Ionis Pharmaceuticals, Inc. ($IONS)

So conversation, I think, is not surprisingly going to start with just the commercial opportunity for olezarsen in sHTG. And you've got an important FDA action date coming up here, June 30. So maybe just talk about how you're positioning for your first major launch as a company. Commercially, you've launched this drug Tryngolza for an ultra-orphan indication, but now you're migrating to Zigly with a very big market, a more complicated probably end market, I would imagine. And so maybe just level set in terms of how Ionis is getting ready for kind of a transformational event for you as a company.

Yes, sure. Let me begin with FCS because that's the current indication for Tryngolza. Patients with a genetic cause of severely elevated triglycerides. The commercial launch for Tryngolza has been very, very strong, very positive. And the HCP demand -- patient demand, for patients that have FCS has been very, very strong and continues to get stronger and stronger week by week. That's been driven by the overall therapeutic profile of the medicine as well as the sentiment from both patients as well as HCPs who are managing these patients. These patients are feeling really good. They're seeing their triglyceride plummet. Many of them into -- well into the normal range, and they're seeing a prevention of acute pancreatitis, which, of course, they live in fear of all the time. That launch will continue through the expected SHTG launch that you referred to in June 30, a PDUFA date June 30 with priority review and breakthrough therapy designation. We reported Phase III data for SHTG last year that was just groundbreaking with an 85% reduction in acute pancreatitis and triglyceride reductions on top of standard of care that exceeded 70%, really, really groundbreaking results. And we're leveraging that data. We've leveraged that data to get priority review. This is a multibillion-dollar product opportunity for Ionis, is a wholly owned program, and it puts us into prevalent diseases for wholly owned programs and launches that you referred to. We are well prepared to launch into this multibillion-dollar product opportunity. We have trained -- we have hired and trained our field team. They've been out in the field educating on severe hypertriglyceridemia for cardiologists, endocrinologists with the specialists, but also they've also been identifying accounts. Physicians who are managing these patients at high numbers with high numbers, high volumes of patients that are being handled by these physicians. So we're targeting these patients. We're identifying the high prescribers, and we're going to be ready to launch in June, assuming an on-time approval on June 30.

When we think about the key learnings from the FCS launch and how they're applicable to sHTG, I recall when you were initially launching FCS, there was a lot of discussion we had about patient finding, right, genetic component to the disease. Here, when we think about something much more broad, right, those early adopters of Tryngolza for FCS, how important are they to sHTG early adoption? And maybe just talking about how much broader you need to reach now with the sHTG indication, what that?

Well, it's very important because the physicians who manage FCS patients are also managing sHTG patients. And we built tremendously positive sentiment in that community. Because they see the efficacy and the excellent safety, the tolerability that Tryngolza is offering. And what we're hearing from those physicians is this is great for my FCS patients. I've identified more FCS patients. I want to put them on Tryngolza. When can I get access to Tryngolza for my severe hypertriglyceridemia patients, which, of course, on a volume basis, we're seeing many more of there. So it's launching from FCS to sHTG has provided [indiscernible] a big advantage for us. And of course, we are first to market in FCS. We're going to be well ahead of any competition first to market in sHTG, which has been -- which is going to be really important.

Okay. In third quarter, there will be some competitor data for another sHTG modulating agent. And you have about a 1-year head start to the competition. And I'm just kind of curious how you view the competitive dynamic, right? Like is 1-year first-mover advantage material? Or ultimately, hey, this is a big market, 2 players more than enough to support 2 players, and it may actually be advantageous to have 2 companies out there investing and building out this market opportunity.

In the United States alone, there's more than 3 million people with severe hypertriglyceridemia. About 400 or 1,000 of those patients today are being treated ineffectively really with generic fibrates and [indiscernible]. So this is a growth market. This is an untapped market and a market with high unmet medical need, and there's room for multiple players and more players in this space that deliver effective medicines will only grow that market out even further. With that said, there's -- we're really thrilled, and we believe it's a big advantage to be first to market. Because it allows us to identify those high-volume treaters and get to those high-volume treaters, those treaters who are treating the patients that are at the highest risk for acute pancreatitis or cardiovascular disease, which will be the priority to get those patients in as quickly as possible. So we're going to access to those patients more rapidly and secure those patients. As I said, the experience with Tryngolza and FCS has been wildly positive. So we're expecting that sentiment to translate to sHTG. Patients will stay on drug, and we'll continue to accelerate that by really over a year advantage the market. In addition, it allows us to set up accounts with payers and build a relationship with payers, set price, which we did for our WACC price for sHTG. So there are lots of different advantages that we're taking full advantage of as first to market for sHTG.

