and 100.5% for patients receiving 225 mg every 24 weeks.

The totality of these data demonstrates the significant progress achieved in RNAi drug development and specifically suggests a potential future treatment paradigm where Arrowhead’s proprietary TRiM technology may be prominently leveraged in preventive cardiology.

So, what do we do with ARO-APOC3 and ARO-ANG3? For ARO-ANG3, we are focusing on patients with hypercholesterolemia. ANGPTL3 is a key regulator of lipid and lipoprotein metabolism that inhibits lipoprotein lipase and endothelial lipase.

ARO-ANG3 has a unique mechanism of action to address hypercholesterolemia distinct from other LDL cholesterol-lowering therapies. It may address unmet need in patients with specific genetic mutations, for example patients with dysfunctional LDL receptor.

And it may also be added to other LDL cholesterol-lowering therapies in patients not reaching goal. Patients with heterozygous familial hypercholesterolemia, or HeFH, typically have LDL cholesterol greater than 190 mg/dL and have increased risk of ASCVD. There are estimated to be around 1.4 million patients in the U.S. with HeFH.

Patients with homozygous familial hypercholesterolemia, or HoFH, typically have LDL cholesterol greater than 400 mg/dL. There are around 1,200 patients with HoFH in the U.S. These are the two indications that we are focusing on initially for ARO-ANG3.

Our plan is to have end of Phase 2 meetings in the first half of 2023 and then potentially begin Phase 3 studies in the second half of 2023. We view ARO-APOC3 as having a potentially broader set of indications and patient populations where it may provide a benefit.

It potentially addresses the risk of pancreatitis in severe hypertriglyceridemia syndromes. ARO-APOC3 also modulates multiple lipids and lipoproteins that contribute to the residual risk of ASCVD in patients with mixed dyslipidemia, which has the potential to translate into a decrease in atherosclerosis and coronary disease progression.

APOC3 is a key regulator of lipid and lipoprotein metabolism that inhibits lipoprotein lipase and mediates hepatic uptake of remnant particles in an LPL independent pathway. ARO-APOC3 improves multiple lipid parameters and may provide clinical benefit in a broad population with dyslipidemias.

In clinical studies it has reduced TGs in patients with severe hypertriglyceridemia, including FCS, which has the potential to decrease the risk of acute pancreatitis. It has also reduced multiple residual cardiovascular risk factors, such as APOC3, LDL cholesterol, ApoB, remnant cholesterol, and others in patients at risk of ASCVD.

We are already conducting the PALISADE Phase 3 study of ARO-APOC3 in patients with FCS, which is approximately 50% enrolled at this time. Our plan for the additional indications is to have regulatory interactions in the second half of 2023 and begin Phase 3 studies in the first half of 2024.

These additional indications are SHTG, with a prevalence of around 4 million in the U.S., and patients at risk of ASCVD despite maximally tolerated statins, with a prevalence of around 12 million in the U.S.

Now I want to move on to fazirsiran, our investigational RNAi therapeutic designed to reduce production of a mutant form of the alpha-1 antitrypsin protein, called Z-AAT, as a potential treatment for the rare genetic liver disease associated with alpha-1 antitrypsin deficiency.

Z-AAT accumulation is believed to be the cause of progressive liver disease in patients with AAT deficiency. Reducing production of the pro-inflammatory Z-AAT protein has the potential to halt the progression of liver disease and potentially allow the liver to regenerate and repair.

Data from our open label Phase 2 study were published earlier this year in the New England Journal of Medicine. Those data suggested that fazirsiran was very effective at reducing the production of the Z-AAT protein and that the livers of these patients were able to begin the process of healing.

This is includes breaking down and clearing the accumulated Z-AAT in the liver, decreasing the histologic globule burden, demonstrating histologic improvements in inflammation, reducing biomarkers of liver injury, and ultimately decreasing fibrosis severity.

