Great. Thanks, everyone, for joining us. I'm Andrea Newkirk, one of the biotech analysts here at Goldman Sachs, and I'm really pleased to be joined by James Hamilton, CMO and head of R&D, as well as Vince Anzalone, VP of Finance and IR of Arrowhead. Thanks so much, guys, for joining us.
Thank you.
Thank you.
Maybe we can start with a big-picture question here. Over the course of the last year, you've done a lot to be able to augment your balance sheet, which has been one of the key priorities here. You're also getting much closer to a potential first commercial product. Maybe talk to us here about, as you look through the remainder of 2025, how you're thinking about program prioritization, the near-term catalysts that you see on the horizon for 2025, as well as into 2026, and what drives your confidence heading into these key events.
Sure. I can take some of those and then pass it over to James. Thanks to Goldman and everybody here for having us today. Yeah, I think that you're right. The recent period has been really important for Arrowhead. If you look at us historically, we have always been building to the point where we are right now, which is approaching a first commercial launch. Plozasiran has the PDUFA date in November. I think it's November 18th. That will be our first independent commercial launch, which is a really critical thing for us. Just to review, Plozasiran is a triglyceride-lowering drug. The first indication we're seeking approval for is for FCS, which is a rare disease where we showed really great data from our Palisade phase III study.
The next larger indication is severe hypertriglyceridemia, where we have three phase III studies ongoing, another which we'll start shortly. The approval endpoint for that population is just triglyceride lowering. We are approaching full enrollment for the phase III studies somewhere in the middle of this year, which would enable a completion in the middle of next year, and then a subsequent launch into SHTG after that. What have we done to kind of get ourselves prepared for that commercial launch? One, which is a really critical thing, is the deal that we announced and closed with Sarepta, which made our balance sheet very healthy. We're now funded into 2028 and through multiple potential independent commercial launches, and then subsequent to that, additional partnered program launching in the same timeframe.
In the current backdrop of the current biotech environment, it makes us feel very good and makes us sleep easily at night knowing that we are funded into 2028. Beyond that, we have a really robust early-stage pipeline across multiple different cell types and multiple different disease areas, both spans all the way from rare disease up to very high-prevalent obesity assets. Some of these we'll be reading out later this year, the obesity assets in particular. Some of the programs we have partnered with Sarepta targeting rare muscular diseases have readouts later this year. We feel like we have the most diverse pipeline we have ever had and also the most stable we've ever been financially. We feel like we're in a really good position today.
Great. Maybe let's start with Plozasiran then. To your point, PDUFA, November 18th here. Just maybe given all the noise around everything that's going on with the agency and policy, maybe we can first start, how have your conversations been going? Do you see any risk to the PDUFA date at all? Just would love to hear some updates there.
Sure. I'll start that out and James can fill that in. There's no way to know what's going on with the inner workings of FDA. We feel comfortable, as comfortable as we can feel, because the tenor and the tone and the type of communications we've had with FDA hasn't changed, and they are exactly as we would expect at this stage. Nobody in the biotech investor community likes uncertainty, and neither do we. We feel as confident as we can be with the state of the current approval for Plozasiran, and our hope is that we will be able to launch on schedule.
Maybe just based off of the breadth of the data, and James, feel free to jump in here on how you see this being differentiated from TRYNGOLZA. What are your base case expectations for what a label might look like here?
Yeah, sure. I can't comment specifically on label expectations, but we think that the data that we've presented in FCS, particularly the change from baseline triglyceride data, has an edge, has a larger magnitude compared to what was shown with olpasiran. Of course, there's also the dose frequency advantage, whereas we dose every three months and TRYNGOLZA is dosed monthly. We think that there may be some safety advantages potentially also, that we've not seen any platelet signals or any hypersensitivity or anaphylaxis signals, that some of those are on the TRYNGOLZA label.
How important is the distinction that you studied both genetically as well as phenotypically defined patients? Will that matter to the agency and to the physicians?
I think so. I mean, just as a reminder, that was something that the FDA had asked us to study, was to include both of those, both the genetically confirmed and the clinically diagnosed FCS population in the study. We'll see how that impacts labeling, but I do think that that is potentially important to clinicians who manage both of those types of patients.
