Okay. Good morning. Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Matt Bannon, and I'm a banker here at JPM. I am very pleased to be introducing our first presenting company of the day, Arrowhead Pharmaceuticals, and presenting on behalf of Arrowhead, we have the President and CEO, Chris Anzalone. Before we kick off, I'll just remind folks that we will have time for Q&A at the end of the session. So to ask a question, just raise your hand. We'll get you a mic, or you can ask it through the online portal, and I'll relay the question on your behalf. So, without further ado, Chris.
Well, thanks very much to JPMorgan for inviting us, and thank you all for coming and starting off this busy week. I'm sort of reminded of a tsunami, right? When a tsunami comes, the wave doesn't come immediately. The tide recedes, and so we are in that receding tide right now. And so good luck for the rest of the week. Okay. We are Arrowhead Pharmaceuticals, ticker symbol ARWR. Our stock price as of Friday was $6.456. We have about 136 million shares outstanding, giving us a market cap of around $9 billion. And as of our last filing, we had about $920 million of cash and investments. That's not including, however, $200 million from Sarepta that has been invoiced but not yet received, $200 million from Novartis, which has been received but not reflected in filings yet, and $930 million in recent offerings.
Our job is to bring RNA interference to patients. We have had our first commercial launch. Rudemplo was approved in the US, as well as Canada and China, to lower triglycerides in patients with familial chylomicronemia syndrome, or FCS. We see this as a multi-billion-dollar opportunity across future indications, and this will not be the last drug that we will launch. We have a broad pipeline. We have 20 clinical stage programs. These are individual drug candidates in clinical studies, 11 which are wholly owned, 9 are partnered. We have a good mix of early, mid, and late stage candidates targeting anywhere from rare diseases to more prevalent diseases. Our pipeline will continue to grow. We believe we should grow this pipeline to the tune of two to three additional drug candidates every single year.
We've got a proprietary platform that we call TRiM that enables us to bring RNAi to a variety of tissues. We are fulfilling the promise, I believe, of bringing RNAi to where disease is. We have the potential for best-in-class across numerous tissue types now. And then finally, and importantly, we've got the financial resources to push all of this forward. Okay. This is our pipeline. It's quite large. We are a complicated story because we are a broad story. I will try to limit it today to only a few programs. We will talk about Plozasiran and Zodasiran. We will talk about ARO-Dimer-PA, and we will talk about ARO-INHBE and ARO-ALK7. These are all in the cardiometabolic space. The last two are obesity candidates. We'll also just briefly touch on ARO-MAPT. That is our first wholly owned CNS candidate.
The rest of these are either partnered or partnered candidates, with the exception of ARO-RAGE, which is a pulmonary program, and we are right now in a phase 2 study in asthma patients. Okay. We'll start with the platform. Quickly, our targeted RNAi molecule platform, or TRiM, now is able to address seven different cell types and counting. We think that we can get to a new cell type every 18 or so months. So we can now, right now, address the liver, lungs, skeletal muscles, CNS, adipose, ocular, and cardiomyocytes. Importantly, five of these seven are in clinical studies as we speak. We think that we are the clear leader in bringing RNAi where disease is. So we'll start with the cardiometabolic vertical. So lipid disorders can be characterized by a spectrum of elevated levels of triglycerides and/or cholesterol, and we are addressing the entire spectrum.
On the right side of this, you can see as triglycerides elevate, the increase of acute pancreatitis risk increases. On the left side, as LDL cholesterol levels increase, the risk of ASCVD or atherosclerotic cardiovascular disease increases. As I said, we are addressing the entire spectrum here. On the triglyceride side, familial chylomicronemia syndrome, or FCS, is characterized by patients with triglycerides in the thousands often, very high triglycerides, and an extremely high rate of acute pancreatitis. Slightly less severe is SHTG, or severe hypertriglyceridemia. These are patients with triglycerides generally better than 500 that also have an increased risk of pancreatitis. We believe that ApoC3 could play a role in ameliorating these conditions. We thought that if we can knock down ApoC3 expression in the liver, we could lower triglycerides. And in fact, that's exactly what we've done with Rudemplo, formerly Plozasiran.
