Hello everyone. Good morning, and welcome back to H.C. Wainwright's 28th Annual Global Investment Conference. I'm Patrick Trucchio, a senior healthcare analyst at H.C. Wainwright. It's my pleasure to welcome our next speakers, CEO Chris Anzalone and CMO and head of R&D, James Hamilton at Arrowhead Pharmaceuticals. Arrowhead's a commercial stage pharmaceutical company developing RNA interference or RNAi therapeutics with broad pipeline across cardiometabolic indications and CNS. Arrowhead's REDEMPLO plozasiran was approved by the U.S. FDA in 2025 as an agent dye to treat triglycerides in adults with familial chylomicronemia syndrome, or FCS. At the end of August, Arrowhead presented the full 12-month results of the pivotal phase III SHASTA-3 and SHASTA-4 trials in severe hypertriglyceridemia, or SHTG, in a hotline late-breaking signed session with the European Society of Cardiology Congress and plans to file supplemental NDA by year-end in SHTG using a priority review voucher.
It's a huge year for Arrowhead. Pleasure to have you with us. Just first, it's been a transformational last few months, FCS launch, two positive pivotal trials, priority review voucher. For those who are new to the Arrowhead story, can you give us an overview of the RNAi platform, why subcutaneous RNAi to the liver became such a robust franchise?
Sure. First, thanks very much for having us. It's a pleasure to be here. We have been banging our head against the RNAi wall now for over 15 years. As you point out, the first tissue that we could address is the liver, hepatocytes. But we decided early on that in order to extract proper value from this technology and to treat as many patients as we could, we needed to get outside the liver. As early as 2010 or so, we started working on technologies to get us outside the liver. Where we are now is we've got a broad platform that enables us to get into several different cell types, five of which are represented in clinical candidates right now.
We've said publicly that we think we can get into a new cell type every 18- 24 months, and we believe we'll continue to do that. While the first leg of our journey was in the liver, it was certainly not the last. I think we'll talk about CNS today as well as probably some other cell types. Our goal all along was to build a very broad-based company, which was a new thing. It's a different thing for a small biotech company to do. We were not focused on one or two areas. We were focused on a large number of them. Things were hard for quite some time, but it feels like over the last 18 or so months, we have finally broken out.
We have become a commercial company, and we now have something like 21 or 22 individual drug candidates in clinical studies.
REDEMPLO is launched in FCS. Maybe before we get into more specifics on that program, maybe you can just talk about the launch. How is it going? Where is payer policy landing? How are things proceeding?
Sure. First, just to be clear, plozasiran or REDEMPLO is an APOC3 inhibitor, and it was developed to silence APOC3 and therefore lower triglycerides. We view this as a two-step drug, if you will, from a commercial standpoint. Step one is to be approved in a narrow indication, FCS, familial chylomicronemia syndrome. It is an ultra-orphan indication. However, there are a class of patients that we have discovered that we call clinical or clinically defined FCS that make this a bit of a larger population. We have been focusing a lot on that population. Our goal then was to expand the label and treat severe hypertriglyceridemia, and that is about a 3.5 million person market in the U.S. So we launched an FCS a bit ago, and the launch has been good.
It has taken us a bit of time, a couple of quarters to get contracting worked out with payers, but we are there now. We are able to serve both, as I mentioned, genetic FCS as well as clinical FCS. There could be as many as 15,000 or 20,000 or so clinical FCS patients. We have also been ramping up our sales force. When we first launched, it was a very narrow sales force, about 20 or so sales reps. But as we were into the market, we realized that there really were more of these clinical FCS patients than we had first anticipated. We have begun to ramp this. We ramped pretty aggressively over the summertime. We will have another phase of growth in January, February timeframe, and that will enable us to prepare ourselves for SHTG launch sometime in the second quarter, we believe, of 2027.
Recently presented full SHASTA-3 and SHASTA-4 12-month data set at ESC. Can you summarize this data set and why it's meaningful?
Sure. James?
Sure. I can take that one. The top line data for SHASTA-3 and 4, first and foremost, we were achieving about 80% reduction from baseline in triglycerides, and this was all in a severe hypertriglyceridemic population, so triglycerides greater than 500 at baseline. That reduction in triglycerides translated into a statistically significant improvement in the rates of acute pancreatitis, which is the major problem those patients have. There's maybe some other issues around cardiovascular disease, but the life-threatening pancreatitis that can be recurrent in that population is the key clinical event that's driven by triglycerides. The reduction in triglycerides correlated with a reduction in acute pancreatitis. Depending on the population, the risk reduction was 78% to greater than 80%.