These were very encouraging signs for the potential of fazirsiran to help patients with AATD liver disease. We now look to the fazirsiran Phase 2 placebo-controlled SEQUOIA study and to regulatory interactions on the Phase 3 study.

The SEQUOIA data are mostly in now and we are waiting to receive feedback, if any, from the FDA on the proposed design for the Phase 3 study. These are expected soon, so we and our partners at Takeda will together determine the best way to communicate these publicly.

Takeda is still on schedule to begin the Phase 3 study in the first quarter of 2023, and we are confident that we can have an update publicly on SEQUIOA and guidance on the Phase 3 prior to that. I will now turn the call over to Dr. James Hamilton.

James?.

I want to give updates on four of our earlier stage programs that include three pulmonary candidates targeting RAGE, MUC5AC, and MMP7, and on our candidate targeting complement C3. Let’s start with C3.

ARO-C3 is an investigational RNAi therapeutic designed to reduce hepatocyte expression of complement component 3, or C3, as a potential therapy for various complement mediated hematologic and renal diseases. We are conducting a Phase 1/2 clinical study now that includes two parts.

Part 1 is placebo controlled in healthy volunteers and includes single ascending dose, or SAD, cohorts and multiple ascending dose, or MAD, cohorts.

All of the SAD and MAD cohorts are fully enrolled and participants are being followed to assess safety and tolerability, dose response based on serum C3 levels, and duration of effect at various dose levels. We are confident that we will have sufficient data in the first half of 2023 to report interim results from Part 1 of this study.

Part 2 is open label in eligible subjects with paroxysmal nocturnal hemoglobinuria, or PNH, and complement-mediated renal diseases, including IgA nephropathy and C3 glomerulopathy.

Data from Part 1 will inform Part 2 dose selection, which we expect to happen in the coming months and then the patient cohorts will be opened for enrollment in the first half of 2023.

We are very excited about this program and believe it has the potential to address multiple serious complement-mediated or complement-associated diseases with unmet need in the renal and hematologic spaces.

We know that complement C5 inhibitors are disease modifying in conditions such as PNH and believe that proximal C3 inhibition may confer advantages over C5 blockade. For example, C5 monoclonal antibodies only block the terminal complement pathway, and many of the proximal complement actions remain intact.

In addition, clinical validation exists for C3 inhibitors, and we believe RNAi-based C3 inhibition could have clear dosing advantages over other mechanisms. Furthermore, alternative pathway inhibition is likely of key relevance for treatment of conditions such as IgA nephropathy, C3 glomerulopathy and potentially other glomerular diseases.

AROC3 is a subcutaneously administered candidate with an expected long dosing interval of once every three months or less frequent. We think this would be much more patient friendly than current C3 inhibitors that require a high volume infusion multiple times per week. I will now move on to our three pulmonary candidates, starting with ARO-MMP7.

ARO-MMP7 is designed to the reduce expression of matrix metalloproteinase 7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF. MMP7 is thought to play multiple roles in IPF pathogenesis, including promoting inflammation and aberrant epithelial repair and fibrosis.

Silencing MMP7 expression in a rat IPF model reduced inflammatory cell infiltration, limited lung fibrosis, and preserved pulmonary function. In August, we filed a CTA to begin a Phase 1/2 clinical study of ARO-MMP7.

The Phase 1/2 study will be similar in design to our other first in human studies and includes a healthy volunteer portion followed by a patient portion.

Now, moving on to our two other pulmonary programs, ARO-MUC5AC and ARO-RAGE, our investigational RNAi therapeutics designed to reduce production of mucin 5AC, or MUC5AC, and the receptor for advanced glycation end products, or RAGE, respectively, as potential treatments for various muco-obstructive and inflammatory pulmonary diseases.

These two programs are on largely parallel paths and at approximately the same stage. They are both in Phase 1/2 studies designed to assess safety and tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers first and then in patients with asthma.

For both programs, we are approaching full enrollment of the healthy volunteer SAD cohorts and are well into enrollment of the healthy volunteer MAD cohorts.

