All right. Good day everyone. Welcome to day two of Cantor Global Healthcare Conference. For the next session, we are very excited to host Arrowhead Pharmaceuticals. Representing Arrowhead, we have Daniel Apel, CFO, and Andy Davis, SVP and Cardiovascular Metabolic Franchise Lead. Gentlemen, thank you so much for joining us today.
Thank you.
Thanks for having us.
Maybe we could start off with some of the hot topics. You had a presentation at ESC for plozasiran in SHTG. What has been the physician feedback since the ESC presentation, and what attributes of the profile do you feel are really aligning well with the physician community?
Yeah. Thanks, Prakhar. We did report out our SHASTA-3 and SHASTA-4 clinical study results at the European Society of Cardiology. The physician feedback has been incredibly positive. This is actually good timing. We conducted market research here in New York just last week with physicians getting their sense of the data. Similarly, this week, we are conducting market research in Los Angeles. So we have received lots of physician feedback. I would say it circles generally around three key areas: efficacy, safety, and dosing. From an efficacy perspective, the attributes they tend to focus on the most was the potency around the TG reduction, so up to 81% triglyceride reduction. The reduction in acute pancreatitis, so 78% reduction in acute pancreatitis, which was statistically significant across the pooled analysis.
Then importantly, they talk about more than 90% of subjects in the treatment arm getting below 500 mg/dL , which is a guideline-directed threshold for acute pancreatitis risk. So those are kind of the three data points that they tend to focus on as it relates to efficacy. From a safety perspective, they tend to circle on a number of differentiating aspects. In particular, the fact that with plozasiran in those studies, we saw no meaningful increases in liver enzymes, no statistically significant difference in hepatic fat fraction, no thrombocytopenia, reduction in platelets, and no hypersensitivity reactions, which they view as differentiating within the class. So those have been some compelling messages that we have heard back from physicians through this research.
Then lastly, the every three-month dosing does present some unique opportunities for patient benefit as far as only four injections a year and the potential for improved adherence over time as well.
Okay. Got it. Yeah, we thought some of the safety data was also differentiated. Maybe on the liver fat, maybe after the ESC, there is still some questions whether this matters or not in terms of the real world. For olezarsen, you see an increase in liver fat, but it is transient and it decreases. We have seen lower liver fat, but it could also be as differences in sample size of the patients that underwent MRI. I guess all things being considered, again, is that meaningful enough of a differentiator for you?
Yeah. I think we can talk about what we saw or didn't see in SHASTA-3, SHASTA-4, and we didn't see an increase in hepatic fat fraction. Olezarsen did. I think it still remains to be seen how that will play out over time. The open label extension data was presented out to 24 months, and there was still elevated hepatic fat in the open label extension. We'll see how that plays out from an olezarsen perspective, but we can at least confidently say from a SHASTA-3, SHASTA-4 in our MRI-PDFF sub study, we did not see a statistically significant difference in hepatic fat fraction. There is some potential analog here as well around the difference between ASOs and siRNAs as it relates to hepatic fat fraction.
You may recall from the previous vupanorsen data related to ANGPTL3, that being an ASO, there was an increase in hepatic fat fraction that led to the discontinuation of that therapy. We similarly have an siRNA targeting ANGPTL3 zodasiran, and to date, we haven't seen an increase in hepatic fat fraction. It's possible this is attributed to the mode of action between ASOs and siRNAs. I think it still remains uncertain at this point, but the one thing we can say confidently is coming out of SHASTA-3, SHASTA-4 in that sub study-
Right
which was powered for safety, there was no difference.
Okay. Some of the other attributes like injection site reactions, hypersensitivity, you already have some of that experience in the FCS setting, right? Because the drug is approved. I guess, again, does that come up a lot in terms of the FCS population, which should have implications for SHTG as well as we think about the two drugs?
When you say does it come up a lot, meaning does it come up in relation to olezarsen resulting in switches to plozasiran?
Yeah.
Because we don't have hypersensitivity.
Right.
Yeah. We see about 10% of prescriptions presently are olezarsen switches.
Okay.
The vast majority are APOC3 treatment naive, and that's our focus. There are a variety of reasons for the switches, some of which are attributed to tolerability and safety issues related to hypersensitivity or thrombocytopenia. Yes, the answer to your question is it has come up. But I would say our principal focus from a commercial strategy is on the APOC3 naive population.
Okay.
And that does make up the vast majority of prescriptions that we see.
Right. And one thing your competitor will flag is that the dosing flexibility for olezarsen, 50 mg and 80 mg, so the ability to down titrate to 50 mg/dL if patients have that flexibility. Plozasiran was just a flat dose. What are your thoughts on that?
