Arrowhead at RBC Conference: Strategic Insights on Drug Pipeline

On Tuesday, 20 May 2025, Arrowhead Pharmaceuticals (NASDAQ:ARWR) participated in the RBC Capital Markets Global Healthcare Conference 2025. The company, led by CEO Chris Anzalone, presented a strategic overview of its financial stability and promising drug pipeline, while also addressing upcoming challenges. Arrowhead’s robust financial position, with capital secured into 2028, was highlighted alongside potential profitability through business development deals. However, the company also faces hurdles in regulatory reviews and market competition.

Key Takeaways

• Arrowhead has secured sufficient capital to extend its cash runway into 2028.
• The PDUFA date for Plazasiran is set for November 18, with a launch anticipated late this year.
• The company is exploring opportunities for ex-US partnerships for Plazasiran.
• Arrowhead is advancing its obesity program, focusing on INHB and ALK7 targets.
• A transformative deal with Sarepta enhances Arrowhead’s financial and operational prospects.

Financial Results

• Arrowhead’s cash runway is secured into 2028, allowing for multiple drug launches without needing additional capital.
• The company anticipates reaching profitability with one or two additional business development deals.
• A business development deal is planned for this year, focusing on traditional-sized agreements with a discovery component.

Operational Updates

• Plazasiran:

- Set for a PDUFA review on November 18, targeting the FCS market with a potential launch late this year.

- Significant triglyceride reduction observed in clinical trials, with 80% reduction from baseline.

• Fazisiran:

- Potential launch with Takeda anticipated in the 2027-2028 timeframe.

• Olpassiran:

- Expected to launch with Amgen around 2027-2028.

• Obesity Program:

- Evaluating INHB and ALK7 targets, with initial data for INHB expected later this year.

• Muscle Program:

- The Sarepta deal supports the development of subcutaneous administration for muscle-targeted therapies.

Future Outlook

• Plazasiran:

- Aims for a smooth regulatory review, considering ex-US partnerships.

• Obesity Program:

- Plans to progress only one target to Phase 2 based on initial data.

• Muscle Program:

- Focus on developing subcutaneous administration, potentially reducing the need for IV infusions.

• Alpha-1 Antitrypsin:

- Takeda is expected to complete Phase 3 trial enrollment by 2024, with a potential launch in 2028.

Q&A Highlights

• Plazasiran Label:

- Arrowhead hopes the label will cover both genetically and clinically defined FCS patients.

• HbA1c Signal:

- Viewed as a biological effect of improved triglyceride metabolism, not a safety concern.

• Shasta Five Trial:

- Focused on acute pancreatitis, aiming to strengthen the payer story in Europe.

• Cardiovascular Outcome Trial:

- Plans for a trial are contingent on securing additional capital.

For a detailed understanding of Arrowhead’s strategic plans and financial outlook, refer to the full transcript below.

Full transcript - RBC Capital Markets Global Healthcare Conference 2025:

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Great. Thanks, everybody. Luke Casey, senior biotech analyst here at RBC Capital Market. Today is our great privilege to have Arrowhead Pharmaceuticals as part of our twenty twenty five global health care conference. Representing the company, we have Chris Anzalone, who is the chief executive officer, and we have a very, very long list of questions here.

Thank you for joining us. But maybe before we jump into some of the individual programs, it’d be very, very helpful if you can just give us an overview of Arrowhead, maybe what progress has the organization made over the last few months, and most importantly, what’s ahead here.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: Sure. First, thanks very much for having us. It’s a great pleasure to be here as always. Boy, that that’s a hard first question. We we have we have a lot has happened in the last several months, not the least of which is that we have we have really solidified our balance sheet and and have have, we think, clear capital into 2028, which is an important time frame for us because it gets us, you know, into several launches.

You know, we think we will launch our lead drug, plazasiran, into FCS, you know, late this year, but into SHTG, a much larger market, I mean, ’27. Fazisiran, our AAT drug, you know, with Takeda, could be could be launched in the ’27, you know, ’28 time frame. Olpassiran with with Amgen could launch around that time frame as well. And so while we don’t quite have enough cash to get us to profitability, we can kinda smell it. You know, I think we are only a couple business development deals away from that potentially.