In both the SAD and MAD, we have various methods to assess target engagement, including in induced sputum and bronchoalveolar lavage fluid, and for RAGE we are also measuring serum sRAGE protein, a circulating biomarker for RAGE target engagement in the lung.

We anticipate that we will be able to report interim results from Part 1 of these studies and begin Part 2 in patients with asthma in the first half of 2023.

These are potentially important new medicines that address targets that have been difficult to drug using other modalities and are designed to treat muco-obstructive and inflammatory lung diseases in fundamentally new ways.

We are excited to see and share these results and we are confident in the progress we’ve made on our pulmonary TRiM platform and these generation 2 candidates. 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 fiscal 2022 was $176.1 million or $1.67 per share based on 105.4 million fully-diluted weighted average shares outstanding.

This compares with net loss of $140.9 million or $1.36 per share based on 103.7 million fully-diluted weighted average shares outstanding for 2021. Revenue for fiscal '22 was $243.2 million, compared to $138.3 million for 2021. Revenue in the current period primarily relates to our collaboration agreements with Takeda and Horizon.

Revenue will be recognized as we complete our performance obligations, which includes managing the ongoing AAT Phase 2 clinical trials for Takeda, and delivering a Phase 1 ready candidate to Horizon.

There remains $128.4 million of revenue to be recognized associated with the Takeda collaboration which we anticipate will be recognized over the next two to three years, and there remains $6.7 million of revenue to be recognized for Horizon, which we anticipate will be recognized [technical difficulty].

Please remain on the line. Your conference will resume shortly..

Sorry, folks, we had a connection problem there. I'll continue about halfway through our -- my prepared remarks. Net cash used by operating activities during fiscal 2022 was $136.1 million, compared with net cash provided by operating activities of $171.2 million during 2021.

The increase in cash used by operating activities is driven primarily by higher research and development expenses. We expect our operating cash burn to be $70 million to $90 million per quarter in fiscal 2023 and we expect capital expenditures up to $200 million as we near completion on our footprint expansion projects, including GMP manufacturing.

Turning to our balance sheet, our cash and investments totaled $482.3 million at September 30, 2022 compared to $613.4 million at September 30, 2021. The decrease in our cash and investments was primarily due to cash used for operating activities. Our common shares outstanding at September 30, 2022 were 106.0 million.

As Chris mentioned earlier, on November 9, 2022, the Company and Royalty Pharma entered into a Royalty Purchase Agreement, pursuant to which Royalty Pharma agreed to pay up to $410 million in cash to the Company in consideration for the Company’s future royalty interest in olpasiran, originally developed by the Company and out-licensed to Amgen in 2016.

Pursuant to the Royalty Pharma Agreement, Royalty Pharma paid $250 million upfront and agreed to pay up to an additional $160 million contingent upon the achievement of certain clinical, regulatory and sales milestones.

The Company retained rights to $400 million in development, regulatory and sales milestone payments potentially due from Amgen from the same 2016 out-licensing agreement. Pro forma cash and investments at September 30, 2022 including the Royalty Pharma cash receipt would be $732.3 million. I will now turn the call back to Chris..

Planning for the fazirsiran Phase 3 is complete and currently under review with the FDA, and SEQUOIA data are in.

We expect to be able to give guidance on the P3 and present top line SEQUOIA data with Takeda shortly; Interim Phase 2 data from ARO-ANG3 and ARO-APOC3 suggest that both drug candidates are doing what they are designed to do, and we have good plans as to how to apply these in various patient populations.

We expect multiple end-of-Phase 2 meetings in 2023 and to initiate multiple Phase 3 studies shortly thereafter; Progress with ARO-MUC5AC and ARO-RAGE in Phase 1/2 studies has been good.