We are addressing FCS as we speak. As I mentioned, we are approved in the U.S., Canada, and China to treat FCS patients. We have ongoing phase three studies to expand our label to enable us to treat SHTG patients. On the elevated LDL side, heterozygous familial hypercholesterolemia patients are characterized with LDL levels greater than 190 milligrams per deciliter, and the very severe form of homozygous familial hypercholesterolemia is characterized by LDL levels greater than 400. This is a rare disease, but obviously an extremely severe disease. We know that PCSK9 inhibitors can treat this, less so for the true homozygous familial hypercholesterolemia patients, but certainly HeFH patients. We also thought that ANGPTL3 could play a role here. And so we have developed Zodasiran, which is an ANGPTL3 inhibitor, and we are focusing that to treat HoFH patients.
Now, between these two are mixed hyperlipidemia patients. We think there's about 20 million of these patients, and these patients are characterized by elevated levels of triglycerides and elevated levels of LDL cholesterol. These patients have increased risk of cardiovascular disease, and we are seeking to treat these patients with ARO-Dimer-PA. This is a dimer, or a bispecific, if you will. This is a single molecule that is designed to reduce expression of both PCSK9 and ApoC3 at the same time, and therefore, hopefully, reduce LDL cholesterol and triglycerides at the same time. All right. Let's start with Rudemplo. This is our first approval. Rudemplo is now approved in the US, Canada, and China. It is the first and only RNAi-based medicine that is FDA-approved to reduce triglycerides in adults with FCS. It is also the first FDA-approved medicine utilizing our TRiM platform.
We launched this towards the end of November of 2025. We think it's positioned as a very promising new medicine for FCS. We saw dramatically reduced triglyceride levels in patients with genetically confirmed as well as clinically defined FCS in the phase three studies. We saw about an 80% reduction from baseline of these triglyceride levels. This really moves the needle for these patients because, again, these patients had triglycerides in the thousands, and we normalized some of these patients. We got something like 75% of them below 880, which is known to be a substantial increased risk threshold for acute pancreatitis. We got something like 50% of them below 500, which also is a risk threshold for acute pancreatitis. We saw reduced incidence of pancreatitis in the phase three study. This is dosed in a convenient once every three months at home SubQ administration.
We have a strong label with no contraindications, warnings, or precautions, and we've got an innovative, we think innovative, consistent one Rudemplo price model that prices this at a single price across current and future indications, so we think this is an important medicine because this is an important disease. There are challenges around diagnoses. Many of these patients are not diagnosed until later in life. There is a substantial human cost. Acute pancreatitis is always a severe medical condition and can be fatal in some instances. Importantly, when a patient has their first bout of acute pancreatitis, they are then more likely to have subsequent bouts of pancreatitis, and those will be more severe. In addition, there are other sequelae that these patients suffer from. In addition to acute pancreatitis, they have severe brain fog often. They will have recurrent bouts of abdominal pain.
And there are substantial direct economic costs associated with this. A single bout of pancreatitis can cost upwards of $60,000 plus per episode, and 93% of these episodes involve inpatient stays with an average stay of 10 days. So while this is an important patient population for us, we'll be building on this. As I mentioned, we are approved in FCS patients. We think there's about 6,500 both clinically defined and genetically defined FCS patients in the United States, and these patients are in extremely high risk of acute pancreatitis. The broader population here is high-risk, severe hypertriglyceridemia patients. These patients have triglycerides above 880 milligrams per deciliter or above 500 with a history of pancreatitis. We think there's about a million people in this population, and they are at very high risk of pancreatitis.
And then the broader population, the severe hypertriglyceridemia population, or SHTG, these patients will have triglycerides above 500. We think there's about three million of these in the United States, and these folks have an elevated risk of acute pancreatitis. Now, importantly, we have ongoing phase three studies to support label expansion into this broader SHTG market. We expect this phase three, or these phase threes, to read out in the third quarter of 2026, and we expect to file an sNDA in the fourth quarter of 2026 to enable us to launch into this broader population in 2027.
All right. With that whirlwind, let's move to Zodasiran, our ANGPTL3 silencing agent.
So you remember this slide? Zodasiran is on the far left here. We think that it can be used to treat HoFH. So we think there is a very rare population.