I think that also that might be an important distinction ex-U.S. in European markets where you have to prove value. I think that whether it's on the label or not, the fact that we studied that population and saw very similar results is helpful when we're coming up with these value dossiers for national payers.
Are you surprised at all that TRYNGOLZA appears to be receiving coverage for both subsets of patients, even without the fact that they only studied it in genetically defined patients?
Yeah, I think the jury's still out on that. I think we've started to hear some excerpts from policy documents. I think that's not true across the board. It's early. We're rooting for Olezarsen and for Ionis. This is a patient population that has had nothing, no treatment. They've lived a very restrictive lifestyle with a restrictive diet, and they've had recurrent bouts of pancreatitis and hospitalization. This is good. This is good for the field. We are also encouraged that physicians are using this, that they're putting patients on commercial drug. I know that the first quarter, a lot of the use would have been with their QuickStart program, and it wouldn't have shown up in revenue. The fact that physicians are using this and are finding patients to put on this is really helpful.
I think that for FCS, it might not be as readily obvious, but for SHTG, we want to have multiple voices in the marketplace. For SHTG, there have not been very effective treatments, and there are 3 million - 4 mill ion people with triglycerides over 500 and almost a million people with triglycerides over 880. It is a very underserved population. Having two companies doing pharmaceutical marketing and promotion is really helpful in doing disease state education. We are happy that Ionis and Olezarsen are in the market. This is good for both of us.
Maybe more specifically on that point, what will it mean to have a second player in FCS? When you come to market and you become the second approved agent there, how do you and TRYNGOLZA coexist?
Yeah, I think that James's earlier point is we think that there are meaningful points of differentiation with Plozasiran versus Olezarsen. I think that we are having very fulsome discussions with payers. We have been interacting with payers since, I think it was November of last year. We will have about a year of those interactions once we launch, provided we get approval in November. I think that it will be a competitive market, but it's a short-term market. Let's remember that Olezarsen will be completing their phase III studies for SHTG later this year. We will be completing ours next year. That's really the big commercial opportunity that we want to maximize for. That's the potential multi-billion dollar a year opportunity that we both can grow.
Our two companies can coexist and grow this market and help many more patients than if there was just one of us in the market. There is a way. Again, James did mention these, but there is meaningful differentiation, we believe, from Plozasiran versus Olpasiran.
Maybe given that point, that there is meaningful differentiation, how do you think about pricing Plozasiran relative to TRYNGOLZA? If there is this added benefit, can you price at a premium?
Yeah, I want to be kind of guarded on pricing forecasts for now, because that's something we're right in the middle of. There's many different scenarios here, both with FCS pricing as well as SHTG pricing. We want to see a little more on the uptake of how FCS goes, also what the data look like from the Olpasiran phase III studies and SHTG. We're doing a lot of work on that now. I don't want to necessarily talk about what we're going to do. There would be an argument to be made for pricing it at parity or pricing it at a premium and maybe even giving price concessions if there's more access. Again, it depends on the backdrop of which patient population you're talking about.
The good thing about being second in a market and a very fast follower, we are not that far behind Olpasiran with either launch, is that we get to react to the way the market reacts. Payers will have a little more familiarity with the marketplace than they would have if you're the first to launch.
You and Ionis have both talked about potentially taking a price cut once the label expands to SHTG beyond just FCS. Presumably, Ionis gets there first and drops their price. Would you also need to drop the price of Plozasiran at the same time as when Ionis enters the market for SHTG, or is this something where you can maintain your FCS level pricing until you're specifically on the market for SHTG?
Yeah, again, I don't want to talk too specifically about what our plans would be there. Our base case would be that we would have a new product per se, a new SKU when we launch in SHTG. Patients would slowly move over from the FCS SKU to the SHTG SKU. The exact pricing level, we're still working on that.
Okay. Maybe for SHTG, you have SHASTA- 3, 4, and then also 5, which is pretty unique relative to your competitor. Maybe talk to us about the rationale and the thinking behind running a separate trial for SHASTA 5 and how important that is both to physicians, patients, as well as payers.
You want to cover that one, James?
Sure. SHASTA- 5 is the pancreatitis study that enrolls a population that is at high risk for having pancreatitis events. It is a smaller study. It is not nearly the same size as either of the SHASTA studies, but these are patients that have had events in the past and are high risk for having further events and still have severe hypertriglyceridemia. Our view on that study is it is really a study for the payers, particularly in Europe. It is not something that is required for approval, but we do think that showing a material benefit there in terms of rates of acute pancreatitis will help with reimbursement down the road.
