We are live. All right, get situated up here. All right, we're good to go. All right, good morning, everybody. My name is Cory Kasimov, one of the senior managing director here at Evercore ISI. It's my pleasure to host our next discussion with Arrowhead Pharmaceuticals and the company's VP of Investor Relations , Vincent Anzalone. Vincent, thanks very much for being here today.
Thanks, Cory.
So just to start, as I kind of reflect back on 2025 and the year that almost was, what do you see as Arrowhead's biggest accomplishments over the course of the year?
Gosh, there's a ton going on at Arrowhead. I want to say thank you to you, Cory, and thanks to the Evercore ISI team for having us today. But even though our pipeline is almost 20 drugs deep and multiple drugs in Phase 3 studies, there is no question that launching our first drug after being at this for almost two decades is by far the most significant event for us as a company. You as investors know that there's thousands of biotech companies, and very few of those launch drugs independently. And then even fewer of those get to be profitable ultimately. And then even fewer of those get to be really the new class of large biotech, large cap biotech. And we feel like now we are set up to do all of those things. So let's talk about the launch, Redemplo.
The drug was plozasiran, now launched as Redemplo. We were approved last month, actually just a few weeks ago, to treat FCS, to reduce triglycerides in patients with either genetic FCS or clinical FCS. And I think that's an important distinction because we are the only triglyceride-lowering drug that's been studied in both of those populations. And so that kind of expands our commercial opportunity. We currently have Phase 3 studies in SHTG ongoing. That's a SHASTA- 3 and SHASTA- 4 and SHASTA- 5 study. And then another Phase 3 called MUIR , just to increase the number of patients for the safety database. Those studies should read out in the middle of next year or in Q.
They'll be finished in the middle of next year and read out in Q3 of next year, and then allow us to file an sNDA by the end of 2026, and then launch in SHTG in 2027, and that's really a large, underappreciated commercial opportunity.
Okay, terrific. Well, a lot to go through, not a lot of time to do it. But let's start with Redemplo. And I guess I'm curious kind of how you see the competitive dynamics potentially playing out here, particularly as it relates to Ionis.
Sure. So olezarsen is a really good drug. And we were having these discussions in an investor meeting just 10 minutes ago. I think that in a world where only olezarsen existed, it would be great uptake and fantastic for physicians and fantastic for patients and grow a market that really didn't exist before. We think plozasiran has some key differentiators over olezarsen. But the truth is that we're not looking to. It's not a market share play. It's really a play where both of us can grow this market together. It's the high TGs and especially the exceptionally high TG market, the SHTG market with high acute pancreatitis risk. This commercial market, pharmaceutical market, really hasn't existed at all. It's very underserved, and there's an enormous unmet need. And patients really have had nothing that's moved the needle.
And so to the extent that we and Ionis together can do disease education work and continue to have clinical studies that show the huge value that this provides to patients and to caregivers and, more importantly, to the health care system, we think that together we can grow this market and make it really large. And I'm not saying that stock price is always right, but if stock price is right over the last couple of quarters, investors are starting to recognize the real size of this opportunity. And we're just at the beginning. We and they are just at the beginning of making this real.
It's always refreshing because it doesn't happen very often when management teams talk about launches in that way. Everybody can win. All right, so you mentioned the SHASTA studies, three, four, and five. Can you talk a little bit about the design there and what each one's meant to show?
Sure, so SHASTA- 3 and SHASTA- 4 are basically carbon copies of each other. The FDA wanted us, and they gave the same guidance to Ionis, which is why they had CORE and CORE 2. They wanted us to run two well-controlled or two placebo-controlled studies instead of one larger one, and so we'll talk about them kind of interchangeably, so we're looking at 25 mgs of plozasiran versus placebo. It's about 750 patients, randomized two to one active versus placebo. We just published today, actually just this morning, the baseline characteristics, and so the population is very similar to what Ionis had in CORE and CORE 2. Triglycerides were very high at screening and at baseline. I don't have the number right in front of me, but it is a severe population.
I think 37% of the patients had TGs over 880, which is really when risk of AP starts to get steep. That curve of AP risk is positive and goes up from 500 to 880. But at 880, it really starts to get steep. And so those are the super high-risk patients. And then about 20% of them had had history, had reported a medical history of pancreatitis in the past. So we feel good about the population. They get dose once every three months for a year. Primary endpoint is TG lowering at 12 months. But then we have secondary endpoints where we're looking at different time points. We're looking at the difference in acute pancreatitis and treated versus placebo. And so it's, again, very similar to what you've seen with CORE and CORE 2.
