Hello, everyone. Good morning. Welcome back to H.C. Wainwright's 27th Annual Global Investment Conference held on September 8th to 10th, 2025. I'm Patrick Trucchio, Senior Healthcare Analyst at H.C. Wainwright. It's my pleasure to introduce you to our next company, Arrowhead Pharmaceuticals. Arrowhead leverages their RNAi platform to develop medicines that silence disease-causing genes. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes, and I'm excited to introduce from the company, CEO Chris Anzalone and CMO James Hamilton, so just to begin, if we could start with an overview of Arrowhead today, the scope of the pipeline, therapeutic areas you're prioritizing, and strategic pillars guiding execution.
Sure. Thanks very much. Thanks for having us. It's really a pleasure to be here. We are a broad-based RNAi company. We have leveraged this modality to get into a number of different cell types, and therefore we have the ability to treat a number of different diseases. And our solution was to do that, to go after all of these. Now, of course, we can't commercialize every drug that we can develop. So our model is dependent upon licensing out and partnering a number of assets in our large pipeline. We'll have 20 individual clinical assets in clinical studies by the end of this year. Roughly half of them, maybe a bit more than half, will be partnered at that point. We are focusing for our internal development and commercialization right now. We're focusing in cardiometabolic space more broadly.
And then we have this burgeoning CNS capability, and we will see where that goes.
Great. The biotech market has had some ups and downs in recent years. And how do you characterize Arrowhead's ability to create value in this environment, and what distinguishes your strategy?
Sure. So biotech, I said, more downs than ups over the last several years. Thank you very much. Look, we have this extraordinarily productive discovery engine, and that's because we've been at RNAi for almost 20 years now. But it's also an outgrowth of the modality. RNAi is an extraordinarily flexible and reliable process. So our model, as I mentioned, is really based on a mix of partnering and bringing our own drugs to the market. If we can do that, if we can do that successfully, we can inoculate ourselves a bit to the downturns of the market because we aren't entirely dependent upon the capital markets for capital. And we brought in, gosh, I don't know, well over probably $2 billion in partnering revenue to date. And that gives us two things.
One, it gives us the capital that we need to push our own programs forward and into the clinic and then into a commercial environment. But also, it puts a number of these assets into the hands of partners who are capable of developing and commercializing these drugs. And so ultimately, it's good for patients and it's good for our company.
Nearing the first PDUFA for the company with plozasiran. Maybe you could introduce plozasiran, the mechanism of action, indications you're pursuing, and the status of development as well as regulatory filings.
Sure. So plozasiran, as you mentioned, will be our first commercial drug. Our PDUFA date is November 18th. It is designed to reduce expression of APOC3. And what we have seen is that if you do that, you also decrease the amount of circulating triglycerides. That allows you to do something special, we think. We know that in some patients, high triglycerides can increase the risk of acute pancreatitis. And so we are focusing plozasiran as a pancreatitis drug. We think there are between three and four million people with triglycerides above 500 mg/dL . And that's an important milestone. Above 500 mg/dL, people have substantially increased risk of pancreatitis as you go off that curve. The first population that we will treat is FCS, or Familial Chylomicronemia Syndrome. These patients will have triglycerides in the thousands.
We are hopeful that we will be commercializing and treating these patients towards the end of this year after our November 18th PDUFA date. The broader market here is those patients above 500 mg/dL . Again, all in, they're three to four million above 500 mg/dL . We think of them as severe hypertriglyceridemia patients or SHTG. We have ongoing phase III studies to support a launch in that population. We're fully enrolled in our phase III studies there. We think that those will be complete sometime in the middle of next year, and we can file an SNDA towards the end of next year to expand into that market.
James, do you want to walk through our development plan for SHTG as well as what we've done for FCS?