And so it’s really heartening to have the kind of pipeline and development ability that we we have, at a time when we don’t need to be accessing the capital markets, which is which would be difficult these days.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. Sure. Sure. That’s very helpful. Maybe let’s, talk about plazasiran here for a minute.

PDUFA date, November 18, I believe. This will be the very first drug ever approved out of the Arrowhead pipeline here, and, obviously, you’re planning to launch that drug solo. Anything that keeps you

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: up at night on that on that applications? Are you anticipating an adcom? Any thoughts there? No. We don’t expect an adcom.

You know, it is you know, our business is full of drama. And so I guess anytime you cannot have drama is a good thing. And I don’t think there’s pretty much drama there. I mean, the data were just clear. You know?

You know, we we lowered triglycerides in a hundred percent of patients that we treated. You know, we were seeing triglycerides, you know, lowering lowering to the tune of around 80% from baseline. Seventy five percent of patients who went on drug got triglycerides below eight eighty, and and and, fifty percent got below 500, which is really saying something because the baseline starting point was was, about 2,500. So, you know, then safety profile looked good, and so and so, you know, we, you know, we expect, you know, a a a smooth, review, and so we look

Luke Casey, Senior Biotech Analyst, RBC Capital Market: forward to going forward. That’s helpful. That’s helpful. How are you thinking about the label at this point? I mean, obviously, your competitors had the pancreatitis acute pancreatitis benefit actually in the clinical sections of the label, but, obviously, you have hit stat seg on on your trial.

Is it fair for us to assume that that benefit is gonna be in the indication sections of the label, or or is going to be similar to your competitors in the clinical section, and does that matter for a commercial uptake?

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: Yeah. So the, know, the short answer is, you know, who knows? You know, let’s see what what let’s see where the FDA puts it. I I you know, look, I don’t think it matters so much in this market. You know, I I think that it is clear in this patient population, that lowering triglycerides is important, and the lower, the better.

The biology here is clear. You know, high triglycerides in this population, you know, can increase the risk of acute pancreatitis. And so so I think it’s it’s a nice to have. I don’t think it’s a need to have. You know, what what I’m interest what I’m a bit more interested in is what the label says around, genetically defined FCS versus, clinically defined, FCS.

We study both populations. We are about, I think, sixty percent or so of our patients were genetically defined FCS patients, and about forty percent were were, were clinically defined, which just means that they look and smell just like the, you know, the genetically defined patients but did not have the known genetic mutations associated with FCS. They you know, both patient populations, responded similarly to the drug. And so my hope is that is that, you know, as as is often the case, the the the label follows what you studied, and so I hope that’s the case. If that is, that I think that that that makes, our lives a little bit easier to bring this to patients who really need it, but we’ll see where that goes.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. Sure. That’s helpful. Maybe big picture, when I reflect on this target, obviously, Novartis has decided to pass on the target, you know, with the Ionis’ molecule. And I’m under the impression that at least maybe you and your competitors have tried to monetize at least the Axios rights for these targets with pharma, but feels to me that pharma is on the sideline here.

One, is that a fair characterization? And two, if not, which I suspect you’re gonna say no, what do you what do you think changes? Is why why is pharma not all over this? Yeah. So so so first, you know,

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: to your first question, I I don’t think that’s fair. We have not shopped this for ex US rights. You know, we are kicking that around as we speak. You know, how much value could we bring in by partnering ex US rights? How much value can we could we extract by by bringing this ourselves, you know, to to various geographies?

And so we don’t know the answer to that yet. Who knows what goes into to any of Big Pharma’s calculus when they when they, you give back an asset? So I can’t really speak to the Ionis Novartis experience. But here’s what I can say. The I think that the biology here is clear, as it relates to not just FCS, but even the broader severe hypertriglyceridemia population.

So these are people with triglycerides above 500. We know that that there is a fairly linear relationship between the between triglyceride levels on one hand and and, increased risk of acute pancreatitis on the other. And we know that at at around five hundred milligrams per deciliter, that risk goes up. The the the slope changes a bit, and then it changes a bit again above eight eighty. So so I think that much is clear, and and and what what what the market has not or what what big pharma and the the the capital markets have not seen is people extracting value from this market because there’s been no way really until now.