Yeah. The reason the label for TRYNGOLZA is quite clear. The recommended starting dose is 50 mg, and only if you can tolerate 50 mg and you need additional TG lowering should you up titrate to the 80 mg dose. The reason that exists is because there was a dose-dependent increase in liver enzymes and hepatic fat fraction. That is not a flexibility argument. That is a mandate from the FDA on how you start the medicine and titrate the medicine. I would say from a plozasiran perspective, we believe the story is simplicity. Single 25 mg dose, no titration required, no need for liver enzyme monitoring. That story of simplicity, we think is likely to be a more compelling message for both physicians and patients, and that is what we hear through market research as well.
Okay, great. Maybe moving on to the launch prep and commercial aspects for SHTG. What work are you doing right now to prep for the launch?
Yeah, there's a lot of work happening to prep for the launch. As you know, Prakhar, we purchased the priority review voucher, which sets us up for a potential launch in SHTG in the second quarter of next year. There's been quite a lot of work in ensuring that our infrastructure is ready to go. The good news there is we had already begun building out our infrastructure in anticipation of SHTG because the launch in FCS was hitting key milestones that served as trigger points for us to increase our investment and infrastructure. Our SHTG field force, for the most part, is already largely intact.
There are still a few gaps to fill around the edges, but if we were to receive an SHTG approval tomorrow, we'd be prepared to go as far as targeting the nearly 20,000 healthcare professionals who we think will play an important role in diagnosing and treating SHTG patients. We think we can access another up to 50,000 patients through non-personal promotions, through the activities that we've already been implementing in FCS around digital means of communicating with our stakeholders. Of course, following the SHASTA-3 and SHASTA-4 data release, we're now actively engaging with payers through the pre-approval information exchange opportunity. Our teams are already out there communicating the SHASTA-3, SHASTA-4 data and navigating the payer dynamics to set us up as best as possible to gain coverage in 2027 as early as possible.
Right. I thought about the ESC presentation, you had a great slide about the different quartiles of the targets that you will or the segments of the market that you can target. Maybe just talk about that. Which segments do you see as initial adopters of this therapy? What's the addressable population in those segments?
Yeah, great question. So recall from SHASTA-3, SHASTA-4, the population was greater than 500 mg/DL . Physicians do further segment those patients based on risk. Risk, as you know, in that two by two matrix I showed on the webinar, is defined really by two attributes, TGs and prior history of acute pancreatitis. Of the roughly 3 million people in the U.S. who we believe have TGs above 500 mg, the highest risk group are going to be those individuals that have elevated TGs and/or prior history of acute pancreatitis. So TGs greater than 880 mg, which we think represents about 800,000 people in the U.S., or those who are greater than 500 mg but have a prior history of AP, so secondary prevention type patients. We think there are probably around 200,000 of those.
Roughly 800,000 to 1 million patients in the U.S. who we would categorize as being high-risk SHTG, who have the highest urgency for clinical need, likely the higher willingness to pay from a payer perspective, and that's the group that we've sized our field force to go after. When I talk about 20,000 healthcare professionals in the U.S. who we'll be going after, it's really that high-risk SHTG segment as the beachhead for our initial promotional activities. Of course, with an eye towards expanding into the 500 mg- 880 mg without a prior history of AP, who are also still at risk of AP, but less so than the other cohorts in that two by two diagram I showed. The beachhead will be the high-risk SHTG group.
Okay. For patients who had a prior history of AP, I think the number you cited was close to 200,000. I think there's still a little bit of an uncertainty on what that number could be. So what's your number based on? Is it based on some sort of claims analysis? Because it seems like there's diagnosis, like what's actually causing these acute pancreatitis events and the subsequent hospitalization. It's a little bit hard to track.
Yeah, it is difficult to pinpoint an exact number. Our estimates are based off of secondary research, understanding historical event rates within populations who have different levels of triglycerides in addition to claims analysis. So we've done a breadth of analyses in order to come to those figures. But there is, I would acknowledge, there is still some uncertainty there. In some cases, it's not exactly clear whether AP events are attributed to high triglycerides. You can make some decisions based on lab values as well, but there's still some uncertainty there.
I would just add, though, Prakhar, the piece that I think gets missed in all of that is we believe there are still also a fair number of patients who actually aren't presenting to the system, who have acute pancreatitis events or sort of sub-clinical acute pancreatitis, where they have the abdominal pain of sort of unexplained origin radiating to the back. I can't tell you how many FCS patients, SHTG patients I have talked to who uniformly indicate when they feel that radiating pain, they know what the hospital will do for them, which is not feed them and give them fluids and stabilize them and move them on. In their view, they can do that at home.