Sure. Yeah, we could start with FCS since that's the furthest ahead. The PALISADE study, of course, was in the FCS patients, and we had released the data from that study already showing an 80% reduction in triglycerides from baseline and a statistically significant improvement in the rates of acute pancreatitis in that population, and of course, the drug is before FDA now with the November 18th PDUFA date, then behind that are the combination of studies focused on the next indication, which would be the SHTG indication, and the key studies there are the SHASTA-3 and SHASTA-4 studies, and those enroll the SHTG population, so patients with triglycerides at baseline above 500 mg/dL , and those in combination enroll just shy of 800 patients. On top of that, there's another study that is, and the two SHASTA studies are fully enrolled.
The third study called MUIR-3 is essentially to build the safety database of the drug, and that is in the HTG population, so not the severe hypertriglyceridemia population, but the population with trigs of 150 mg/dL to 499 mg/dL . That study is fully enrolled as well and will be supportive of the SHTG SNDA.
Great. And how do you view the patient landscape in FCS, and what are your sort of early impressions from payer engagement?
Yeah. So the population here can be thought of in two ways, I think. There's the genetic FCS population. These are the patients with these known genetic mutations associated with chylomicronemia. And we think there's less than a thousand of those in the United States. Then there is a population that do not have those known genetic mutations, but still have triglycerides in the thousands, still have recurring bouts of pancreatitis. We think there's more of those, maybe five or 10 times more of those. We study both populations. Both responded equally well to the drug. And so we'll see what our label says. Our anticipation is that we can help both patient populations. People don't care what their genes are.
They care about whether or not they have enhanced risk of pancreatitis, and so we would like to help both of those, and we are in discussions with payers around both. We'll see what the label says.
How should we think about differentiation of plozasiran compared to ASO, and what are the read-throughs from the latest data?
Sure. So look, the FCS market to a lesser extent, but broadly, the SHTG market is an education market. This is a market that has not been addressed before because no one's been able to lower triglycerides substantially until now, really. So the fact that two companies are helping payers and providers understand and patients understand the importance of treating elevated triglycerides, the better, I think. Having said that, if you look at the two competing drugs, we feel pretty good about where we stand. If you look at the FCS phase III's, we saw around an 80% reduction in triglycerides from baseline. Ionis saw about a 40% reduction from baseline. Again, it's difficult to compare two different drugs across two different studies, but the data suggests that we may have a more active drug. We also are dosing once a quarter, and they're dosing once a month.
And so we like where we sit there. Now, they announced some compelling data, I think, in their phase III SHTG studies. We haven't seen all the data set, but they toplined it last week, and they sound very good. They saw good reductions in triglycerides. They said an improvement in acute pancreatitis. That's a great thing for the field. It's a great thing for patients. And so I think there's no bad news there for anybody. Good for them, good for the field, and I think that reads on our drug as well.
Right. Terrific. So there's a lot of programs at Arrowhead, so I'm going to maybe go through some of these one by one. So next is zodasiran in HoFH. Maybe you can introduce us to zodasiran, walk us through the mechanism, and sort of the unmet need in this indication.
Sure. So zodasiran is designed to decrease the production of ANGPTL3. And what we've seen there is when you do that, you see a lowering of LDL cholesterol as well as a lowering of triglycerides. There was a number of places that could go. We decided to stick only with HoFH, at least for right now. It's a very narrow market of patients with severely elevated levels of LDL cholesterol. In the handful of patients, a handful of HoF patients that we treated, we see very good reductions in LDL-C. And so we think that the chances of success in our phase three are quite high.
Again, it's a very narrow market, but we think we have something compelling for patients where we can get very low or impressive LDL-C reduction on top of statins and even PCSK9 inhibitors and dose once a quarter compared to the antibodies that are dosed more like once a month.
Is the intention to bring this program forward on your own or with a partner?
Yeah, we'll bring that on our own. This felt like found value to us from a commercial standpoint because the physicians that our sales folks will be calling on are the same ones largely as they'll be calling on for plozasiran. So we're just adding one drug into the bag. So the incremental commercial costs are very low, but we think there is revenue to be had.