We expect interim data that could provide clinical proof of concept in the first half of 2023; ARO-C3 is progressing well in a Phase 1/2 study and we expect interim data that could provide proof of concept in the first half of 2023; Our discovery engine continues to perform and we expect to announce the next cell type we will be targeting in the first half of 2023; We have provided better clarity with respect to our balance sheet with our sale of olpasiran royalty rights for $250 million upfront plus $160 million in potential additional payments.

This is on top of the remaining $400 million we could access in clinical, regulatory, and sales milestone payments from Amgen; and finally, we have announced our 20 in ‘25 campaign.

Our plan of having 20 individual drugs in clinical trials or at market in 2025 will be a remarkable accomplishment that, we believe, would represent a large leap forward for medicine and position Arrowhead as a truly unique and impactful biopharmaceutical company. Thank you 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 Maury Raycroft from Jefferies..

Just going to ask one on AAT.

Wondering if you can clarify if you or Takeda has shared the Phase 2 biopsy data with FDA? And if their feedback will be based on the biopsy data or only the serum biomarker knockdown data?.

Javier?.

Yes, the feedback that we're looking is at the Phase 3 protocol design that was already discussed twice. And as Chris said, we already -- Takeda already incorporated most of the feedback. So this is more a procedure than anything else. And the SEQUOIA data is not part of this feedback that we're looking for.

In other words, the SEQUOIA data that was necessary to inform the Phase 3 was already presented and is part of the discussion that we’re having with the agency over the last four or five months..

Got it. Okay. Okay.

And then for the AAT data that you have in hand, can you comment on what you're seeing and better set expectations for what you will disclose? And if you start the Phase 3 in the first quarter of next year, do you think the update will happen in December or more likely around JPMorgan meeting in early January?.

Yes. I can't give too granular guidance on the timing for the update. But I'll tell you my hope is that we can do that in December. We just have to see what schedules look like. We expect the feedback, if any, from FDA almost any day now. And so we do have time to get that in, in December. And so we'll see.

With respect to giving further guidance on the SEQUOIA data, we're just not going to do that. We will provide that update at the same time as we give guidance on what the Phase 3 will look like..

And our next question comes from Luca Issi from RBC Capital..

I have a quick one on APO versus ANG. It looks to me you're prioritizing APOC3 over ANG3, especially for the larger mixed dyslipidemia population.

Can you expand a little bit more on the rationale behind the decision? And is it fair to assume that you're looking for a partner for APOC3 given that you need to run a cardiovascular outcome trial?.

I'll take the second part, and then I'll hand the first part over to Javier. The answer is no, we are not looking for a partner for APOC3. That, to us, feels like an important opportunity for us. The data have been from our perspective, unequivocal.

And we see a large opportunity in large markets as well as smaller SHTG market and, of course, the very small FCS market. So we like the opportunity, and we intend to conduct that cardiovascular outcome study ourselves and to commercialize that drug ourselves..

Yes. So a couple of things. So first, the Phase 2 data or the interim data that we presented at the American Heart Association really confirmed what we learned in the Phase 1/2 studies. So it wasn't about prioritization, it was about to really learn and confirm the specific therapeutic effect of these two molecules.

And as we said before, ANG seems to be a drug that is more focused on hypercholesterolemia, and that is how we see the opportunity.

Now that's a much crowded space, when you think about the general hypercholesterolemia population, but this drug has a very unique pathway and mechanism of action that can address these specific smaller population, that is rare HoFH and the not so rare HeFH.

So it's not about prioritization, but it's about where the profile of this drug fits in the context of clinical care, particularly when you fast forward a few years from now. So ARO-APOC3, as you saw the data that we knew about the severe hypertriglyceridemia populations is confirmed, and it's very remarkable and is consistent.

And as I always said, with these therapeutics, we have 100% response with regard to hypertriglyceridemia. So our initial plan to go with the two severe hypertriglyceridemia syndrome, the FCS or the SHTG, continue to be the same.