So these drugs are effectively being positioned as pancreatitis-sparing drugs, right, ultimately from the core study results. And so as you think about these individuals who had past events, right? I would imagine they are that initial first adopter, right, of the therapy, most highly motivated. Is that your sense? Are these patients -- is your feedback from physicians, KOLs that these are the types of patients who might be more asking about when a therapy like this can become available? Are they because of these past events perhaps under the care of a specialist who might be aware of clinical stage data as opposed to maybe more of a community-based doctor?

Out of the gate focus will be on the high-risk patient population. One segment of that high-risk patient population are patients that have had a history of acute pancreatitis. The other segment of that population is patients that have triglycerides 880 milligrams per deciliter and above. They're at high risk for their first time AP event, if they haven't had one yet. The motivation by patients that have had an AP event in their past is extremely, extremely high as it is HCPs, of course, because there's nothing they can do for patients that come to an ICU with an APU event. It is incredibly painful. Patients don't want a second event. So they are highly motivated. However, HCPs that are managing patients with triglycerides and above, whether they've had an APU event in the past or are also highly motivated because they want to prevent that first AP attack from happening. Once you have APU attack, the chance of having additional attack goes up exponentially, leading to organ dysfunction and destruction. So it's HCPs are highly motivated whether or not they have had a history of AP or not, but certainly, patients that have had AP, they don't want another one.

All right. Great. Maybe just help reconcile you revised the pricing in advance of the sHTG launch for pricing to be more in line with a broader market opportunity that is sHTG. I guess just trying to understand that versus some comments recently about wanting to wait -- payers wanting to wait until they see a final label to have more meaningful discussions. Is that just mechanical, right? Like payers just need to fundamentally have a label? Or are there specific label outcomes that you feel like are going to drive access relatively a PA to label, like a PA that matches study entry criteria? Because if that were the case, that would suggest broad access, I would argue.

So let me start with the $40,000 WACC price that we announced for sHTG that went into effect on April 1, how we got there. That price was the product of 1.5 years, maybe even 2 years of research with payers and HCPs. We first had to -- once they have the Phase III data to understand which HCPs are going to prescribe Tryngolza to which sHTG with what priority based on the Phase III results. As I mentioned, the Phase III results were groundbreaking. We then took that HCP demand research to payers to understand where their limits would be with respect to putting in place blocks of -- NDC blocks or other blocks that would delay access for patients due to price being too high. We believe that we've threaded the needle perfectly to maximize access and to maximize value with a $40,000 WACC price. The conversations, the discussions we've had with payers have been deep, intense, very positive, very productive. We are aligned on the $40,000 WACC price. We do not believe the label is going to impact access in any way. We kind of know what the label is, and that's what we presented to payers. We received breakthrough therapy designation, which basically gets translated to the ultimate indication saving, which is patients with sHTG as defined by triglyceride 500 and above as an adjunct to diet, and that's the label we expect. We do expect acute pancreatitis to be in the label probably in the clinical trial section because the results were so statistically significant and was a prespecified secondary endpoint. And it's important to have it in there. With that said, we don't think that that's going to drive adoption because everyone is aware of the data already for publications and presentations. And certainly, the payers are aware of it, and that has resonated extremely well with them to prevent ICU hospitalizations, prevent potential fatal outcomes and so on. So payers are pressing to...

The last point you made, the omission of the language that is in some triglyceride lowering therapies front page to say this drug has not been studied for pancreatitis reduction, whereas you've now studied it. I imagine that label language will be deleted from a Pringles label for sHTG. Is that right? And sales reps not sort of alluded to the fact that, that label language is now...