Right? You know, there there hasn’t there has never been a drug candidate to decrease triglycerides to the extent that we are doing that. And so and so we think this is a grossly underdiagnosed and certainly underserved market, because there have been no treatments. You know? And we will be among the first two treatments, you know, to really move the needle on this.

And so and so, you know, that’s that’s a good news and bad news. Right? And the good news is there are patients who need this, and we and and we’re coming. The bad news is this is this is a this is a a an education play. So we’ve got MedAffairs, you know, out there, you know, helping to to, develop this market.

And look. You know? Yes. We have a competitor here, and and the easy answer is the easy answer to to the question about about whether or not that’s good is is it’s never good to have a competitor. That’s not true.

You know, this is an education play, and I think two companies will help payers and providers and and patients understand the need to lower triglycerides better than one. And so and so we’re happy to have two of us at this. Sure. Sure.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Maybe two quick questions. Maybe one on the safety side and the other one on the efficacy side. I mean, on the safety side, we have seen a little bit of a signal for h b a one c for this molecule, so love to pick your brain on that, again, whether that’s, you know, something that keeps you up at night or not. And then second, talk to us about Shasta five and why you decided to run a dedicated trial to show acute pancreatitis benefit. Again, your competitor here is using a different strategy where essentially the benefit is gonna be captured as a secondary endpoint.

So, again, two part questions. One on safety. How should we think about h b a one c signal? And then two, Shasta five, tell us about why you decided to do that, and maybe if you can talk about, like, powering assumptions and how you’re planning to, design that trial, that’d be much appreciated.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: Sure. So so on the a one c question, so I don’t view that as a safety signal. I view that as a biology signal. So so these patients, were not properly or not completely metabolizing triglycerides, and and by knocking down APOC three, we are enabling that. And so so that needs to go somewhere, and that becomes substrate, you know, that that that that that’s part of the gluconeogenesis.

And so for some diabetics, for some prediabetics, you see a slight increase in a one c. From our perspective, that is, that’s that is an acceptable trade off because because, you know, there are plenty of ways that we can that we that that physicians can manage that. You know, we just say, look. You know, keep your eye on on a one c and and and adjust meds as necessary, you know, in those diabetics or prediabetics. So, anyway, that’s on that’s on the a one c.

On the on the, Shasta five side, so Shasta five is our is our, study that is that is focused solely on acute pancreatitis. And so we’ve got three studies right now, three phase three studies ongoing, that are that are that are aimed at at regulatory approval of posazaran for severe hepatitis rightemia. That’s, and then and then we have we have a a fourth study called CHAST five that is that is not necessary for regulatory approval, but we think could be helpful, from a payer standpoint. And so so in this population, we are we are treating, a population that that is enriched for for those are who are who have a greater risk of pancreatitis. And so these are these folks will have triglycerides above a thousand.

They will have had pancreatitis in the past, and so and we’ll be treating them for a year. We we again, we we we thought that was a nice to have, not a need to have. We know it’s not it’s not critical from from regulatory standpoint. We know simply lowering triglycerides in this population is sufficient, but we thought, for payers, it would be helpful, you know, to, you know, to to show these data. You know, somewhat helpful in The United States, but probably very helpful in Europe.

And and so, yes, you know, it could be that that by pooling, Shasta three and four, we could we can also see an an improvement in, pancreatitis risk. But just as belt and suspenders, we decided to do this one as well. So I think it’s important. Bigger or smaller than 200 patients?

Luke Casey, Senior Biotech Analyst, RBC Capital Market: That’s a five.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: I don’t think we’ve I don’t think we’ve said. It’s not it’s not a very large study. K. And it’s I’m sorry. I said it’s a year long study.

It’s an event driven study. That’s right. And so so, you know, we don’t think it’ll be too long, to count up a number of the, you know, enough events, because it’s enriched for for those patients who are who are, you know, at greater risk of pancreatitis.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. Helpful. Let’s maybe pivot to obesity. I guess maybe two part question. One, if you can talk about big picture, you know, why you decided to go for, both inhibi as well as ALK seven.