I guess I'd be curious your thoughts. Ionis is not taking that approach. Presumably out of SHASTA- 3 and 4, you might be able to pull out a signal. If Ionis is able to show it in their core studies, is this something that you could maybe change your strategy, your regulatory strategy, or your thinking around these trials to be able to similarly show this type of data?
Yeah, I think we really wanted to guarantee that we were set up to show that difference, right? This study allows the SHASTA- 5 study allows us to do it. We didn't want to bank on either our studies, SHASTA- 3 and 4, maybe showing pancreatitis improvement, or the Ionis core studies maybe showing a benefit. We wanted to kind of make it definitive that we were going to study this and hopefully show that there is a benefit.
Okay. Just to clarify there, can SHASTA-3 and 4, can they be amended in any way to have that be either to power the study more to be able to detect that or to have that be an endpoint that you could then use with the regulatory agencies?
I think we could pool data from those studies, certainly from the SHASTA studies, and take a look.
Got it. Okay.
I think one critical thing here is that the population that we are studying in the SHASTA studies and that Ionis is studying in the core studies, it's not enriched for patients that are at high risk of acute pancreatitis. It is a pretty big ask to show a statistically significant reduction, even when pooling in a one-year period. The one big benefit of SHASHTA- 5 is that it is an event-driven study. We are not restricted to treating and then assessing at one year. We treat and enroll patients until we get a certain number of events, and then we unblind it and look at the differentiation there. I think that is important because the lower risk the population, the longer you should watch them to see enough events on placebo.
You probably know this better than I do, but my understanding is that there's not an expectation of a statistically significant difference in the core and core two studies with AP. It's just that there might be a trend that they see. Again, to James's point, we wanted to give ourselves the best chance of showing a statistically significant change or difference between the two groups.
How important is that to show a benefit on acute pancreatitis, not just for the payers, but?
Yeah, I mean, I think that's the goal when you're talking about, especially when you go further up in the triglyceride spectrum. That's the goal, is reducing acute pancreatitis risk. How you define that could be with adjudicated pancreatitis. It could be some patient-reported outcomes. That's the goal with this. I think that the further you go from U.S. commercial payers, the more you're going to want to show value. Value can be defined in many ways, but an obvious clinical outcome and reduction in hospitalizations and pancreatitis events and hard clinical benefit, the better. I think the trade-off would be without having that, to gain broader access in ex-U.S. markets, you might have to take pretty extreme price concessions. I think that you have a lot more pricing power the stronger your value proposition is.
Got it. Maybe one more from the cardiometabolic portfolio here, the dimer that you have, your PCSK9 APOC3 dimer. Maybe talk to us a little bit more about that and when we can expect to see some updates.
Sure. I can touch on the dimer. We just shared some of the dimer data as a poster at NLA last week. This one's pretty close. I think we haven't given specifics on when it'll be in the clinic. Probably before the end of this year, we should be in a position to at least file a phase I and would anticipate studying that. This is two linked siRNAs, one that targets APOC3, another that targets PCSK9. The intent is to have an LDL effect as well as an APOC3-driven triglyceride effect. The perfect population for that would be the mixed hyperlipidemia population, which is, of course, one of the largest populations out there that's still pretty unaddressed in terms of available treatments.
We can study that population early on and kind of get right into that group in a phase I study and see how we're able to impact both LDL and triglycerides.
As you think about maybe this mixed hyperlipidemia population where you have talked in the past about cardiovascular outcomes trial, potentially running it with Plozasiran, does this become an attractive alternative? Maybe the dimer becomes the asset to bring forward.
It could be. I think we have to wait and see how the data look. I mean, we still think that Plozasiran could potentially address that population as well with large reductions in triglycerides and large reductions in non-HDL cholesterol and really no meaningful changes in LDL per se, but still significant reductions in ApoB that could be beneficial when studied in an outcome study in that population. We'll have to see how all of those different lipid parameters look with the dimer.
Got it. Okay. So CVOT potentially on hold till you understand the profile of the dimer.