Yes, absolutely. We do not expect -- obviously, it was studied for AP outcome, and it was highly successful. So it will -- that statement will not exist in the label. In fact, we'll have AP data that we expect to have in the clinical trial section of the study. The other point I think might be worth mentioning is guidance, clinical trial or clinical treatment for FCS and sHTG the guidelines, the Tryngolza is indicated in the guidelines for FCS, and we expect that Tryngolza will be in the guidelines for sHTG pretty quickly after approval as well. The guidelines were adjusted very quickly. And Tryngolza singled out as a treatment for FCS, we think a similar same thing will happen for sHTG.

That recommendation presumably will be tied to the pancreatitis outcome benefit. I know there's some theoretical possibility, right, that in like a comorbid diabetic patient lowering trigs might actually have cardiovascular benefit, but that hasn't been studied. I doubt it will ever be studied. But if you can speak to how you'd envision guidelines and recommendations evolving within the launch of the product?

I think the guidelines will be focused on the triglycerides. If patients are above 500, they need an APOCIII inhibitor and Tryngolza will be the first one out there by a long shot to be the treatment for to manage sHTG. It will not be in the guidelines for managing cardiovascular outcome because we didn't study that outcome, as you pointed out. With that said, although the high-risk patient population that we're focused on is primarily patients that are above 80 and/or have a history of acute pancreatitis. There are a lot of patients that have triglycerides well above 500 that have cardiovascular disease -- and that -- those are the other comorbidities that round out the million-plus high-risk patient population. Cardiologists recognize that having triglycerides that high puts them -- disposes them to cardiovascular risk, and they're going to want to get their triglycerides down to the normal range, which we achieved more than 80% of the time in our sHTG Phase III trial. So we do believe that, that's going to be an added benefit for the sentiment towards prescribing Tryngolza is also those patients that have a history of cardiovascular disease because they recognize that this is a contributor to cardiovascular disease.

Okay. And then just circling back to price. I believe both you and your competitor have declined to speak specifically about kind of what gross to net would look like over time. But can you just maybe remind us about payer mix? Because I imagine with the government plan patients, there will be some mandatory rebating that needs to be offered. And imagine like rare orphan comps and maybe even oncology drugs might be a good proxy for the spread between gross and net. So any high-level commentary that you can...

Sure. I mean what we can say is that when we first discussed the market opportunity in the U.S. for Tryngolza and sHTG in January of this year, we assumed the net price that we announced of $10,000 to $20,000. We're still doing our market research. So we have a lot more work to do, a lot more payer research to do. That was a net price that was used in the U.S. As we developed our HCP demand research and then had our payer engagement research completed, we settled on the $40,000 WACC price. That's going to bring us in meaningfully higher than our original net price, which is the main driver behind our upgrading our peak product sales in the United States beyond $3 billion. We upgraded it from $2 billion to above $3 billion. And that's because our net price will be higher in that $10,000 to $20,000 range. Other than that, we're not -- we're really not going into more detail about net pricing and rebating at this time. Okay.

And maybe a few questions just on safety. Olezarsen safety looks pretty pristine. Do you think this is going to be easy drug to administer. Monitoring requirements can sometimes be add a layer complexity for drug. Do you think this will be a drug that has many safety monitoring requirements tied to it in the sHTG setting?

Yes. No. I mean, first of all, FCS has no monitoring. It's a clean drug and no monitoring was required. That's one of the reasons why the launch has gone so well in FCS. And we don't expect monitoring in sHTG. Why would we? It's a very clean profile, extremely clean profile, and we don't see the need for monitoring at all. And right now, all of our discussions with the FDA have been going very smoothly, and that supports my set conclusion.

Yes. Because what I wondered is there's obviously going to be a lot of work done to determine patient triglyceride level at baseline. imagine they may look at something like liver fat at baseline and whether or not there might be any sort of requirement to follow and look at how both of those clinical measures are over time, presumably the same measurement.