You know, a couple of your competitors are just doing inhibi. And I think probably, you know, most investors look at ALK seven as a maybe a little bit higher risk, higher reward type of bet given it’s an adipose tissues. But, like, walk us through why it makes sense to do both and maybe, ultimately, what are you decide to do for go for one versus the other. Let’s maybe start with that. Yeah.

Yeah. Okay.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: It’s a good question. So so just a level set. So here’s the pathway. Inhibin E encodes, or or arrow INHB knocks down the gene encoding for inhibin e. Inhibin e is a is, is a subunit of activin e.

Activin e binds to ALK seven. ALK seven is expressed on adip in adipose tissue, and it and it helps to regulate, fat storage. And so so we know from genetic studies, we also know from now animal studies that, that if you decrease either inhibin E or ALK seven, it induces lipolysis in in in animals’ intent to burn fat. So so we decided to go after both because because we feel quite confident that that, you know, we’re good at at knocking down hepatocyte, targets. And so so the the risk profile of of ARO I and HPE was low.

We can we can do it in our sleep, and so we pushed that into the into the clinic. ALK7, as you as you point out, is maybe a bit higher risk and a bit higher reward. In the animal studies, that was a bit more potent than than ARO INHBE, which makes intuitive sense. Right? Because that’s that’s the receptor, and we know other ligands bind that receptor.

So it makes intuitive sense that that could be a more powerful drug candidate. But as you say, you know, we’ve never been an adipose before in humans. In animal studies, it works very well. It’s very potent. You know, we see good durability.

And so we have, you know, we have a a we’re we’re quite optimistic that that will work as well, but you don’t know until you know. So we figured, you know what? Let let’s push both these into the clinic, and let’s see which works better in humans and then take take that one into phase two and beyond. Sure. Sure.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: So it’s fair that at some point you’re gonna make a call on one versus the other? Yeah. Yeah. Be the would be the right way to think about it?

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: I think it’s the right way to think about it. Yep. My my my hope is that is that is that the difference is clear, you know, in this phase one, two study, and then we’ll and then, you know, we will we will take just one forward.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. Sure.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: And I tell you, I’m I’m rooting for ALK seven. You know? I want the best drug to win, but but but if ALK seven, if if that translates, then that is a really interesting drug. You know, it worked very well in animals. As I mentioned, you know, the for the hepatis for the ARO I and HPE, the hepatocyte directed drug canopy, we would expect once a quarterly dosing.

ARO ALK7, you know, could dose less frequently and maybe more like every six months. So we look forward to seeing how that goes.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. Sure. That’s very helpful. You’re going to obviously show us some initial data for inhibi, you know, later this year. You know, when I look at your preclinical data, you and Wave, it feels to me that monotherapy, so just this drug alone, maybe derives, like, five to 10%, weight loss.

Is that five to 10% the right bogey for us to think about it in monotherapy, not in combination with tirzepatide? Yeah.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: I I think that’s the wrong way to look at it, and here’s why. So, look, we are our job is not to put the GLP, GIPs out of business. Those drugs work. Now they’ve got their they’ve got their challenges, and so we think there’s a lot of white space around them. You know, muscle sparing is an important one.

You know, some of these GI AEs are important. Some of the central AEs are important. And so so, you know, we think there is plenty of room in this, frankly, quite heterogeneous population of obese individuals, you know, for multiple modes of action and and and ultimately probably combination approaches. You know, what what we wanna see, you know, early on, in this phase one two study is we wanna see some weight loss. We’ll see how much it is, but we wanna see some weight loss.

And importantly, we wanted that to be high quality weight loss. We are among other things, we are we are doing full body MRIs, and so so we can look at at, how much visceral fat is lost versus versus, muscle. What we saw in animal models was stunning. You know, we saw we saw, you know, we saw weight loss, in animals, that was that was nearly exclusively, visceral fat and and and and not muscle loss. That’s important.

Second, you know, these animals weren’t eating less food than control animals. You know, they were they were able to lose this fat while eating the same amount of food, just by ramping up their their fat metabolism. That’s a very intriguing potential product profile. And so so, you know, I think all we need to see in this phase one two study is, yes, we see some weight loss, and, yes, it is high quality weight loss. Now let’s take it forward and do longer term studies to see how much weight loss we get.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. Sure. Super helpful. Maybe just to, when I look at your MAD portion of the trial, it looks like you guys are only gonna do two doses. That’s correct.