We think there's only one to 2,000 patients in the United States with homozygous familial hypercholesterolemia. In a phase two study, we saw about a 41% reduction in LDL-C in HoFH patients, and when those patients were on background therapy of PCSK9 inhibitors, we saw about a 62% reduction in LDL cholesterol, so we do believe that we have a real place to play here. We have a phase three study ongoing in HoFH patients that's enrolling right now. We hope to be fully enrolled sometime in the first half of 2026, and we expect our go-to-market product to be a quarterly, subcutaneously administered drug that can be administered at home. We think that compares favorably to ANGPTL3 monoclonal antibody treatments that are monthly IV infusions, so importantly, this would be a small incremental lift for our commercial folks.
We'd be leveraging our same commercial team that is commercializing Rudemplo, and we'd be calling on the same physicians, and so for us, this feels like found value.
Let's now move on to ARO-Dimer-PA. This is our dimer that is designed to silence both ApoC3 and PCSK9
So this is our first dimer, and we think the world's first dimer that in a single molecule, we can silence two genes at the same time. There are a number of potential advantages to a single molecular entity that can target two genes at the same time. Certainly, there are regulatory advantages, and also, these two siRNAs are internalized during the same receptor turnover. This is a big move for us, not only because we think it's a potentially powerful drug in and of itself, but it's a good proof of concept.
There are a number of dimers that we can envision in the liver as well as in other tissues that we expect to develop over the next several years,
So ARO-Dimer-PA has worked well in animal studies. Shown here is in spontaneously dyslipidemic monkeys. We saw good reduction in non-HDL cholesterol, good reduction in LDL cholesterol, and good reduction in triglycerides. We would expect this to translate into humans. We have, generally speaking, seen good translation from our non-clinical studies into clinical studies, so again, you remember this slide. The middle portion here is where we are focused for ARO-Dimer-PA, the mixed hyperlipidemia population, so we think there's about 20 million people in the United States with elevated LDL cholesterol and elevated triglycerides. They are at greater risk of ASCVD. There is no complete treatment right now.
So we think that if ARO-Dimer-PA achieves similar LDLc reductions as current PCSK9 inhibitors and provides triglyceride reductions as well, it could be a very powerful therapeutic. We expect to begin dosing in mixed hyperlipidemia patients this month in a phase 1/2 study. And importantly, we expect initial clinical data towards the end of Q3. This is important because we think that by the end of Q3, we'll know if we have a drug, if we are seeing good LDL reductions, if we are seeing good triglyceride reductions, and it's well tolerated. I think we have something that could be truly special here.
Let's move to obesity.
So not withstanding the great success that we've seen with the GLPs of late, there is substantial unmet medical need in obesity. We think the future of obesity care will include recognizing specific subtypes of obesity.
Not all obesity is the same disease. We believe that reducing visceral fat is going to be important in order to achieve cardio-kidney metabolic outcomes while also retaining lean muscle mass. We also think that combining therapies is going to be a powerful approach to various populations. So this is an example of the subpopulations that we see. We know that patients with obesity and type 2 diabetes lose less weight on incretins than non-diabetics. That's important, and we think this could be an important population for us to address, at least initially. So our first two candidates are ARO-INHBE and ARO-ALK7. These are both addressing this Activin E ALK7 pathway. The take-home message here is that hepatocytes will produce Inhibin E that can dimerize to become Activin E. Activin E then can bind to ALK7 on adipocytes and essentially tell adipocytes to store fat.
We looked at that pathway, and we said to ourselves, "If we can disrupt that, we can increase lipolysis and potentially decrease fat storage in patients." Our animal data supported that hypothesis, as well as genetic analysis has supported that hypothesis. So we have ongoing phase 1/2 A studies right now. We still have a ton of data to collect, but we did release an early snapshot of some of these data about a week ago or so, and we think the data are interesting. Again, we have a long way to go, but we think they're interesting.
Excuse me. ARO-INHBE saw dose-dependent reductions in Activin E and circulating Activin E. We saw a mean max reduction of -85% after a single 400 milligram dose, and we saw max observed reduction of -94%. ARO-INHBE monotherapy reduced visceral fat.
We saw a 9.9% reduction of visceral fat after a single dose at week 16 and a 15.6% reduction in visceral fat at week 24. We did full-body MRIs of these patients, and so we have good data on fat loss. Now, importantly, when we combined ARO-INHBE with tirzepatide, we doubled the weight loss in obese diabetic patients compared to tirzepatide alone. We saw about a 9.4% weight loss at week 16 with ARO-INHBE plus tirzepatide compared to a 4.8% weight loss at week 16 with tirzepatide alone. Importantly, this was high-quality weight loss. ARO-INHBE plus tirzepatide gave us about a 23% loss of visceral fat, a 15% loss of total fat, and an incredible 76.7% liver fat reduction. This is about a threefold increase in fat reduction compared to tirzepatide alone.