There is this group of patients out there that is sort of unquantifiable at this point, who are not presenting to the healthcare system because they are managing their acute pancreatitis or abdominal pain at home. Through just water, water, Gatorade, water, Gatorade, bone broth are some of the solutions that I have heard patients talk about in the past. Even though the data tells us one thing, and again, it is an imperfect science trying to capture what that data tells us, there is also no doubt a group of patients who are not presenting who I think would present if there were a better solution like the APOC3 inhibitors.
Got it. I guess for patients who are identified in the system, once they have had an AP event, how are these patients right now actively managed and do you have to bring back these patients into the system and the treatment care? Why should not any patient who have had a history of prior AP be on these drugs? What is the constraint? Maybe apart from access, but just-
Yeah. Apart from access, the current paradigm for these patients is stabilization in the emergency room. In some cases, triglycerides are not even checked. Once stabilized in the emergency room, discharged for follow-up with a gastroenterologist, or if someone was keen enough to do a triglyceride test and suspect that TGs could be the source for acute pancreatitis, referral to the endocrinology department or lipid clinic. I would say there is work to do around ensuring that there are diagnostic pathways for these patients.
Of course, those who have had acute pancreatitis events more recently, are going to be more in the system than those that might have had acute pancreatitis events further back, and so it might require a little bit of effort from a systems perspective to identify those patients in the EHR system and call them back in to see what their status is and whether or not they could benefit from APOC3 treatment. But physicians will acknowledge that every single one of these patients who they believe have TG-induced acute pancreatitis should be treated.
Okay. Maybe, on the priority review voucher that you bought as well to speed up the launch, I feel like you were a little bit behind, but not that far behind in the grand scheme of things, versus other olezarsen. I guess, what were the drivers of buying a PRV to speed up the launch? I guess maybe, does it help you in terms of getting coverage for 2027 as well, and maybe close the gap on the coverage even on the government channels, maybe?
Yeah, no. I'll step in on that one. On the government channels, we're in active engagement with them before, so regardless of whether it was later in the year or earlier, we're going to get engaged and we're not truly seeing actually much of an issue there right now with FCS. So it'll be a matter of just making sure we update the policies and gain the right coverage. For the PRV, it's kind of at the end of the day a no-brainer. Just by shifting in, we have our product with a particular patent life. Just by shifting in by four months, it had a 3x ROI. That's even before you talk about potentially reducing their first mover advantage, potentially getting a few more basis points from being out there and competing earlier. That actually magnifies it considerably.
So financially, it made all the sense in the world. It brings the medicine to the patients even earlier. I think in a lot of payers' eyes, just even shortening that four months, there's an awareness that Plozasiran is going to be out there, in a fairly short time period. So it was an important decision, one which I think was pretty straightforward once we made it.
Okay. Maybe moving on to the payer side for SHTG. You had announced pricing even before the phase III data had come out, which is $45,000 list price. Now that you have the data in hand and maybe you've done some research with payers as well, what's the feedback now on the payers from pricing and how would they expect to cover plozasiran?
Yeah. You're right, our REDEMPLO price was a WAC of $45,000 per patient per year. We haven't received any pushback on that from an FCS perspective. We're getting access to FCS patients through all of the large payers whom we've been engaging with, so there's been no concern from a pricing perspective, a list price perspective in FCS. Similarly, although the conversations are still early, of course, with SHTG, because the data was just released a couple of weeks ago, we don't anticipate there being concerns given the high unmet medical need for this group of patients and frankly, the cost to the system of acute pancreatitis. Acute pancreatitis is a costly event. The acute event itself can be upwards of $50,000, just as a single AP event for some extended period of time in the ICU.
When you start looking at published research around the cost of the acute event plus subsequent costs following the next 12 months, you can get costs very quickly upwards of $100,000, north of $100,000 for these patients. Payers, we believe the willingness to pay for these patients will be high. I think so far, the policies that we're seeing for TRYNGOLZA in SHTG leave room for optimism. I think those policies I would describe as being favorable for the class presently. Again, it's still early innings, but the policies that have been published are effectively, for the most part, greater than 500 mg. Treatment with either a fibrate or an omega-3 fatty acid, which would be consistent with guideline-directed therapy and not a concern because most of these high-risk patients will have been treated with these agents anyway.
Then a specialist prescriber, so a lipidologist, endocrinologist-
Okay.
preventive cardiology. I would describe those prior authorization forms that are presently out there as being favorable for the class.