If I got that right. Like, is that enough to actually show, like, a, you know, meaningful reduction in body weight? Like, I mean or because historically, you guys, I believe, in the MAD portion of your trial, you should have done three or four, if I recall it correctly. Why why just two? Is that too, you know, too small?

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: Yeah. Because, again, you you know, look at what we’re going for here. You know, we’re we are not our goal here is not to show some amount of weight loss that that a patient is gonna wanna have after after two years of therapy. Our goal here is to is to show the drug is doing what it’s intended to do and then move as quickly as we can into a longer phase two study that would that would then, you know, allow us to understand how much a person how much weight a person could lose over a longer period of time. And, also, you know, keep in mind that the durability of both these drugs, expect to be quite long.

Right? You know, we are dosing at day one, and day thirty. Just we we we crib it like that just so we can we can do a shorter study. But but the point is, you know, we should have we should have good knockdown in ARO I and HBV for a good four months after, you know, after that second dose, and for ARO ALK seven potentially even longer than that. So I I think I think that we can learn a lot after only two doses.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. Sure. The benefit of siRNA. Right? Like, long long pharmacology and That’s right.

You know,

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: it can be those, less That’s incredible.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Many many other therapies out there. So, no, that makes it makes a lot of sense. You maybe already alluded to it, but, what are the other endpoints that are gonna be focused on other than body weight? You you mentioned full body MRI, but, like, any any other endpoint that will really, point in the direction that this therapy’s muscle sparing or, like, any anything else that we should think about?

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: Sure. Yeah. So so, you know, so there are some biomarkers that that will that could potentially, help us see that that that we that, the fat is being burned, you know, free fatty acids, cholesterol, etcetera. But but the big ones are you know, would be the full body, MRI, weight loss, of course, with the hip to to waist ratio, that sort of thing.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Got it. Very helpful. Maybe let’s pivot to muscle. I mean, obviously, congratulation or deals with Sarepta, which is obviously extend your runway quite materially and and, you know, which is obviously in this environment, you know, transformative transformative for the organization. But maybe just going going into the science, walk us through like, many of your competitors are going after transferring, whether you’re looking at video or dying versus you guys decide to go after integrin receptors.

Like, walk us through why you think that’s the better way to go about it.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: Sure. So first, yes, the Sarepta deal is transformational for us because of because of of what it did, you know, to our balance sheet. But, also, it it was very important because it puts these two, among other things, it puts these two drugs that we think are really important good drugs into the hands of a company that is really good at developing them developing them quickly and bringing them to the patients who need them very quickly. So so it is you know, the the our goal here really was was, you know, was multiple here. Yes.

We need to bring in capital, but we also wanted to find, you know, a good home for these and other and and other drugs, and we haven’t found So yeah. So, look, we are agnostic as to how we get our RNAi, molecules into cells. And so and so, you know, we interrogate antibodies and fabs and and and peptides and small molecules, what have you, and we just we just, you know, follow whichever works best in our hands. And we tested, you know, antibodies and fabs, for our muscle, program, muscle platform, and the, the alpha b beta six targeting peptide, you know, with a small lipid tail also, just work the best. Mhmm.

So so that was great. And and the the the the the follow-up to that is that is that and these are small. You know, it’s a little peptide. It’s not a big antibody or a fab. And so what we our expectation is that we will use somewhere between a tenth or maybe a fiftieth, the amount of total drug compared to to dyneinavity, you know, in large part because because we’re using this very small targeting moiety, but also, you know, we expect to have, you know, a very potent RNAi molecule.

So what does that do? You know, a, that that could have benefits from a safety standpoint. You know, like anything, you know, the the the the smaller amount of something you can inject in somebody is a is potentially good because who knows, what long term safety issues, you know, can arise, you know, as you put in more more drug. But second, it could potentially allow us and Sarepta to toggle to a administration rather than IV, and that could be transformational. You know, if we could have, you know, a once a quarter injection with these drugs rather than, you know, once a quarter, IV infusion, That is a huge benefit.