This is very interesting, and we look forward to following up on this with additional data.
ARO-ALK7 is earlier than ARO-INHBE, but we've seen interesting data. This is the first RNAi therapeutic, at least that we know of, to show knockdown of an adipocyte-expressed target in humans. We saw mean reduction of minus 88% ALK7 mRNA expression. We saw max reduction of minus 94%. Now, again, this is very early data, but ARO-ALK7 could be an even more active agent than ARO-INHBE. We saw a minus 14% placebo-adjusted reduction in visceral fat after a single dose in monotherapy of ARO-ALK7 at just week eight. Again, we've got a lot of data to collect still, but we think we are off to a very interesting start. So what are our next steps?
We are expanding current studies to include increased numbers of patients to increase our power. We'll extend follow-up to better understand drug durability and activity out to a year. We'll initiate a monotherapy cohort in obese diabetic patients, and we'll also initiate additional combination cohorts with other GLPs in addition to Tirzepatide. We are running to initiate phase 2B studies as quickly as we can. Importantly, the current studies and even the expanded current studies are not gating for this. These will include combination studies with Tirzepatide as well as other GLPs in obese diabetic patients, and they will also include studies aimed at determining whether or not INHBE and ARO-ALK7 could be used as maintenance therapy once GLPs are removed. Our obesity pipeline is not finished. We'll continue to expand this in the near to midterm. We expect new liver and adipocyte targets.
We expect dimers targeting two adipocyte targets. We expect dimers targeting two liver targets. And we also expect to leverage our subcutaneous CNS platform to address central targets.
So we've got multiple potential commercial launches in coming years. On the independent side, as we mentioned, we have launched Rudemplo for FCS. We launched that in November of 2025. We expect to follow that up with launching in SHTG with the same drug in 2027. We expect to follow that up with launching zodasiran in HoFH patients in 2028. We could follow that with ASCVD indications with ARO-Dimer-PA and follow that with, we think, a number of obesity candidates, including the initial ones, ARO-INHBE and ARO-ALK7. These are all wholly owned. On the partnered side, we have late-stage partner programs. Olpasiran is our Lp(a) reducing agent that is partnered with Amgen.
They are in phase 3 studies right now. We also have fazirsiran that's partnered with Takeda that is looking at alpha-1 antitrypsin deficiency-related liver disease. We are in phase 3 studies there. And importantly, that's an important economic component for us. We have 50/50 profits here in the U.S. with Takeda, and we have 20%-25% royalties ex U.S. And so that's meaningful to us.
Okay, let's touch on CNS before we walk out of here.
Neurodegenerative diseases are, of course, an enormous burden and an extraordinary unmet medical need in the world today, and we thought that RNAi should play a role here. So we've developed a CNS-targeting TRiM platform that enables us to address the CNS via a simple SubQ injection. It's composed of a transferrin targeting ligand that is linked to an siRNA molecule.
We have seen deep and durable knockdown in animal studies across even deep brain regions. We see convenient subQ dosing that could enable us to dose monthly or even less frequently. And so far, at least, we've seen a favorable safety profile. We see about a 10x safety margin over what we believe could be the efficacious dose in humans in NHP and rodent studies. So where are we? We have already a fairly substantial CNS pipeline. Shown here is our first wholly owned CNS candidate, ARO-MAPT. It's designed to silence MAPT, which encodes for the tau protein. We are in a phase 1/2 study as we speak. We think that we can address both Alzheimer's as well as smaller tauopathies with this agent. We've seen good animal data. We've got a ton. Just shown here is an example.
We see good reduction in tau in non-human primate models. Importantly, we can monitor that reduction in tau expression in the CSF, and that's exactly what we expect to do in this phase 1/2A study. Where are we with our ARO-MAPT program? It has the potential, we think, to treat Alzheimer's as well as more rare tauopathies. It is systemically delivered and has shown potent and long-lasting MAPT expression in NHPs with potential for monthly or less frequent dosing. Our current formulation supports subcutaneous administration of 150 milligrams of siRNA total volume of less than four milliliters. We are continuing to optimize our formulation here. Our GLP tox studies were good. Our NOAEL was the highest dose tested, and we are, as I mentioned, in phase 1/2A studies. Now, let's go back there.