What we are learning and I think that was a key feature of our Analyst and Investor Day is what is the unmet medical need in cardiovascular risk reduction in the next five to 10 years? And we believe that the LDL cholesterol issue is probably well taken care of and the rest of the risks come from different sources of lipid and lipoprotein, most of which are addressed with the ARO-APOC3 molecule.

So in conclusion, we see the opportunity where the unmet medical need is and ARO-APOC3 fit very well with those criteria. So it's not about prioritization, but it's really going to where the drugs have the biggest promise..

Yes. Look, I think that our development programs worked exactly as we design them to work. We have these two drug candidates that were clearly active and clearly had some overlap in their activity. And people would ask how we're going to apply these two drugs to various patient populations.

And our answer always was we need to look at the data, and that will guide us. That was not a satisfactory answer to some people, but that was the answer. And now do we have an interim look got a better idea about how these will help various patient populations. And so now I think we've got a good idea.

Again, as Javier said, we don't view this as prioritizing. We view this as just following where these drugs are going to have their greatest benefit in which patients..

And our next question comes from Ellie Merle from UBS..

For the initial pulmonary readout in the first half of next year, I guess what are you looking to see in terms of the degree of protein knockdown based on the dose levels that you're studying in healthy volunteers? And I guess when you think about pulmonary delivery, I guess, what is proof of concept for the pulmonary platform look like from this readout or if perhaps we do wait for longer-term data?.

Sure. Look, I think these are well-validated targets, particularly MUC5AC. But I think even RAGE and certainly MMP7. And so our thinking is that if we can see a well-tolerated, deep knockdown in healthy volunteers, that is a substantial clinical proof of concept. We will also have some data later in the year on -- in various patient populations.

But I think if we can see good consistent knockdown in healthy volunteers that's well tolerated, I think that is giant leap forward for the entire platform and certainly for the individual candidates. With respect to how much knockdown we need, I don't think we're setting expectations for ourselves here. I think we want to see what we see.

But our hope is that we see consistent and at least relatively deep knockdown. And if we can, I think that given the importance of these targets, I think that they will have disease-modifying effects..

And our next question comes from Joel Beatty from Baird..

For the lung programs, MUC5AC and RAGE, I think in your prepared remarks, you mentioned that both of these programs are going to reaching the top of the SAD cohorts and also flowing MAD cohorts.

How do you decide the peak dosing of those? Is this kind of preset? Or are you looking at safety or efficacy markers?.

So the dose levels for the SAD and MAD are largely preset. And then as we go from one dose level to the next, we have an independent Data Safety Committee that reviews aggregate safety data and boats to allow dose escalation from the dose just completed to the next higher dose. Hopefully, that addresses your question..

Great.

And then for the cardio drugs APOC3 and ANG3, do you see the market opportunity as more of displacing current drugs and being used in place with them or as add-on therapies to the current set of drugs in the market?.

I think it's a little bit too early to opine on that. That's a broad question. Give us some more time so we can complete the Phase 2, and we have a better idea about what that looks like and we can go from there. But at this point, I don't think that we want to get into how we slot into various therapeutic paradigms..

And our next question comes from Edward Tenthoff from Piper Sandler..

Two questions, if I may. Just housekeeping, what was the fourth quarter weighted average shares outstanding, if you have them to 3 decimal points? But then for Chris, kind of level question. You guys have been so successful at partnering different therapies. You've been clear that cardiovascular is a key area of focus.

How are you really looking at the pipeline going forward? Like is pulmonary disease going to be an area of a secondary focus? Are you going to look to partner some of those therapies? How should we be thinking about sort of where you guys are going to stay focused and specialized?.

Sure.

Ken, do you want to address the first question?.

Yes. The weighted average shares for Q4 were 105.879 million.

Awesome. And then again, just in terms of higher level, obviously, a focus on cardiovascular disease.

What else are you guys thinking about partnering or what is going to be core?.