I don’t know that that we can get there. I think we’ll know this year. Sure. And that would just be a that would be a really important differentiator if that can work, for for both of those.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: That’s helpful. That’s helpful. Can you just maybe talk about what I mean, I appreciate this is more a question for Sarepta, but, like, what data we’re gonna see this year from those two programs? So I think you you are on the record saying that Sarepta actually did the deal, after seeing some initial clinical data. Can you just tell us a little bit about what they have, you know, seen so far, and what are you gonna show us?

Are gonna show us only PKPD, or are you gonna show us also function, VHOD, and, like, walk us through what we’re gonna see in the second half of the year?

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: K. So let’s not overstate, you know, what they saw before before a deal was done. There was precious little clinical data, at the time that we did the deal. And so they saw everything we had, but it wasn’t very much. And so, you know, you know, people have surmised, oh, since they did the deal, does that mean that that they saw clinical data that were great and the drug’s gonna work?

The answer is no. It was too early. So we don’t so we did not know at that point, and we still don’t know. You know, we’re dosing patients. It’s placebo controlled, but they’re all but but but all of the it’s it’s it’s entirely in patients.

And and we’re we’re we are enrolling patients at a pretty good clip. And so my expectation is that this year, there will be enough data generated, throughout the year that could be presented, I think. It is entirely up to Sarepta as to when and how they might present those data. But I think my hope is that there is enough that can be presented at some point. Sure.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Sure. That’s very helpful. Maybe going back to your cardiovascular pipeline. I mean, I think you guys have mentioned a few times the potential of running a cardiovascular outcome trial, and there’s been discussions on what target and exactly how to run that. And I feel like still a healthy debate among the investor community on whether that’s a good idea or not for a small smaller biotech companies.

So just, I guess, walk me through what’s your latest thinking, especially in the context of your burn, around whether you’re willing to run a cardiovascular outcome trial? And if so, what target, and what’s what’s the strategy there?

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: Yep. That’s a great question. So so the answer is we are we have not started a cardiovascular outcomes trial right now because, I don’t have clarity on the additional capital that it will take to do that. You know, what we think is so, you know, we have we have a protocol ready to go for for pilsasiran. We call it Capitan.

We’ve got an executive committee. We’ve got KOLs who are who are lined up, ready to go and excited about it. You know, there’s a lot of reason to believe that that lowering triglycerides in this hyperlipidemia population will be a hyperlipidemia population will be a good thing in terms of ASCVD risk. So so we are we are all in on believing that. We just need better clarity on on on where that capital is gonna come from.

So so that’s gate number one. Gate number two is is, it’s not clear what we would take in when we have that clarity. Right? So so posasiran has its benefits. You know, it’s it’s it’s Cbot ready now.

Know, we’ve got a lot of safety data, you know, between the SHTG study and the and the FCS study and such, and so we’re ready to go. We have another another candidate that will be in the clinic this year. It’s it’s our first dimer. It’s actually, I think, the world’s first dimer that is designed to knock down both PCSK9 and APOC3. And we love that idea, you know, to hit both the LDL pathway as well as the triglyceride pathway.

The downside to that is that we’re just starting that this year, you know, in the clinic later this year. And so it’ll take a little bit to get to, you know, to phase three ready. So, you know, we’re weighing all of these right now. You know, we are competent in the biology. We’re competent in in at least posazaran, and then we’ll just wait to see, you know, where the additional capital will come from and and then whether or not we wanna wait a bit for the, for the dimer.

Got it. Got it. That’s helpful.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: But it sounds like the dimer could be maybe in the cards here.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: And the dimer is cool. It’s you know, it’s it’s a it’s a it is from an innovation standpoint, it is breathtaking. You know, the idea that that with a single single chemical entity, we can we can attack both those pathways. And and the biology risk is very low, I think, you know, because it’s because the the PCSK9 LDL pathway is clear, and and the APOC3 triglyceride pathway is is highly supported.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Got it. Got it. Super helpful. Maybe I know we’re running out of time here, maybe two more questions quickly. One, on alpha one antitrypsin, I guess two questions.