Just on the obesity programs, ARO-INHBE and ARO-ALK7 , maybe you can talk about just sort of how you're viewing your obesity pipeline, the current sort of obesity treatment landscape, where these treatments fit in, and then next steps for these programs.
Sure. We're very excited about those and future obesity candidates, particularly because we can now address adipocytes, and as the largest endocrine organ in the body, there is an awful lot we can do there for obesity and other metabolic disease more broadly. James, do you want to give an overview of that INHBE ALK7 pathway?
Yep, sure. So the first of the two programs to enter the clinic is ARO-INHBE . And this suppresses expression of the Inhibin E gene. The gene product is Activin E. That's the protein. And that is a protein expressed by the liver that binds to the ligand on the adipocyte, ligand being ALK7. And that signaling process is telling the adipocytes to store fat, essentially. And this signaling gets dysregulated in the setting of caloric excess. So if you're eating a lot of carbs, a lot of fat, the Activin E levels go up, and that signals more fat storage. The idea here is to intercept that message and silence the expression of either Activin E or the receptor being ALK7. And we can do that with ARO-INHBE in the liver. That's the GalNAc chemistry.
And then ARO-ALK7 uses a new chemistry that targets the expression of the gene in the adipocyte. So that's a new chemistry, and that's also now in the clinic.
And we see a ton of white space in obesity. The current players do a very good job of leading to substantial weight loss relatively rapidly, but there are openings there. Sarcopenia is one, of course. Other GI AEs are another. What we have found in our animal studies is good weight loss, good high-quality weight loss, visceral fat weight loss, a muscle-sparing scenario, and without caloric restriction. And so we like where that could sit around GLP-1 agonists. It could be that this is used in combination to increase weight loss that is high quality.
Second, it could be used as a maintenance therapy. People may need to lose a lot of weight, so they can go on one of the GLP-1s and then come off it and maintain weight loss, maybe continue weight loss with Inhibin E or ALK7 o r it could be used as a monotherapy.
Importantly, though, we would not expect the rapidity of weight loss that you see in the GLP-1s. Those lead to rapid weight loss. The way this pathway goes is more of a slow burn, and so it could be over time that you see the same kind of weight loss you see with the GLP-1s, but that will be over a longer period of time. In a shorter period of time, these just don't act that way, and they would not lead to that kind of rapid weight loss, but again, the quality of weight loss is what we're looking at.
Right. And so just moving to the RNA dimer platform. So I think Arrowhead's pioneering RNA dimers. This is the first one, I think, is PCSK9 APOC3 candidate expected to enter clinics soon. What's the scientific rationale behind this program, and what differentiates it from existing single-target approaches?
Sure. We're really excited about that. James, do you want to talk about PCSK9, the biology around PCSK9 and APOC3 for ASCVD?
Yeah. So I think PCSK9, the statins and the antibodies have clearly shown the ability to lower LDL cholesterol by large amounts, 50%, 60%. So we think that's one component of the ASCVD story. It's pretty clear lowering LDL cholesterol improves cardiovascular risk. The triglyceride component, or it's really more the remnant particle component that are contributing to atherosclerotic risk, has not been. Nobody's been able to touch that yet. The fibrates don't lower triglycerides enough or remnants enough. Neither does the fish oil or statins. APOC3 is probably the molecule that could do it or the pathway that could do it, the gene target. So we think combining these two, reducing LDL cholesterol and then reducing the triglyceride remnant particles, you should have a dual effect on a hazard ratio, right? You should really be able, in theory, to have a pretty impressive reduction in cardiovascular risk.
And also, what's so exciting about that for us is at least two things, right? I think one is that we know how to deliver RNAi molecules to hepatocytes, and we're quite good at knocking down gene products there. And so I think the technical risk here is relatively low. Yes, this will be the first dimer or bispecific ever in the clinic, but we've seen very good animal studies, and we expect good translation. Second is that I think we know if we have drugs sometime around the middle of next year, we'll know what LDL cholesterol lowering looks like in patients. We'll know what triglyceride lowering looks like in patients. And should that translate, we can move relatively quickly into these broader cardiovascular outcomes studies that I think would allow us to address this mixed hyperlipidemia market in a way that no one's ever done before.