Importantly, we will have our initial readouts, we think, sometime towards the end of Q3. We are taking CSF samples from healthy volunteers as well as patients, and so we can see how well we're knocking down tau. That's very important as a proof of concept, certainly for the drug. If we see good MAPT knockdown, that's an important thing for this drug candidate, but also for the broader platform. If we are able to knock down MAPT, it would suggest that we can knock down other gene targets in the CNS. And I think we are off to the races at that point, and there are a number of good targets we can go after and a number of unmet medical needs that we can help to alleviate. So we have a number of upcoming milestones in 2026.
First, we'll have a whole year of commercial sales of Rudemplo in FCS. As I mentioned, we are now approved in the U.S., Canada, and China. We are waiting approval in Europe. We have phase three studies of plozasiran in SHTG population. We think these will read out in the third quarter of 2026 to enable us to file an SNDA in the fourth quarter, and importantly, we think that's a multi-billion dollar opportunity. We think that's a broad population, and plozasiran, Rudemplo has performed very well in SHTG patients in the past. ARO-Dimer-PA is targeting PCSK9 as well as ApoC3 reduction. We will begin dosing, we think, in the next year over January or so, and we think we can have our first clinical readout in the second half of 2026, probably more towards the end of Q3 2026. We think that's going to be important.
If we see good LDL reduction, good triglyceride reduction, and it's well tolerated, that would suggest that we really do have something powerful to treat those 20 million people in the US with mixed hyperlipidemia. Our obesity franchise will continue to grow. We'll have new targets, including dimers, we think. We'll also have additional ARO-INHBE and ARO-ALK7 data presented throughout 2026. We have an emerging CNS pipeline with systemic delivery via subQ administration. We will have early ARO-MAPT data presented in the second half of 2026. Again, I think that could be towards the end of Q3 2026. And then finally, we have the cash to push all of these programs forward. With that, I'd like to open the call, the meeting to questions.
Any questions from the audience?
Chris, maybe I'll start with MAPT as a target. Others have gone for it.
So what's your advantage here? I didn't see the others on the side, but I know others have. So what's your advantage here, and what's the goal for knockdown?
Sure. So I think the MAPT is arguably the best validated target for Alzheimer's, and the biology is clear for other tauopathies. That is fairly clear. Other attempts have used intrathecal injection, and we've seen some good results that have been encouraging. We think that if we are able to accomplish this subQ injection, the systemic delivery that we would obsolete any IT-administered product overnight. We will see if this translates into humans. We've had very good luck. We've got a virtually 100% track record of animal data translating to humans, but we'll see if this translates. We don't know what the bogey is for how much knockdown you need to see a clinical benefit.
Some of Ionis's data have suggested that if you can see 50% knockdown, that you could see a clinical benefit. That to us is probably the best milestone we have. We've seen better than that in NHP models, and so we're hopeful that we can see that in humans. We're really excited about this. As I mentioned, the early data here are important for us for two reasons. One, for ARO-MAPT, we think it's a potentially important drug candidate, and I think we'll have our first clue about whether or not it will translate in humans. Also, if we see good knockdown of MAPT or of tau in the CSF, it would suggest that we really do have this ability to deliver to the brain via systemic delivery, and that is extraordinarily disruptive.
We will follow that up very quickly with a number of new candidates in the CNS.
Maybe you could just give us some more color on the market opportunity for Plozasiran, both in FCS and SHTG.
Sure. Let's see. For FCS, it's a narrow population. We think there's about 6,500 patients with genetically defined or clinically defined FCS. This is a substantial unmet medical need, and we are selling into this population as we speak. The real economic opportunity here is in SHTG. We think there are three to three and a half million people in the United States with triglycerides above 500. We know that 500 is a threshold where the risk of pancreatitis increases substantially. It increases again at 880 or so, and we think there's about a million people with triglycerides above 880.