Right. Okay. And then the liver fat data from SHASTA- 3 and SHASTA- 4 coming, I think, about third quarter of next year. How important is that in a commercial setting for both FCS as well as eventually SHTG?
Yeah, so in our past studies, we really haven't seen it, so we did a Phase 2 study called SHASTA- 2 in the 25 mg dose that we're taking forward. We didn't see any change in liver fat. That was a shorter study. It was a six-month study as opposed to a 12-month study, so in SHASTA- 3 and SHASTA-4, we will be collecting liver fat data for a subset of patients at baseline and then at some post-baseline time point, so if it's a signal that will emerge, we'll catch it. Again, we don't expect it because we haven't seen it before, but we will be looking.
Okay. And then I guess we'll move on in the interest of time. I wanted to ask about the dual PCSK9, ApoC-III candidate. Very compelling concept. Are there any specific safety concerns that you're watching for with this approach to make sure you tease out?
Yeah, I'm glad you asked that because it's a new program, and I think that when you talk about a company launching a new drug, that tends to take all the oxygen in the room, but this is one that we are really, really interested and really excited about, and also, it's consistent with our goal for the future, which is to grow our cardiometabolic commercial franchise, and so right now, that franchise has Redemplo, which is launched in FCS. In 2027, we'll launch in SHTG. We also have an ANGPTL3 program, zodasiran, which is targeting HoFH that we hope to have fully enrolled next year and then complete in 2027, and then this dimer you're talking about, the PCSK9 ApoC-III dimer, would then be another drug that we can add to that commercial cardiometabolic bag.
So what the goal is here for the Phase 1/2 study, and we'll be initiating that in the next month or so. We've already filed the CTA, and patient dosing will start early 2026. Essentially, the technology and the idea is that there's a lot of clinical experience, both with clinical studies and with marketed products of reducing PCSK9 leading to LDL reduction. We know what to expect there, and we can do that well. And then now there's an emerging experience with clinical and ultimately commercial with ApoC-III inhibitors. And we know that they lead to dramatic triglyceride reduction. So the LDL market has been somewhat well served and has been a big benefit to patients with high LDL and high ASCVD risk. The triglyceride, or more importantly, the triglyceride-rich lipoprotein VLDL remnant cholesterol space really has had nothing.
We think, and the genetics and all the published literature supports this, that that is one of the main causes or a serious cause of that residual risk of cardiovascular disease after everything else is kind of well controlled. So we think that running a cardiovascular outcomes study for the mixed hyperlipidemia population, so patients who are elevated on both sides of that spectrum, will have a high probability of showing a benefit for ASCVD risk. So in the first-in-man study, the Phase 1/2 study, we're enrolling, or we will be enrolling directly mixed hyperlipidemia patients. We're going to look at single dose and multiple dose, which we should have initial readout, call it Q3 or so of next year.
You don't tend to get this with cardiovascular drugs, but we think that those data will give us, and if successful, will give us what we need to make a decision about whether we move forward with a cardiovascular outcome study and roll right into other Phase 3 registrational studies that look at lipid lowering as the endpoint. It's a potential fast-to-market strategy while there's a large cardiovascular outcome study going on to show the treatment effect.
Got it. So that data next Q3 or thereabouts will really inform the development pathway going forward.
Definitely. Definitely. And your question about what are we looking at, what's the concern there. The technology is we use GalNAc cluster. We have a special linker technology, but it's two siRNAs of different lengths, actually, that are conjugated together. So we're essentially trying to do what each of those individually would do, but together. It hasn't been as simple to make this work. It's not as straightforward as taking two optimized sequences and putting them together. They don't actually work well. You have to select sequences together. You have to do special chemical modifications to make it work. And also, not all siRNAs work well together. There's some competition for RISC loading. So sometimes you'll get a high level of reduction of one target and very little on the other. And so that's kind of what we're really looking at closely in the clinical study.
Can we translate from rodents and primates now into humans with an equivalent level of knockdown that will support a high level of reduction of both targets, high level of reduction of LDL, triglyceride, and TRLs, and a duration that will support once every three months or less frequent administration? The safety, it's a pretty well-worn path with siRNA. It's been not just Arrowhead, but other siRNA companies have had a pretty benign safety profile. This should not be different, and our animal tox doesn't indicate that this is any different, so it's really the stoichiometry, the difference of knockdown between the two targets that we want to look at.