Okay. How do you convince payers to cover these drugs for more moderate triglycerides that fall in the 500 mg- 880 mg bucket, given the event rate for these patients tends to be low? The health economic analysis after you have had your first AP, given the cost to the system, makes sense. But how do you convince payers that, all right, you cover these patients despite the fact that the event rates are so low?
Yeah, you are right in the sense that this group that is 500 mg- 880 mg without a prior history of AP would be considered lower risk than the high-risk subgroup that I had mentioned before. That being said, physicians certainly still view this group as being at considerable risk, despite the fact that it is lower risk than that other group. That is partly because, remember, this 500 mg- 880 mg, these are fasting measurements.
When you talk to experts in the field who can see the swings in triglycerides in a postprandial context, they will often communicate swings of 200 mg/dL- 300 mg/dL . So, you are talking about a patient who might be at 500 mg in a fasting state, but for 16 hours out of a 24-hour day, they might be at 700 mg or 800 mg. The difference between a patient who is in that zone, let us say, versus an ASCVD patient is that the risk of an MI might be attributed to sort of a lifelong buildup of plaque in arteries. In the case of TGs, it does not take much for a bolus of chylomicrons to cause havoc on the pancreas, resulting in acute pancreatitis event. Once you have had that first acute pancreatitis event, you are so much more susceptible to having the next.
So I think physicians have told us, even in that 500 mg- 880 mg group, they still view that as risky because of the movement postprandial and the nature that acute pancreatitis can happen at any given moment based on these bolus of chylomicrons, so they want to prevent that first event.
Okay.
We think that will be an area where physicians will still want to prescribe. Again, it won't be our area of focus commercially out of the gates because we'll be focused primarily on the highest risk segment initially, but it won't be long before I think we begin to put effort over time into educating physicians around the benefit of the APOC3 class and REDEMPLO in particular in that particular cohort.
Okay. A lot of people are thinking about analogs to predict this launch. Novel category, novel drugs, great profile. There are some analogs that have been cited by investors to assess the uptake. We have heard from inclisiran, PCSK9, VASCEPA from Amarin, and even Rezdiffra from MASH. What do you think are good precedent and what do you think is not a relevant analog?
Yeah. It's not clear that any of the analogs you've highlighted, which we'd also identified, are actually great analogs. Just a few reasons why, in the case of inclisiran of course, Part B reimbursed medicine, very different than the dynamic for Part D. I think Novartis out of the gates probably underestimated the need for ASCs, these injection centers in order to support buy and bill.
I think the ramp for inclisiran was probably slower than what we would expect in this class as a consequence of those structural dynamics. The PCSK9 class is an interesting one. On its face, you would think two-player market, Repatha and Praluent for the most part initially in cardiometabolic. That would seem like a natural analog, but I think that also fails to be a good analog because of a variety of reasons, not the least of which is the standard of care in that space was a fairly good standard of care.
Most would argue that high-intensity statins, high-intensity statins plus ezetimibe can be a very effective regimen for reducing LDL-C into levels that are consistent with guideline-directed goals. We don't see that same. By the way, those class of medicines had demonstrated MACE benefit in large outcome studies. The big difference here with triglycerides is you've got fibrates and omega-3s, which are not considered to be that effective in triglyceride reduction, 20%-40% at best. Neither of those two classes has been proven to reduce acute pancreatitis. You have a standard of care which is really suboptimal for this class, and you introduce now these APOC3 inhibitors, which can reduce TGs by upwards of 80% and have now proven to reduce acute pancreatitis in a variety of clinical studies. I think it's just, again, not a comparable analog.
I wish I had a better answer for you around what some comparable analogs might be, but we haven't exactly identified a good one yet.
Am I missing something that you have identified and we haven't talked about in terms of analogs?
No, I think, uhm-
Those are the ones?
Yeah, I think it remains to be seen. I do think there are a lot of these patients out there, 3 million SHTG patients in the United States, close to 1 million who are considered high risk, and the current treatment paradigm is largely ineffective.
Okay.
When you talk to physicians and you talk to payers, they have a desire to improve that model, and the APOC3 inhibitors to date have demonstrated data that can really improve that model.
Maybe remind us about the device presentation. This is going to be administered at home, or the first dose will be administered by physicians and the reimbursement will still be Part D, right?
Yeah. So at-home administration, in the product leaflet for patients, there is a recommendation for the first dose to be observed by a healthcare professional, but it's not required. The presentation for FCS and also initially for SHTG is prefilled syringe and we'll be introducing an auto-injector as well to provide flexibility for patients and providers as to whether they prefer the auto-injector or the prefilled syringe.