Sure. Thanks, Ed. So broadly, of course, that's a dynamic question because as the company grows and as market appetites for various targets and drugs change, of course, that which can be partnered changes. Having said all of that, look, we -- as we've said in the past, we like cardiovascular. We like what we're seeing with APOC3 and ANG3.

We like the idea of building commercial force to address those. We like the staged approach there starting with HoFH and expanding into HeFH. We like the idea of starting with small FCS, expanding into SHTG, and expand into mixed dyslipidemia. Now with regard to the pulmonary, look, that's a very interesting area.

We think that's a target-rich environment. That feels to us like another liver. And we think, look, there we can address that market. I think there are 600-or-so-thousand pulmonologists in the U.S., and we see not two or three or four drugs with eight or nine or 10 drugs. So I think that we will play there.

Now because it's so target rich, I think we also could do some partnerships there at some point. We're not looking to partner these first three right now. But I think there's room there for us to build a real franchise. And then also to work with the right companies on a handful of other targets potentially.

And then you look at our other candidates, C3, that's a very interesting drug candidate to hold on to ourselves. That gives us an awful lot of optionality in terms of how we commercialize that, where we go, how fast we can get there. So anyways, so that's sort of a broad answer to your question, I guess..

And just hats off on the Royalty financing. That was a great deal..

Thank you..

And our next question comes from Patrick Trucchio from H.C. Wainright..

I'm just wondering, I have a follow-up just on the platform. And if you can discuss the relative advantages of the siRNA approach as it compares to others such as small molecules or gene editing, specifically in the area of alpha-1.

So also more broadly across the pipeline, what is your level of confidence that siRNA will be the preferred mechanism in these various targets and indications and the programs currently underway, particularly as these other modalities advance in clinical development?.

Sure. So look, that's a little bit of a hard question to answer broadly because various drug candidates will have specific advantage. But I'll tell you broadly the way we look at this.

RNAi is not the right modality for every indication, of course, but for many indications where you really -- where you need to reduce the expression of some gene product, it's a good one.

I think we've shown -- we and others have shown time and time again that RNAi appears to be a potentially better modality than antisense oligos in terms of dosing schedule, in terms of depth of knockdown in terms of safety. We think that will continue, at least as it relates to hepatocyte targets, and we'll see if that applies more broadly.

When you look at gene editing, look, I think that's an interesting idea. I think that we're not quite ready for prime time there. And I think that there is a permanence associated with gene editing that may be -- that may cause some pause with at least for certain indications.

What's great about RNAi is that we get a good, long, durable effect, but yet it is ultimately reversible. After some period of time, that drug wears off and it doesn't knock down the gene product any longer.

What would concern me at least in the near to midterm with the gene editing approach is that the idea of having to unCRISPRize something is a daunting one. And so I think it's still a bit of an early technology.

But at least as it relates to the indications we're going after, we believe that RNAi at least in our current pipeline is likely to -- and from my perspective, at least the preferred modality..

Yes. That's helpful. And then earlier in the call, there was commentary around increased clarity on which programs and how large the pipeline could become in the next few years with the goals outlined through 2025.

So I'm wondering if you can elaborate a bit more on this commentary, particularly regarding gating factors involved in deciding which targets or disease to pursue, such as the level of genetic or clinical validation required? And how many programs either in terms of new INDs or some other metric would you be expected to announce on an annual basis going forward as you expand the pipeline?.

Well, yes. So we're excited about our 20 in '25 program. We feel comfortable that we'll get there. I think 20 clinical candidates, whether wholly owned or partnered is a lofty goal, and I think we're going to achieve it.

Regarding genetically validated targets and such, if you go down our pipeline, I think that there is pretty good consensus that these are all well-validated targets, with the possible exception of HBV just because it's a complicated virus, of course.

But everything else, I think, clearly, there is consensus among KOLs that if you can reduce the expression of these various targets, positive phenotypes will result. And our goal is to continue with that. Second, if you look down our pipeline, everything we've gone after, we've been the first RNAi player there.