All of this was matched with really a pretty clean safety profile. We didn't see any evidence of thrombocytopenia or hypersensitivity reactions. Our liver safety profile was really pretty quiet. The transaminase elevations in the active arms looked similar to those in the placebo arms. Then something that we've been asked about quite a bit over the last year or so was liver fat or hepatic steatosis. We measured liver fat with MRI in the study and saw no clinically meaningful or statistically significant increase in liver fat versus placebo. All around, we were really pleased with the data on both the efficacy, the pharmacodynamic side, and the safety side.
Severe hypertriglyceridemia is a far broader population than FCS. Can you talk about the data that you've generated so far and how we should think about the meaningfulness of pancreatitis risk reduction, triglyceride reduction, and how this sort of translates across these different patient populations?
Sure. James?
Yeah. In the SHTG population? Again, I think that the It's a spectrum, right? SHTG, FCS is the worst form of SHTG, and there's some overlap in these clinical FCS patients with just SHTG patients. Of course, the rates of pancreatitis increase as the triglyceride rates or levels get higher. We view those patients with triglycerides above 880 and a history of pancreatitis as the highest risk population. In fact, in that subset, in the SHASTA-3 and SHASTA-4 pooled data, the risk reduction was 100%. There were no events on active in that population. That's probably the population that is most amenable, at least earliest, to treatment, and where the most medical need is. That being said, we also saw events in patients with triglycerides just greater than 500, but with a history of pancreatitis.
There's also need kind of further down the chain of triglyceride levels, if you will.
Yeah. Look, the value proposition here is clear. The biology is clear. We know that as triglyceride levels increase, the risk of pancreatitis increase. We know that there is a sharp increase in that risk once people's triglycerides get above 500 mg per deciliter, and then it becomes very steep above 880 mg per deciliter. We have a drug that lowers triglycerides substantially. It's a clean drug. It's dosed once a quarter, subcu at home. The value proposition is clear. Even so, this is an education play. This has been an untreated market forever because there's never been a good way to substantially lower triglycerides. While we see a huge opportunity here in a number of patients that need to be treated, it is also our job to help payers and providers and patients understand the need to lower triglycerides.
This is not going to be one of those out-of-the-gate gangbusters launch, we don't think. It's going to be a little bit of a slow burn for the first couple of years. But our numbers suggest that we think this is a $3 billion-$4 billion per year drug in the U.S. alone for us at peak.
You acquired the priority review voucher for plozasiran SNDA. Where does the pre-SNDA meeting stand, and what does the voucher do to timing?
Sure. The voucher will shave four months off timing. That's important for us. Importantly, we are not the first ones into this market. We have a competitor. We think we have a demonstrably better drug, but they're ahead of us. Every month that we can shave off is important for not only shifting our curve but also potentially changing the shape of that curve. We are a bit flat-footed because they have a several-month lead on us, and we just wanted to narrow that. That was important. It was worth the money to buy the voucher. I'm sure what was the other part of the question?
Oh, just what does it do to timing?
Yeah.
Where does the SNDA stand?
Sure. We are, I say we, I'm not doing anything. James' team is furiously writing the SNDA, and we anticipate to submit that by the end of the year.
Great. Maybe you can talk about the differentiation compared to ASO. Is it in the efficacy? Is it in the safety and tolerability profile? Is it less frequent dosing? Where is the differentiation? How do you expect that to play out over time as this slow burn sort of launch progresses?
It's all of those things. Look, ASOs can do some things that siRNA cannot do. ASOs can be involved in exon skipping because they get into the nucleus. That's great. ASOs can be untargeted and get into various cell types, and there are many cell types that we cannot yet get into. There is clearly a value for ASOs. But when you can do either, it has been shown repeatedly now that siRNA that is engineered correctly leads to better durability, leads to a deeper knockdown, and leads to a safer drug. That's the case, I think, with our competitor here. Ionis has a drug that works. Their phase III data were compelling. But we just think that we have an edge here. We are a demonstrably safer drug, as James mentioned. We don't have any issues with transaminase elevations.
We don't have any issues with liver fat, no hypersensitivity, no thrombocytopenia. We are a simpler drug. It's a simple quarterly subcu injection rather than monthly. We don't require liver monitoring and titration up to a higher dose. Everyone gets the same dose level. We're stronger. We continue to show deeper reductions in triglycerides. This just feels to us like a better platform. Having said that, as I mentioned, this is an education market, and having two of us promoting drugs that work is a better thing for patients overall and for this market overall.
Just regarding the MUIR program, is the plan still to leverage that data alongside SHASTA-3 and SHASTA-4 in the filing? If so, where does MUIR stand? When does this read out? What do you need to show there? Maybe you could just provide some background on MUIR.