One, does that placebo response still keeps you up at night or not? This is biopsies. All is very noisy. And then two, and I I could be rocky, but it looks to me that maybe enrollment in that pivotal trial is going a little slower than some of us were hoping for. So, like, how how engaged is Takeda?

How committed are they to continue to push on on that side? Also, in the broader context of we are seeing innovations for alpha one antitrypsin coming from a lot of other molecules that maybe can do both liver and lungs. So, like, just walk me through what’s the latest on on alpha one. Look.

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: We think that’s a great drug. You know, we I it it is clear to us at least that that that drug does what it’s intended to do. You know, we we we nearly completely eliminate the production of the of the Z protein. We know that it is the accumulation of that Z protein that causes fibrosis, and we have even seen a a a decrease in fibrosis after a pretty short period of time in a handful of patients. To your point about about the the placebo effect, that’s a noisy endpoint.

Sure. You know, fibrosis is is gonna be a bit noisy. It’s not because and it’s noisy not because there is a placebo effect. It’s noisy because, you know, people will read, you know, f two or f three differently depending upon who’s reading it. And so so that was that was, that was taken into account when we were powering the study and when we were, you know, deciding how many patients would be in it.

So we feel comfortable that that that, yes, it’s gonna be it’s gonna be there’s gonna be some noise there, but but the drug works so well that we that we think with I think it’s a 20 or so patients. I can’t recall exactly. But the number, it is the primary the primary endpoint will be sufficient to see it see real benefit. So that’s that. Second, on on enrollment, look.

Takeda appears to be extraordinarily committed to this. You know, they talk about it publicly a lot. It it’s it’s it fits squarely into their wheelhouse. You know, they are they are in the enzyme replacement business as well, so they’re they they are they are calling on these physicians. And so so they appear to me to be to be committed to it, and they’re and they’re spending time and money.

They have guided that that that phase three will be fully enrolled this year. If they if they stick to that guidance, then, you know, this this, you know, this, that study could read out in 2027. That would be helpful, and it may launch 2028. Regarding, other therapies, look, we are the only game in town right now. Sure.

And and, you know, people have come up with with, you know, these really elegant ideas like a corrector that could go in there and correct the the misfolded z protein. It’s a beautiful idea, but doesn’t work in practice because the stoichiometry doesn’t work. Sure. People have talked about about, gene therapy. No.

That feels to me still irresponsible, you know, because who knows what the long term effects of of gene therapy is. And if we can address this, you know, with a reversible, you know, RNAi, modality, why not do that? Sure. So so, you know, we feel like like, Takeda, and we are in a good spot with this drug. We think there’s a ton of patients that are waiting for this.

And and it’s and it you know, it makes it makes a really economic impact for us. You know, have $50.50 profit share in The US and 20% to 25% royalties ex US. And so we are we are committed to this as well. We hope that we can get to market quickly.

Luke Casey, Senior Biotech Analyst, RBC Capital Market: Super helpful. Last question. Business development, how are you thinking about it? You obviously have a long track history of, BD unfavorable economics, including, obviously, the Sarepta. Like, how are you thinking about your your runway at this point and ways to potentially extend it?

Yep. So so as I

Chris Anzalone, Chief Executive Officer, Arrowhead Pharmaceuticals: as I mentioned early on, you know, we have cash into 2028 right now. I’d like to do another business development deal this year. You know, don’t think the size of Sarepta that, you know, that was a unicorn. You know? But but, you know, I would like to do to do a more traditionally sized b BD deal this year.

And then and then we’ll probably take a little bit of pause to see what our bandwidth looks like because I would because my hope is that is that if we can get a deal done this year, it will include a discovery component, and let’s and I don’t wanna overtax our discovery team because, you know, we need to to make sure that we are we are always creating our own wholly owned drugs. But I again, I would expect to do a BD deal this year to extend the runway a bit more, and then we’ll see about

Luke Casey, Senior Biotech Analyst, RBC Capital Market: next year. Got it. Super helpful. Have a lot more questions, but one more time. Chris, thanks so much for joining us here at RBC.

Thanks, everyone, and we’ll talk soon. Thank you. Yeah. Thanks so much, Eric.

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