I'd like to continue that at least in the near term, I think we will be continuing that. And then finally, with respect to our ability to get outside the liver, as we talked about with pulmonary, with skeletal muscle, we'll be announcing our next cell type in the first half of next year.

With all of these, it gives us the ability to run out and take land, right? We don't see any near-term competitors in these extra-hepatic spaces at least so far. And so it gives us the ability to really be choosy and go after targets that are well validated to decrease our biology risk..

And our next question comes from Madhu Kumar from Goldman Sachs..

Maybe following up on Ellie's question, what do you think is the dynamic range of RAGE and MUC5AC knockdown that will be predictive of clinical benefit in these obstructive pulmonary conditions?.

James?.

Yes. So for RAGE, I would say, based on our animal data, we were in the Alternaria model that we presented at ATS, we were wanting to get better than 50% knockdown, 60% to 70% knockdown in that particular animal model.

And then for MUC5AC, I think if you look at the patient data versus the healthy volunteer expression level for MUC5AC that patients have maybe tenfold more MUC5AC compared to what the healthy has. So I think that -- and you probably don't have to bring the patients back to normal levels to have a benefit.

But particularly in the patients, I think there's pretty significant dynamic range in terms of MUC5AC knockdown such that if you get 50% reduction in MUC5AC expression, we may see an associated clinical benefit. I don't know if that addresses your question..

No, that's helpful.

Maybe on AAT, I guess kind of -- how much different would you expect the SEQUOIA data to be from the Phase 2 of label extension given kind of like patient recruitment in SEQUOIA relative to the open label extension? Like is there any reasons are going to be a significant difference in kind of the disease course in the SEQUOIA patients relative to the open label extension?.

I don't believe so. No, they should be similar. Look, we always viewed that open-label data as important in terms of pegging a story. It was a small number of patients, but we thought it pegged the story. And we have been looking for -- we've been hoping that SEQUOIA would confirm that story..

And our next question comes from Mayank Mamtani from B. Riley..

Thanks for squeezing me in and I appreciate you putting out the 2025 campaign. So maybe on the SHASTA study, a quick follow-up on the two pancreatic events that you saw there.

Admittedly in a blinded manner, but is that what you would expect for a study this size? And in general, like what would be the event rate for SHTG study? And maybe a second part, as you think about validating triglyceride as an approvable endpoint for either SHTG or for larger mixed dyslipidemia indication, how are you sort of thinking about that next year?.

Yes. So with regards to the two cases of pancreatitis are well within the expected event rate, which is about 3% to 5% per year in this patient population. So we saw two cases in about 200 patients and by the time we -- I mean, by now we have almost one year follow-up in most of those patients. So yes, the event rate is what we expected.

And the second part with regard to the Phase 3 study, I think we commented on this before, the registration program for ARO-APOC3 in the severe hypertriglyceridemia indication does not need pancreatitis endpoint for approval.

But of course, we would like to enrich the patient population as much as possible to provide information about pancreatitis risk reduction, which is the goal of therapy. And that would be very important for many other reasons really to translate the clinical benefit, to define the value proposition and so forth.

So the approval path does not require pancreatitis, but we will do our best to have enough number of patients at high risk, so we can see the risk reduction in pancreatitis as a consequence of normalizing triglycerides levels..

And then just a quick one on A-1 AT. Are you able to comment on how -- as you think about Phase 3, how are you thinking about placebo response? Because there have been studies recently put out independent of this program and also by Takeda about how to sort of think about F2, F3 patients differently.

So is there anything you could comment on that on the placebo response for Phase 3, how you might be thinking about?.

So we're going to use the totality of the data available to estimate the placebo rate and that would be part of the equation for the effect size and the power for that study. So you will see that in detail whenever we can do this event with Takeda and present the SEQUOIA data and the Phase 3 study design.

So we, of course, use the totality of the data to plan for that study..

And our next question comes from Keay Nakae from Chardan..