Right. That's interesting. And then maybe just on the CNS platform, can you walk us through the mechanism, delivery technology, and data supporting the lead program in ARO-MAPT ?
Sure. James, do you want to?
Yep. Yep. So this is a different conjugate. This is a method of delivering, targeting the transferrin receptor, using that pathway to deliver siRNA across the blood-brain barrier. We've shown some of the data from this program last year during an analyst day and showed good distribution to different brain areas and equivalent or better knockdown using this BBB platform compared to an intrathecal route of administration. So we think we can hit key brain areas with this platform, including the deep brain, so brain regions like the striatum that are historically difficult to target. Our first program going into the clinic before the end of the year, as you mentioned, will be ARO-MAPT . That targets the MAPT gene, which codes for tau protein.
Tauopathies or diseases caused by accumulation of tau, tangled tau protein, are a variety of diseases, including Alzheimer's and frontotemporal dementia, things like that. But Alzheimer's is certainly the largest of the tauopathies.
Right. How do you see the broader CNS opportunity for RNAi? And how large could this sort of platform be, and how many programs could you ultimately have?
We see this as a very productive platform. The animal data have been good, not just for MAPT , but we also have a program that was just partnered with Novartis against alpha-synuclein for Parkinson's. We have another program against HTT for Huntington's disease, which is partnered with Sarepta, and we will have additional candidates, we think, next year. There are an awful lot of important targets that we can go after, and should this translate, and this is a big caveat because we'll see. We'll see next year if this translates from animals to humans, but should it translate, we think it is highly disruptive and allows us to address a number of different neurodegenerative diseases in the, frankly, near to midterm.
All right. Great. You have a lot of partnerships. So maybe you can talk to us about your partnering strategy and then specifically with Sarepta, how we should think about that particular partnership, the milestones, and sort of the programs as they progress.
Sure. So we have partnerships with Sarepta, with Takeda, with Amgen, with Novartis, with GSK. As I mentioned, an important part of our model is partnering some of our assets with other large pharma while keeping a substantial amount to commercialize ourselves. With Sarepta, we are working with them primarily in the muscle space. My expectation is that we'll have some data by the end of the year in the first two against FSHD and DM1. That partnership continues to move forward. They have had some setbacks, but we expect them to continue on with the partnership. We think it's important to them strategically. We just hit a $100 million milestone, gosh, a month or so ago. We expect to hit another $200 million milestone by the end of this year. And we expect to continue to work productively with Sarepta.
There's multiple programs that are advancing. Clearly, the PDUFA in November is a clear inflection point for the company, especially at the first commercial drug. Can you frame for investors the most important events and milestones in the next six to 12 months they should be looking for? And what do you think investors may be missing about the story?
Sure. I'll let investors decide which they think is most important. But in roughly chronological order, I think we'll file a CTA for the MAPT program shortly. We will then file a CTA for the dimer program, the bispecific, the PCSK9 APOC3 dimer. We'll have our PDUFA date November 18th. By the end of the year, I think we'll have some early Inhibin E and Alc7 data. I think also by the end of the year, we'll have some early DUX4 and DM1 data. That's for FSHD and DM1. And then into next year, we'll have some more Alc7 data sometime in the first half of 2026. Then we'll start to have some MAPT knockdown data from CSF. That's important and a real validating event, as well as dimer data for APOC3 knockdown, triglyceride knockdown, PCSK9 knockdown, LDL cholesterol reduction.
And then our phase 3s will read out for SHTG with plozasiran. And then we expect to file an SNDA sometime towards the end of next year to expand the market into SHTG. So we have an awful lot over the next 12 months. And I think I don't know which one's most important, but I think all.