And so this is a fairly broad population that should respond well to this drug candidate. Boy, I think that literally everybody that we've treated has had a reduction in triglycerides. I think that this works consistently across patients. As I mentioned, in the FCS study, we saw about an 80% reduction of triglycerides from baseline. Our phase two in SHTG patients suggested similar good reduction in triglycerides. And so the chances are this should be an active as well as well-tolerated drug. And this is near term for us. As I mentioned, the phase three supporting the expansion into this broader SHTG market will read out in the third quarter, and we expect to file an SNDA in the fourth quarter to allow us to launch into this population around 2027. We've got a question here.
just want to understand a bit on our pricing strategy for Plozasiran in terms of FCS and SHTG and also the competitive dynamics with the other players in the space. That's my first question. The second question is on ARO-INHBE. I understand we have pretty good phase 1 data, and that translates to roughly additional 5% weight loss. And in terms of development strategy, are we mostly looking to do that with a GLP-1 appetite combo in the studies going forward? And how do we think of the chance to replicate the phase 1 data into larger trials going forward? And are we going to do a partnership with any large pharmas in terms of this obesity development?
Okay. Thank you.
On the pricing strategy, look, FCS is a narrow population, and we could have priced that at many hundreds of thousands of dollars because the drug works well and it's a narrow population. We didn't think that was the right thing to do because the big economic opportunity here is in severe hypertriglyceridemia. We are pricing this at $60,000. That is the price for FCS patients. That will also be the price for our expected price, at least for SHTG population. It was important for us to help payers understand the value of this drug, and that just can take a bit of time. We thought that if we jump out at this lower price, we will sacrifice some near-term revenue, but longer term, we think we have a better chance of this being priced appropriately.
As we talked about earlier, a single bout of pancreatitis can cost upwards of $60,000. So there are substantial direct economic costs associated with FCS and SHTG, but there's also lesser sequelae such as brain fog and abdominal pain. And so anything that we can do to ensure that we get the right price for the broader population is a good investment for us to make. And so that's why we did it. And so far, it's been well received by payers, but we're still early here. On the inhibin E side, let's see. The question there had to do with follow-up studies. So yes, you mentioned that our phase one data were good. Let's temper that. They look interesting. These are very early data. These phase one studies are not even complete yet.
This is an early snapshot that gives us some hope that we are on the right track, but we still have a long way to go. Should these data hold and we continue to see these favorable data, we would feel really good about phase 2 studies. Having said that, we've seen enough to go ahead and start at-risk planning for phase 2 studies. The obvious patient population here is in obese diabetics. The drug seems to work well there, at least in combination with tirzepatide. We don't have monotherapy data in that population, so we're going to interrogate that shortly. We are amending our protocol right now to get into those patients right now. We do think that at least the early data suggest that when combined with tirzepatide, we can make a real impact on these obese diabetic patients.
We will do broader studies in that population with triglycerides, but we'll also do it with other GLPs. It's important. Should this bear out, it's important that we can show that the background therapy of some type of GLP can be applied to ARO-INHBE and potentially to ARO-ALK7. Hopefully, we are agnostic, right? It's not just triglycerides. It could be Sema. It could be other ones. So those are important. We are also interested to know, and this is a little bit of a trust fall, but we are also interested to see if this could be used as maintenance therapy. Whether it's GLPs or other strategies, we are pretty good at helping people lose weight. We are not good at helping people keep weight off. And so we see a big opportunity there.
And so we will start studies that will be withdrawal studies, right, where patients will lose weight on a GLP with or without Inhibin E and ALK7, and then we will see if we can keep that weight off by keeping them on Inhibin E or ALK7. Again, we have no data there yet. Excuse me. And so we'll see where that goes, but we see that as an intriguing possibility. But again, for the near term, I think our best bet here is in the obese diabetic patients, either in combination or potentially as a monotherapy. Excuse me.
I think your slides alluded to the potential for a dimer in obesity. Is Inhibin E and ALK7 the possibility or no because different cell locations? How does your technology?
Yeah. Yeah. It's a great question. So this idea of dimers for obesity is a really cool idea.
We're really excited about that. It would not apply specifically to inhibin E and ALK7 because those are two different cell types, right? Inhibin E is expressed in hepatocytes. ALK7 is expressed in adipocytes. And so the dimers that we're thinking about would be single cell type dimers, if you will, right? So there are other obesity targets that we can go after that are expressed in hepatocytes. And so we imagine dimerizing or knocking down at the same time inhibin E as well as some of these other targets. And on the ALK7 side, we know there are other adipose-expressed targets that we can go after that we can combine with ARO-ALK7. That won't be this year. We are developing those now, and that's more like a 2027, 2028 timeframe, but we will be developing those.