We don't expect hepatic fat to be measured at all in the real-world setting on the market at baseline or any other time. Let me level set here a little bit. So in our Phase III study, we reported a small increase in liver fat in patients with sHTG that was dose dependent. It was small, but most importantly, there was no clinical sequela, no clinical outcome, no adverse events or reactions related to that, right? So there's nothing to monitor. There's no correlation with ALT. MRI imaging of a lab observation that has no clinical consequences is just not something that would be required. It's just an observation. It's also an on-target effect. We know that from a competitor program that has a silencer that reported in Phase II, a dose-dependent increase in liver fat. And it makes complete sense. What we're working through using the APOCIII mechanism of action are 2 pathways that are substantially and rapidly lowering triglycerides as circulation. One is to break down the LDL particle, the triglycerides fatty acid. The second is to clear through the liver very rapidly. And the liver does a very good job of clearing out the fat that chunk is true. But there was some residual liver fat that we saw in the -- at the 12-month time point in the Phase III study. What I can tell you, though, is that we continue to monitor these patients that are in the open-label extension, and we're seeing as expected that the liver continues to compensate and clear out the liver triglycerides, we're seeing a return to baseline at 1 year, which further continues to get the baseline at 2 years, and we're going to report that data at a medical congress later this year. So we don't expect any monitoring.

Is it crazy to think, I think, with the WAYLIVRA liver fat went down, it was not down mediated ASO, is it just noise?

I don't think it's noise. I think WAYLIVRA is a very different class of molecules. As you mentioned, WAYLIVRA, which was a first-generation non-GalNAc molecule was not directed precisely and exclusively to the liver. It was also used at a very high dose, a dose of 15-fold higher than what we used for Tryngolza. That's because it's not a GalNAc. WAYLIVRA is probably affecting APOCIII in other tissue beds, including the GI tract, which if you inhibit APOCIII in the GI tract, you will block chylomicron absorption and other aspects of triglyceride metabolism. So we think that it's a different animal entirely and that it's broadly distributed, whereas Tryngolza is distributed precisely to the hepatocyte and that's we're getting our...

Okay. And then lastly, just the status of your semiannual APOCIII modulating therapy, when could we get an update on next steps? And how quickly could something like that move through development?

Quickly, the high priority for us is to focus entirely on less convenient -- or less frequent dosing, semiannual dosing or once a year dosing. And that conclusion is supported by the Phase I, II -- the Phase I data that we reported last year in patients with mildly elevated triglycerides, we are following cessation of dosing. We're seeing a lasting lowering of triglycerides and APOCIII that's approaching a year in duration with very, very high potency. We're going to start the Phase II study in sHTG patients very soon and we expect to wrap that study up pretty quickly, and we're already discussing next steps to initiate Phase II development. So we're moving that forward rapidly. It's an entire -- the focus is entirely on less frequent dosing. It's going to be hard to match to exceed the data that we've already generated in Tryngolza. So it's really less frequent dosing.

Okay. Maybe shifting gears to DAWNZERA set for HAE launch. This one is exceeding our expectations so far in the early going. And I know you guys have been firm, but you think this is an underappreciated therapy and a big value add to the HAE setting. So maybe early observations in the launch. Anything exceeding your expectations? I know this is largely a switch market as you frame it. And so I imagine the early adoption is primarily coming from switches. So anything you can say to help us better understand what's going on in the early days there.

Yes. The demand by patients and HCPs has been very high for DAWNZERA as prophylactic for HAE. As you know, there are several other products already on the market for HAE prophylaxis. So this is a switch market, unlike Tryngolza, where we're first to market and the launch execution has gone exceptionally well. We're very pleased with the demand. We have a free drug program to get patients on top of DAWNZERA as quickly as possible. It's about a month of free drug, and then that allows them to get the experience and then they're moving over to commercial very rapidly. So we're really, really thrilled with execution on free drug as well as commercial drug. But we're thrilled about the demand for the drug and the compliant patients are staying on drug. It's reporting very, very positive experiences. What has really been a surprise to us was -- has been how much the mechanism of action has really resonated with HCPs. They are so used to antibodies and small molecules and treating these patients for their whole careers. Something new. We're targeting RNA for the first time, something different. And of course, the profile has supported that as well. It's a switch market. We're seeing switches from all other available prophylactic treatments today. The majority, of course, are Takeda [indiscernible]. So because that the majority of patients that are being managed today is obviously on that medicine. So we're seeing switches from all the other prophylaxis we're seeing switches from on-demand treatment. We're also seeing newly diagnosed patients coming on to DAWNZERA. So we're really pleased with the launch. It's going to be a big year for DAWNZERA.

And you mentioned the free trial program what does the conversion rate look like once you're in that program? And do you have a line of sight? Is there a big queue of patients that are entering into the peer program?