Sure, yeah. MUIR is complete. The database is locked, and that's part of our filing that'll be submitted to FDA. That study was entirely based on a need to have a safety database of at least 1,500 patients on drug for a year, and the FDA allowed us to enroll, since it's easier to enroll just HTG patients, they allowed us to enroll MUIR with the HTG population. About 1,000 or so patients enrolled in that study. The other components, of course, are the SHASTA-3 and SHASTA-4 studies. Those three make up the bulk of this SNDA.
Great. I just want to shift over to familial hypercholesterolemia. Yosemite program, complete enrollment. I think data is expected around the middle of next year. What are your expectations around this data, and should we expect that zodasiran is the next launch, possibly as early as 2028?
Yeah, so that study is fully enrolled. It is on autopilot now, and I think the timing that you mentioned is correct in terms of when we would see data. It is an interesting circumstance because we have a company that was partially funded and owned by Arrowhead, by Visirna, that is a Chinese company that has the Chinese rights to zodasiran. They recently at ESC presented their phase III data that showed a 44%, greater than 40% reduction in LDL cholesterol in an HoFH population. That is about what we showed in our phase II also, so those are two pretty consistent data points. I do not think it is a stretch to say that we would land somewhere in that range in our phase III study, but we will have to see that down the road.
That is a straightforward launch for us. I do believe that is our next launch after SHTG. The sales force we are building for plozasiran, for REDEMPLO, is focused on endocrinologists, cardiologists, lipidologists. This is an easy lift for zodasiran. We will just add this to the bag. We are already calling on these physicians. For us, this feels like found value, and it does feel like this could be a helpful drug for HoFH patients.
Have you framed the possible size of this drug over time?
We haven't really talked about that. It is an ultra-orphan. It is a small indication.
Right.
Regeneron is treating them right now with an antibody. Our goal here was to have similar effects with a more patient-friendly dosing schedule, and I think we can hit that.
Can you give us an update on your obesity program and just more broadly how you're seeing obesity and where does Arrowhead, where do you fit in this very large market?
Sure. We're dipping our toe in the obesity market. There are some very interesting targets, and so it makes sense for us to see what we see there. The first two are activin E and ALK7. Those are both part of the same activin E pathway. Activin E is made in liver, ALK7 is a receptor in adipose. We released some data early this year. We'll release more data towards the end of this year. James, you want to talk about some of that?
Right. The update end of this year will primarily be focused on ALK7. We'll have some new activin E data as well, and we'll give some details on the activin E phase II MASH study that we're getting up and running right now. We're in the process of getting some regulatory feedback on the study design. That should be finalized study design-wise in time for the end of the year data update. For ALK7, I think we'll have, of course, data on weight loss in some of the different subpopulations that we looked at. Particularly interesting to us is this diabetes subset, type 2 diabetic subpopulation, that they tend to lose less weight on GLP-1s, so it might be a unique area of need.
In addition to the weight loss data, we'll have data on changes in body composition, visceral fat, total fat, lean mass based on MRI, and then, of course, safety data.
We'll have our third obesity candidate that we'll file a CTA on by the end of this year.
Got it. Would you, with this next data set with the obesity programs, would you be moving them forward to larger phase II trials? Would you announce which indications, which trials? Are these programs that you think you would move forward on your own, or would you look to partner?
We are not actively shopping these right now. We are open to partnering if it makes sense, but it is not required at this point.
Would the data, the next data sets, would that enable you to move to larger phase II trials?
Yes. That would dictate whether or not we move on to larger phase II studies, yes.
ARO-DIMER-PA read out just this week. We had the first in human data. Can you provide us an overview of this program and the data that has been shown?
Yeah. So ARO-DIMER-PA, this is the first, at least as far as we know, clinical data using a dimer technology, so two linked siRNAs as a single molecule. In this case, the two linked siRNAs, one of the siRNAs targets PCSK9, the other targets APOC3. So the intent here is to hit nearly all of the atherogenic lipoproteins. I guess we miss Lp(a), but we are hitting all the remnant cholesterol and the LDL cholesterol metabolic pathways. The data that we described yesterday, this was from the single escalating dose cohorts, and there are five cohorts. We just reported top-line data, and we will share the details at a medical conference.
But we were seeing really great reductions in APOC3, greater than 80%, better than 70% reductions in PCSK9, and that translated into, I think, 54% reduction in LDL cholesterol, better than 70% reduction in triglycerides, around 60% reduction in non-HDL cholesterol, and about a 50% reduction in ApoB. It is really that last value, the ApoB value, that I think is the most telling, because that represents all of the atherogenic lipoproteins. If you can lower ApoB, you are not only lowering LDL cholesterol, but also lowering things like remnant cholesterol, VLDL. I think that the single dose data, those were largely consistent with what, or better than what inclisiran has reported out and some of the other PCSK9s have reported out. So we felt pretty good about those data.