You'll probably hear about some non-clinical data in the nearer term, but those won't be in the clinic in 2026. That is for sure.
Got it. On the ApoC3 and PCSK9 dimer, can you just give us an overview of the opportunity there?
Sure. Yeah. We're also really excited about that. We think there are about 20 million people in the U.S. with elevated triglycerides as well as elevated LDL cholesterol. Everybody knows that LDL cholesterol is a risk factor for atherosclerotic cardiovascular disease. We've got tons of data there from statins to PCSK9 inhibitors, and there are good curves that you can dial in. If you can reduce LDL by X%, you can reduce ASCVD risk by Y%. That's well understood. What is new or is newer is the importance of triglyceride-rich lipoproteins, as characterized by triglycerides.
Those may be even more atherogenic than LDL cholesterol. They have not been well studied because there's not been a good way to lower triglycerides in the past. We now have a way. And so we love the idea of addressing these two independent risk factors. You lower LDL cholesterol, you lower triglycerides. We know patients with mixed hyperlipidemia have an increased risk of ASCVD. And so if we can knock down these two factors, we think that we can substantially reduce the risk of ASCVD. And importantly, this is a funny situation where I think over the course of only a few quarters, we will have a pretty good idea if we have a drug here. We'll know if we're well tolerated, and we'll know if we are getting reasonable LDL reduction and reasonable triglyceride reduction.
I don't think we have to have as good a reduction of LDL as PCSK9 inhibitors, but we have to have substantial reduction of LDL. I don't think we have to have as good reduction of triglycerides as we see in Plozasiran and Rudemplo, but we have to have good reduction of triglycerides. If we see that, I think it'll give us good confidence that we have something that could really play in this market, and it's a very large market. Importantly, there is a nearer-term regulatory pathway that could potentially enable us to be approved based solely on LDL reduction. That could be a fairly small study. That could be a year-long study. And so we think we could get to market fairly quickly with what we think could be a real game changer in this large market.
Yep. Question?
Maybe just one question. You mainly talked about the patient populations and the opportunities in the US. How do you see these trends taking to the European market or rest of the world?
Sure. Sure. The question is, we were talking about US populations, but how do we see these drugs being applied to European markets? And the answer is, look, patients are patients. We do expect to market these drugs in Europe and beyond, and we are formulating our strategy on how we do that. There may be some geographic partnering. I think over time, we will certainly be selling into international markets. The question is, when do we jump into that? And we have not made that decision quite yet. And it just occurred to me. There was another question over here earlier about Inhibin E that I did not answer, which was related to partnering.
Let me be clear on obesity and partnering. We are not looking to partner Inhibin E and ALK7 right now. We think there's too much value for us to create by ourselves. We can handle this right now. We think these phase twos could be really value-generating, and we can execute ourselves. And so it's important for us that we keep these wholly owned, at least for right now. Yep. Go ahead.
Can I have a question on the cash management? When do we expect to have breakeven, and what are we going to do with the existing $900 million together with the money from Sarepta and the recent raise? How do we prioritize these later-stage trials?
Yep. It's a good question. So we have not guided on when we get to breakeven at this point.
I think we'll probably do that sometime in 2026, but we haven't done it yet. But I can tell you just qualitatively, with the $920 million or so dollars that we reported in our last filing, plus $200 million from Sarepta, plus $200 million from Novartis, plus 900 plus million of gross proceeds from these offerings, plus another $50 million that we expect to have from Sarepta in the February or so timeframe in 2026, we have plenty of cash, plenty of cash to push these important programs forward. And that actually dovetails well into what I mentioned earlier about ALK7 and Inhibin E staying wholly owned. This capital allows us to push these forward in a wholly owned fashion, and we think that's the right thing to do for our shareholders and for our stakeholders. Same thing with ARO-Dimer-PA, same thing for Plozasiran.
We can launch that independently in SHTG, at least in the United States. Same thing for zodasiran. We can launch that independently, at least in the United States. And then let's see where our follow-on candidates go.
Thanks so much, Chris. Thanks very much.