It's very high, the conversion. We haven't reported the specific numbers. We're not going to do that right now. It's competitive, but it's very, very hard. And that's because the patients are getting great experiences with DAWNZERA on treatment.

Okay. Maybe we've got 5 minutes, so just some quick hitters here. But we know it makes timely given you published baseline demographics, I think, over the weekend. How would you kind of level set investors now that we have that data out there, see differences, your trial versus HELIOS-B and what that either portends in terms of added risk or opportunity, a lot of focus on the task combination data sets, right, to sort of be incremental for the sinuses class?

Well, first of all, as by far the largest study ever conducted in ATTR cardiomyopathy. We're very well powered for a positive outcome. The first answer that was approved for ATTR cardiomyopathy, just greatly supports our -- the likelihood for a highly positive outcome because we're getting TTR lowering as good, if not better, excellent drug profile and our study is more than double the size of any study that's ever been conducted in this patient population to date. So we're very well powered for the primary end point. The baseline demographics that we reported this weekend really not a whole lot of surprises. There are more similarities between our program and the HELIOS-B study than there are differences. As we've signaled too well in advance, the demographics continues to shift in cardiomyopathy. We've been saying that we're going to have more patients on baseline that we're going to be adding on to in our study, and that's what we reported, about a 56% at baseline patients on tafamidis. It is not that much more than HELIOS-B but more. We also have some more -- a higher percentage of patients with a higher percentage of [indiscernible] patients that are hereditary, because it more rapidly progresses. None of that puts any of the primary outcome, at any risk because our study is so large, it's so well powered. We actually think it is the real world setting that is going to generate data that is going to resonate really well with cardiologists in managing patients. Because those are the demographics that patients that these physicians are managing today. Patients are on tafamidis. They want to know they're not doing well. They're progressing. What evidence do you have that combination is going to actually provide further benefit. And our secondary endpoints are laid out, and we're going to have a very sizable subgroup in combination usage that we're going to be able to report on. So if there is a complementary mechanism between a silencer that stabilizes 50% to 70% and then knocking down the rest with a silencer, we're going to have the data to convince HCC that combination usage is the way to go.

And if you generate that data, can you talk about that as like a IonisAstra company-specific benefit that could allow you to swing the competitive pendulum and potentially fulfill the base on -- I think eplontersen and you'd be the only company, I think, that could promote, right, this data and presumably gets at least in the clinical Section 14 of the label.

That's correct because it is prespecified secondary endpoint. We elevated it to that. It's upside. It's significant upside. Our base case, AstraZeneca has reported this as well as $5 billion product opportunity for WAINUA, assuming we replicate the other silencer that has come out that data. We're well positioned to do that. Additional data that is favorable, including combination usage is the key differentiator and is key revenue up.

Where do you expect given some of the recent announcement on the prefilled syringe and for Part B, where this market is going to go, right, for you? You think it's going to be more of a Part D drug, more of a Part B as in boy, drug?

So let me first start by saying that the ability to self-administer Wainua by patients themselves once or a month has resonated incredibly well in the polyneuropathy launch and will be magnified many, many folds exponentially in a much larger cardiomyopathy indication. The ability to self-minister is a big, big differentiator. With that said, AstraZeneca felt that flexibility optionality would be very nice to have. So they're like those centers of excellence that do buy and bill. So they came out as they pushed forward a prefilled syringe that would be administered by a physician as a Part B approach for using a buy-and-build strategy. It's really just optionality that they can have. The primary driver for Wainua going forward will be the advantage we have with self-administration using a simple once-per-month injection, that room temperature stable, can be carried around taking on vacations and so on. That will still be the main driver.

Maybe 2-word answer. What are you most excited about between tau, Lp(a) and Angelman?

All of them. Pelacarsen is a big deal. We're looking forward to the data in the second half of this year. We're looking forward to the tau data in midyear this year. What we're hoping to see is data that supports moving to Phase III development. That's the first tau lowering drug ever in history, another first potentially for Ionis. And we love the Angelman's program, but it's a little bit further out. We're expecting to complete enrollment second half of this year and then to get the Phase III data next year for that program. So I'll leave it there. And we're excited about all 3 of them.

All right. So thank you. With that, we're out of time.

Thanks, Jason. My pleasure.