Got it. It should be an interesting one. All right, so moving on again, but staying in cardiometabolic. Curious about the go, no-go criteria for moving forward with INHBE and ALK7.
Sure. I'm glad you brought that up because that is something that we do see as fitting into that long-term commercial strategy, but I didn't mention it at the outset. So the Phase 1/2 studies for both of those, those are really robust studies. Each of them has a single ascending dose monotherapy part, a multiple ascending dose monotherapy, and then a multiple ascending dose in combination with tirzepatide. And that last part, I think we're only looking at two doses, not the full suite of low subtherapeutic dose up to more than optimal dose. I think we select two doses for that. So we're not looking for Phase 2 or Phase 3 data, which is weight loss at a certain time point that's competitive with standard of care.
We're looking to establish that the pathway, that INHBE ALK7 pathway translates from first genetics into animals, which we've seen, and then from animals into humans. And that can take many different forms. Certainly, we're looking at weight loss. We're doing full body MRI for both studies. So we're going to look at whether fat is being shifted, whether you can reduce fat stores, specifically visceral fat, and not affect lean mass. And then there's a handful of blood-based markers of pathway activation. But that's really our main goal. Show that we can reduce the target, obviously establish safety, know what the dosing interval is, and then look for key points of signals that we can actually inhibit that pathway in humans. And just as we don't have much time, so a 30-second explanation of the pathway.
INHBE is essentially a ligand, or an activin E is the ligand. INHBE is the gene that gets upregulated when there's excess calories. So it gets exported from the liver, and it tells adipocytes to store that energy as fat. So when you have a big calorie load, it's a way to take those calories and turn them into fat for future energy stores. ALK7 is the receptor on adipocytes that's receiving that message to store fat. So we're looking at both ends of the pathway. So we think that, and the animal data and the biology support this, we think that it does two things. INHBE the pathway will increase lipolysis, so reduce fat stores over time, but more importantly, mute that message so you can reduce fat store and reduce weight gain when people overeat.
Okay. How clear is sort of the regulatory pathway here in light of some of the FDA decisions that have been made in this, and is fat loss versus total weight loss going to be viewed differently by regulators?
How clear is it?
Yeah.
Very unclear, I would say. Yeah, it's an evolving space, and I think that FDA tends to react to very specific questions and data. They don't react to hypotheticals, and I wouldn't expect guidance today to be what guidance is when there are drugs that actually can change body composition and then show a clinical benefit from doing that down the road, so yeah, I don't have a great answer for you other than it's work that has to be done over the coming years, not just by us, but others in the field that are working on it.
Well, so on that point, we're expecting relatively near-term data from Wave on a similar front. How informative would that be for your program?
I don't know what data they're going to show, so I couldn't comment specifically on that. I would say that these are both siRNAs and both looking at the same target. We have different design studies with different patient populations. I think that an interesting thing that we're doing, again, is that combination part. We're stratifying with diabetics versus non-diabetics. If you look at GLP-1s historically, there's a difference in how those diabetics versus non-diabetics respond. Do we see a treatment effect in one or both of those? Is going to be an interesting thing too. Yeah, so I don't know what they're going to show, so who knows.
Okay, so in our last minute, final questions, kind of like a sneak peek into 2026. There's obviously a ton going on between a new product launch and all of these pipeline assets of yours. What would you kind of steer investors towards focusing on in the new year?
Sure. So the obesity data, we will be doing two different, I guess, company presentations on that. The initial data, first week of January for INHBE and a little bit of ALK7, and then call it a few months or a couple of quarters after that, we'll give more mature data for both programs. That's interesting. We'll have the readout for our SHASTA- 3 and SHASTA-4, Phase 3 studies of plozasiran in Q3, which obviously is a very important event for us. The dimer data that we already talked about will be right around that same time. And then a program that we have no more time to talk about, but our MAPT program, it's our first systemically delivered CNS program against Alzheimer's. The target is tau. That will be dosing shortly.
We'll have a readout, first readout in both healthy volunteers as well as mild Alzheimer's patients right around that same time, call it Q3 or so. There's some really interesting stuff coming up in 2026.
Awesome. Big year for sure. Thank you very much for the time today.
Thank you.