I think that's fair. Yeah, and I think that's the right way to put it, is that at the outset, I just mentioned our balance sheet is very healthy. We're funded into 2028, starting a large cardiovascular outcome study, and then the spectrum of multiple large cardiovascular outcome studies makes it not that healthy anymore. We do not want to get to a point where we are needing to raise money or whether we're starting a study that we just do not have the capital to see through. Keep in mind that the pure triglyceride SHTG market is really attractive. It's a very large underserved market. To the extent that Plozasiran is a pure triglyceride drug, that actually makes a lot of sense to us.
We are really excited about the possibility of showing LDL reduction with the PCSK9 component of that dimer and the triglyceride lowering with the APOC3 component. I think those two mechanisms together are really powerful and ones that have not been studied together. The genetics are pretty clear, and we have health records and clinical trial data with LDL lowering going back decades and assessing the ability of triglyceride lowering and LDL together to reduce cardiovascular events in a specific population that James was talking about, mixed hyperlipidemia, which is many millions of patients, 20 million patients. It is a sizable population. It is really interesting. We have approached our executive board and external KOLs who are very enthusiastic about the possibility of this being a meaningful treatment into the future.
I think it also talks to how siRNA is really, we think, perfectly tailored to long-term management in preventive cardiology. It's very tailored and it's very precise. It does one thing. It downregulates the expression of one gene. With this dimer, we can hit two genes that potentially at that point are both clinically validated as having a benefit. We think it's a lower risk proposition.
Great. Maybe with the last 10 minutes, let's turn to obesity since those are some of your biggest readouts that are coming later this year and then early next. ALK7, Inhibi, maybe James, I'll start with you here. Talk about the mechanistic rationale for both of those targets, one being, I think, as being studied across multiple different companies, ALK7, relatively newer.
Yeah, so they're both part of the same axis that starts in the liver, at least with Inhibini, and Inhibini being the gene, Activini being the gene product, and ends in the adipocyte. Activini binds to a receptor on the surface of the adipocyte called ALK7 that also has other ligands that can bind to it. The end result is essentially instructing the adipocyte to store triglycerides as fat in adipose tissue. Our thought was we had sRNAs against both of these targets, both Inhibini and ALK7. The Inhibini targeting technology or the so-called GalNAc technology is pretty well vetted, and we and others have used that technology to silence genes in hepatocytes and numerous different genes, numerous different trials. The safety profile is pretty well understood, so we viewed that as low risk.
When we studied these two different targets in animals, in mice, there seemed to be a little bit of a potency difference, meaning that the differential in weight gain with ALK7 targeting was greater than what we saw with Inhibini. Maybe the ALK7 pathway or hitting ALK7 is a little more potent. The technology we use to silence expression in the adipocytes is an adipocyte sRNA targeting platform that has not been in humans yet. We actually just dosed the first patients within the last week or so. It is just getting started in a phase I. There is a little more risk there because it is first in human. That is the rationale for taking both into the clinic. They both hit the same axis.ALK 7 may have some potency advantages, but it is first in human.
There's some added risk just because it's not as well tested yet, at least the platform. Inhibini uses the GalNAc technology that's, of course, been in numerous clinical trials, and so it's more de-risked. That's the rationale for taking them both into the studies. We'll kind of wait and see which one seems to look better.
Based off of your preclinical work, I guess maybe what differences do you see in terms of the safety profile from ALK7 versus Inhibini?
There's really no difference in terms of the safety profile. Of course, both have been through non-GLP and GLP tox studies in rodents and in monkeys. And the safety profile has not been a differentiator based on non-clinical data. So I don't think that'll be the tiebreaker. It'll likely be something either efficacy or safety data in the clinic.
Okay. I guess maybe as you look to the first clinical data for both programs, if you could frame your expectations for what would be a positive outcome from each program.
Yeah, for both of these, we're not really setting an expectation in terms of weight loss effects. These are both phase I studies, so they're safety studies. Our goal here is to establish a dose range and use the pharmacology, the PD data that we get out of both studies to select a dose for later stage studies for phase II. We'll have knockdown, we'll have PK, and we'll have safety. Of course, we're looking at a whole host of other biomarkers like weight loss. We're doing full-body MRIs, so we'll get a good look at changes in body composition and then some other blood-based biomarkers. I think in aggregate, that'll help us make choices about is one "better" than the other or more appropriate for us to take forward.