Got it. In terms of the investments needed to launch this drug, and maybe Dan, you can chime in as well.
Yep.
The sales force expansion that you're doing, how much is that required? I guess one long-term debate on the SHTG launch is it could be an expensive launch. So Dan, how are you thinking internally in terms of the planning there?
No, I think obviously we've had line of sight on this for a while. We're accelerating it four months. We have largely created the capabilities today for that. There'll be some incremental hiring as we get fully into this, but we've already ramped up our field force presence. We have the capabilities we need on the data side and the targeting side and of this nature. As launches go, I think we're almost ready today and we still have, obviously, anywhere from 9 months to go or so.
Yeah. Andy, remind us about the Salesforce size right now. How many physicians are you able to target?
Yeah. In FCS, we're currently targeting between 5,000 and 6,000 physicians. Think all the lipidologists, those preventive cardiologists, endocrinologists who have an interest in lipidology or connected to lipid clinics. These are the primary group and what the guidelines indicate patients should be referred to these types of individuals. 5,000- 6,000. We'll be ramping that up to 20,000 healthcare professionals for personal promotion. As Dan said, we're nearly fully staffed to accommodate that increased targeting today. We've spent quite a lot of time doing our targeting analysis on those physicians who we think could benefit from education around APOC3, around AP-Risk and around REDEMPLO. That'll be the initial target at launch and that's what we've sized the field force to go after, because that's the group that is largely correlated to the high risk SHTG segment.
Not the full 3 million patients in the United States, but roughly the 800,000 to 1 million high-risk SHTG patients in the United States.
Got it. Maybe on the current physicians that you already target, 5,000 prescribers, are these also high volume prescribers for SHTG patients as well? What's the current overlap?
High degree of overlap. These are going to be people in lipid clinics, connected to lipid clinics. These are going to be specialists and opinion leaders in the field. Remember, FCS, it's on the spectrum of SHTG, so it's almost difficult to think about these two conditions in sort of separate worlds because they're all just a continuum of triglycerides. Yes, high degree of overlap between the 5,000- 6,000 HCPs who we're currently targeting and those that will be in the 20,000.
Got it. I guess maybe the 20,000 prescribers, how concentrated are these physicians nationally? Are there specific regions where you see more presence?
No, I would say it's fairly balanced across the United States, as you might expect, concentrated in key metropolitan areas, of course. So nothing special, I think, about a particular concentration. One can argue there are some founder type populations for FCS, but because it's autosomal recessive, you really don't find large pockets of that. For SHTG, it's one in 100 people have triglycerides greater than 500 mg, and you can find those individuals from coast to coast. Our field force, our data analytics team has used our targeting analysis to lay out where we think these prescribers are, and when you look at that map, there's fairly good coverage across the United States.
Okay. I did want to touch on some of the BD and out-licensing opportunities as well. I think you guys have a great BD team, done pretty good deals.
Sure.
The focus right now is on the cardiometabolic side, but as you think about some of the other assets that you have in the pipeline, which assets are open to opportunities to partner right now?
Yeah. I would say we are not actively looking at the moment. We do not have a near-term need for an out-licensing. Purely in the cardiometabolic space, the bar would be very high, meaning plozasiran we have no intention of out-licensing. We are going full bore in the U.S. We are starting to do the same in the major markets. We might consider some sort of distributed relationship for smaller markets. Zodasiran, which is kind of next for the cardiometabolic franchise, hopefully coming in 2028. That is a really easy bolt-on, that will just follow suit. Then we get to the ARO-DIMER-PA, which is a very interesting program to follow. We did not really touch upon it here. But we will have data in the next month on that. The ARO-DIMER-PA is for both LDL as well as triglyceride-
Yep.
reduction in the mixed hyperlipidemia market. Massive market, 20 million in the U.S. alone, but very complimentary from a commercial perspective. So that would be a very high bar for us to do any out-licensing there. Then we get deeper in the portfolio, we have as well upcoming data on MAPT, which is very exciting, upcoming data on ARO-INHBE later this year. Both of those we are sort of committed to moving forward in the clinical phase at the moment. I am cognizant those can be very expensive phase III. So maybe the bar is not as high, but we are not actually actively looking for those either.
Okay.
Finally, just to round it out, we get to some of the programs that are entering the clinic now. Again, no obvious candidates for out-licensing. But we are bringing quite a few in in the next year, and somehow that could also outpace our development. So those might be considerations at that point.
Okay. That's great. I think that's all the time we have so far, but thank you, Andy, thank you, Dan, for a great overview, and really appreciate the time.
Thank you so much.
Thanks so much. We appreciate it.