We think there's a breakthrough for two reasons. One, on the platform side, it's a clinical proof of concept that we can deliver two linked siRNAs to knock down two genes at once. First time anyone's shown that's important, and we'll take that to a number of indications going forward. Second, it's a breakthrough because it is now the first complete, quote-unquote, way to treat mixed hyperlipidemia patients. These are patients with elevated triglycerides and elevated LDL. There's not a good way to address both these issues right now, and we think we have it. So this is a very exciting potential drug.
Is the next step, would you move into a larger phase II, or would you go directly into a CVOT? What's the future for the program?
Well, we need to finish this study first. Get data after the second dose. The doses are spread out in the multi-dose part of the dose escalation on day 1 and 85. So it takes a while to get post second dose data. But once we see that, the plan would be to select a few doses, two or three dose levels to take into more of a phase IIb study. So probably three doses quarterly, follow patients out, mixed hyperlipidemia patients out for a year, understand what dose, narrow down the dose you really want to take into phase III, and then probably do a biomarker driven phase III, maybe a CVOT in parallel. But our goal would be to get approval based on LDL reduction as a primary, an LDL driven phase III.
Right. That makes sense. Then maybe just on the CNS pipeline, ARO-MAPT, and maybe just any other assets in that platform you'd highlight.
Yeah. I'll start with ARO-MAPT. That, of course, is our subcutaneously administered siRNA intended to silence the MAPT gene, which is the gene that expresses tau. Of course, tau is one of the key drivers in Alzheimer's disease, but also several other primary tauopathies. We use a unique delivery system. The siRNA is linked to a Fab fragment that targets the transferrin receptor, and that's how we get the siRNA across the blood-brain barrier into the neurons, the glial cells, the CNS relevant cell types. We presented some monkey data about a year ago that showed with ARO-MAPT, with the actual drug, we were getting about 60% CSF tau knockdown. The data that we'll be presenting within the next month will be the healthy volunteer data with the same drug, with ARO-MAPT, and we'll be focused primarily on safety, but also CSF total tau knockdown.
There's not a whole lot else we can measure in the healthy volunteers. We are enrolling Alzheimer's patients in that study. That enrollment is ongoing. We won't have those data until next year sometime. The near term data release will be focused on healthy volunteers. Then some of the other programs, mostly partnered programs. We have partnered programs with Sarepta that use this delivery technology. Their Huntington's program
Right
uses this, and then their Ataxin-1 and Ataxin-3 program, and then we have an alpha-synuclein program partnered with Novartis using the same technology.
We have a robust development program underneath that. We expect to have several additional wholly owned CNS targets in the clinic over the next 18 months or so.
Just regarding tau as a target, there's several other programs, BIIB080 among others, that are in a clinic and have read out. What have been the read-throughs from these programs, and do we have an idea of what level of tau knockdown you would need to see to have confidence to move this program forward?
Yeah, I think the BIIB080 program, look, I thought those data were generally supportive. The phase II data, I know there was some questions around their inverse or lack of dose response. But at the end of the day, they showed reductions in CSF tau that corresponded to an improvement in tau PET, and that corresponded to improvements in multiple different clinical rating scales. All in all, we thought those were positive and supportive of the tau hypothesis. Now, those were with an ASO, an intrathecally administered ASO. We're of the belief that not only that route of administration, but the ASO may lead to some safety issues which could have muddied the water on the cognitive rating scale efficacy side of things.
In terms of what we're looking for, we feel like we at least need to achieve knockdown on par with what BIIB080 achieved, so 50%-60%. It's unclear if that's sort of the sweet spot or if more knockdown you'd see more improvements. One thing to consider additionally is if you administer the drug with an intrathecal route, the distribution's really heterogeneous. You get a lot of drug in the cord, some in the cortex, very little in the deep brain regions. If you come from the blood side with a subcutaneous injection, and we've shown this in monkeys, you get much smoother biodistribution of knockdown and of drug concentration. So where we might get the same or similar levels of knockdown in total tau CSF, the source of knockdown might be really different between an IT administered ASO and a subcu administered siRNA.
Right. That's really interesting. Maybe just as a final question, what do you think investors are missing about the story, about the pipeline, about the stage of the company at this point?
It's funny. The reward for becoming commercial is that people only focus on the drug that's commercial. We have a massive pipeline.