I would add one thing that the genetics have been very compelling about people that have loss of function mutations of these genes. There seems to be an advantage there. We have taken that into animal studies, and it looks like if you can harness that pathway with siRNA, you can show that you can reduce fat and spare muscle in animal models. We have translated genetics into preclinical studies. The next step is to see if we can translate those into humans. That is really our main goal. James mentioned we need to establish safety, we need to select a dose, we need to select an interval. Lastly, we need to see at least a few signals that we get that translation, that the pathway is actually we can harness that pathway with siRNA in humans to get a benefit.
Efficacy really comes at phase II. We do want to see signals, but the efficacy is we think will be a phase II event.
Understood. Maybe just at a high level, I mean, you're seeing data come out very frequently, right, about different GLP-1 agents, amylin agents. How do you think about what you have here and the potential to be differentiated or maybe even complementary to some of these other agents that are out there?
Sure. We see a few potential ways to win here. I think one of the things that we're studying is, of course, combination therapy. So either ALK7 on top of tirzepatide or Inhibini on top of tirzepatide. We're running both of those in the clinical trials, looking for any synergistic effects or additive weight loss. That might be one use case. Another could be a scenario where, well, maybe you don't need to lose 20% of body weight, but you could have something that has a more benign side effect profile, but you lose 7%-10% of body weight, and you can do infrequent dosing with not much in the way of side effects. That might be attractive for some patients as well. The third potential use is with maintenance therapy.
If someone wants to start and be on a GLP-1 agonist for a period of time and then come off of that medication, perhaps this lipolytic enhancement pathway could be beneficial to maintain weight loss or slow the rate of weight gain post-GLP therapy.
As you think about, I guess maybe you have these cohorts that are examining the combination, what type of, maybe based off of the work you've done here, but what type of AEs do you think could potentially pop up as you combine these types of agents?
I mean, one of the things that we'll certainly be looking at will be the rates of the GI side effects that are seen with the GLPs commonly. How does that look with the combination cohorts? I think that's probably the most important AE that's known to that class. We, of course, will look for any change in glycemic parameters. How does combination therapy impact HbA1c or blood glucose? Also, I mentioned we're doing the full-body MRIs. We'll get a good look at liver fat in the study to see if there's a change one way or the other.
Great. Maybe with the last two minutes, we've only talked really about two of your programs here, but in the last two minutes, any updates or things you'd like to share about the rest of your pipeline?
One of the things that you'll probably be hearing more about in the coming year involves our CNS platform. We have a program in the clinic now targeting ATXN2 that uses an intrathecal route of administration, and that's partnered with Sarepta. We've been working over the last few years on a platform to facilitate delivery of siRNA across the blood-brain barrier. We have a program that we've only shared preclinical data that targets tau expression in the CNS. Look for that to be entering the clinic over the next 6 months - 12 months.
Great. Vince, maybe one last question for you here. We've talked about the Sarepta deal that very nicely bolstered your balance sheet. As you think going forward, how are you thinking about additional partnerships or collaborations or licensing agreements? What is Arrowhead open to?
Sure. One big benefit of having this extraordinarily productive discovery engine is that we are capable of bringing new candidates into preclinical studies and then ultimately into the clinic much faster than we will be able to exploit ourselves. There will always be more programs that we have developed or started to develop than we're going to commercialize ourselves. I think that the business development is going to remain a core part of our strategy and certainly a core part of our financing strategy. In between now and 2028, where I said we're funded into, we do anticipate doing more deals. I think the size and scope of the Sarepta deal are likely not something that we're going to recreate, certainly not multiple times, but there are opportunities to do product as well as some discovery partnerships. We have the bandwidth to support those.
I think that the size of our pipeline supports more deals. I said this at the beginning, that the next step for us is starting to commercialize our own therapies, which means that we need to figure out how we build commercial to support more than one product. To the extent there are agents within that cardiometabolic space, and obesity may be part of that, they have a higher strategic value for us. I would say we are more likely to hold on to something that we could put into the bag of an existing sales force than we would be for therapeutic areas where we would have to rebuild commercial to support. I would say that we do intend to do additional deals with our discovery engine.
Great. With that, thank you guys so much. Thank you, everyone. Thanks, Vince. Thanks, James.
Thank you.