Chris, one question on AATD, the Phase 3 design, is it your expectation that the agency will or will not require care biopsy data?.

Yes. So the biopsy data is likely to be the key endpoint. That's where we will -- we're thinking, that's what we studied. That's what the disease is defined by. So this is a disease of fibrosis progression and ended in end-stage liver disease with fibrosis. So the goal of therapy is to prevent fibrosis progression or to reduce fibrosis severity.

So that seems to me a logical approvable endpoint in a condition that is defined by fibrosis progression..

And our next question comes from Mani Foroohar from SVB..

I've got a couple of questions more about your own sort of rationale and strategy given that a lot of the analysts have dug into the details of this or that specific program. So I'll start with SEQUOIA.

Did I hear right that that your plan is to disclose the upcoming SEQUOIA data green biopsy alongside the Phase 3 trial design? And if so, could you give me a sense of the rationale of why those two should come out at the same time? And then secondarily, there's been a few people who've asked about your strategy around running CVOTs, which assets to hold on to or not.

Can you give me a sense of what your ballpark estimate around the size, cost and the operational burden of a CVOT would be for you? And how you guys think about the number of studies of that scale that you could run for your assets simultaneously?.

Sure, So the first question is -- I've got more on the first question than the second question. So look, the -- having a complete data set for SEQUOIA and having clarity on what the Phase 3 looks like just happened to come out at around the same time. And so it made sense for us to present both of those at the same time.

And I think they're both related, of course, and they feed on each other, of course. If there was a big time delta between the two, we would have been happy to separate those. But it just turns out that, again, the SEQUOIA data are analyzed and we expect to have final clarity on the Phase 3 data at about the same time.

So it makes sense to do this together. And we'd like to do them in conjunction with Takeda. That makes sense as well. We'll just see when the calendars will align for that.

With respect to the CVOT outlook, we haven't given any guidance on how large a study would be and how much would cost yet, in large part because we haven't had those end of Phase 2 meetings with the FDA. We really want to start to have these discussions before we opine on that because there are several ways you can do a CVOT, of course.

And it just feels a little bit early to opine on that. We will give guidance on that once we have it. But we just -- we're still pretty early here. We've got an interim look. We have a pretty good idea about what the data we think are telling us. And then we still are going to run these studies out to the end and then have end of Phase 2 meetings.

And so I expect that next year sometime we can give you better guidance or some guidance on size, cost, et cetera, for the CVOT..

Can I ask one quick follow-up on that second half of that question? For HeFH in particular, how do you think about the appropriate patient population to study? There are a number of approved therapies out there, PCSK9-targeting and otherwise.

But the universe of available therapies varies pretty wildly across geographies, not just an approval is of actual availability of patients, given reimbursement, et cetera, and real-life barriers.

So how do you think about the strategy between pursuing a study focused in areas where patients don't really have access to approved therapies versus a study an add-on with approved therapies to allow you to access the U.S.

and Western European market with more real world relevant data? Like how do you balance those two? Would you do two CVOTs, would you do two HeFH studies, is there someone to capture the two in one larger multi-arm study? Help me think about how you strategize and think about the likely outcomes for that path forward in that indication..

Yes. Again, this will be unbiased fine answer to you, and I apologize. But until we start to have these interactions with the regulators, it's hard for us to know what -- it's hard for us to give you a good answer on that. Again, keep in mind that we're still -- we still finished that study yet.

We wanted to tell the Street as quickly as we could, where we think we can apply these two drugs. I think we've done that, but we're not yet ready to talk about how we would roll this out, where we’d roll this out, what sorts of studies would support these kind of these of populations until we start to have those interactions..

And I am showing no further questions. I would now like to turn the call back over to Chris Anzalone for closing remarks..

Thanks, everyone, for joining us today. I hope everyone had a pleasant Thanksgiving holiday and have a nice larger holiday season. I apologize for the technical difficulties mid-call today, but we will talk to you soon..

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