Thanks so much for joining us.
Thanks, Jason. It's great to be here.
Conversation, I think, is not surprisingly gonna start with just the commercial opportunity for olezarsen in sHTG, and you've got an important FDA action date coming up here June 30th. 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 the big league with a very big market, a more complicated probably end market, I would imagine. Maybe just, you know, level set in terms of how Ionis is getting ready for kind of a transformational event for you with the company.
Yeah, sure. Let me begin with FCS though 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. You know, the HCP demand or 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 triglycerides plummet, many of them into, well into 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 on June 30th, up to due for date June 30th with priority review and breakthrough therapy designation. You know, we reported phase II 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 groundbreaking results. We're leveraging that data, we've leveraged that data to get priority review.
This is a multi-billion dollar product opportunity for Ionis, a wholly owned program, and it puts us into prevalent diseases for wholly owned programs and launches as you referred to. We are well prepared to launch into this multi-billion dollar product opportunity. 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, you know, at high numbers, with high numbers, high volumes of patients that are being handled by these physicians. You know, we're targeting these patients.
We're identifying, the high prescribers, and we're gonna be ready to launch in June, assuming an on time approval on June 30th.
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? The genetic components 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 and what steps to take.
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. 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. The launching from FCS to SHTG has provided a big advantage for us. Of course, you know, we are first to market in FCS.
We're going to be well ahead of any competition first to market in sHTG which is going to be really important.
Okay. You know, in third quarter there will be some competitor data for another APOC3 modulating agent. You know, you have about a one year head start to the competition, and I'm just kind of curious how you view the competitive dynamic, right? Like is one year first mover advantage material or ultimately, hey, this is a big market, two players, more than enough to support two players, and it may actually be advantageous to have two companies out there investing in building out this market opportunity.
In the U.S. alone, there's more than 3 million people with severe hypertriglyceridemia. About 400,000 of those patients today are being treated ineffectively really with generic fibrates and fish oils. This is a growth market. This is a untapped market and a market with high unmet medical need, 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, 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. We'll get access to those patients more rapidly and secure those patients. As I said, the experience with TRYNGOLZA and FCS has been wildly positive. We're expecting that sentiment to translate to sHTG. Patients will stay on drug, and then we'll continue to accelerate that by really over a year advantage to the market.
In addition, it allows us to set up accounts with payers and build the relationship with payers, set price, which we did, our WAC price for sHTG. You know, there are lots of different advantages that we're taking full advantage of as first to market for sHTG.
The drugs are effectively being positioned as pancreatitis-bearing drugs, right? Ultimately, from the quarter study results. As you think about these individuals who've 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 the 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?
Our 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 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 high, as it is HCPs, of course, because there's nothing they can do for patients that come to an ICU with an AP event. It's incredibly painful. Patients don't want a second event. They are highly motivated.
However, HCPs that are managing patients with triglycerides 880 and above, whether they've had an AP event in the past or not, are also highly motivated because they want to prevent that first AP attack from happening. Once you've had 1 AP attack, the chances of having additional attacks goes up exponentially, leading to organ dysfunction and destruction. 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.
Yep. 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. You know, I guess just trying to understand that versus some comments recently about, you know, 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?
Yeah.
that you feel like are going to drive, you know, access relatively a PA to label, like a PA that matches study entry criteria? If that were the case, that would suggest broad access, I would argue.
Let me start with the $40,000 WAC price that we announced for sHTG that went into effect on April first, how we got there. That price was the product of a year and a half, maybe even two years of research with payers and HCPs. We first had to, once we had the phase III data, to understand which HCPs are gonna prescribe TRYNGOLZA to which sHTG with what priority based on the phase III results. As I mentioned, the phase III results were groundbreaking. We took that HCP demand research to payers to understand where their limits would be with respect to putting in place blocks, NDC blocks or other blocks that would delay access too high. We believe that we've threaded the needle perfectly WAC price.
We are aligned on the $40,000 WAC price. We do not believe the label is gonna in any way. We kinda know what the label is, and that's what we presented to payers. This 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 pre-specified secondary endpoint, and it's important to have it in there.
With that said, we don't think that that's gonna drive adoption because everyone's aware of the AP data already through 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. Payer discussions have gone really well.
Is there not a point to be made, you know, the omission of the language that is in some triglyceride-lowering therapies, you know, front page that 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 TRYNGOLZA label for sHTG. Is that right? Can sales reps not sort of allude to the fact that that label language is now omitted?
Yeah, absolutely. Obviously, it was studied for AP outcome, and it was highly successful. It will, that statement will not exist in the label. In fact, we'll have AP data 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. 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. These guidelines were adjusted very quickly, and TRYNGOLZA was singled out as the treatment for FCS, and we think it 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 trig might actually have cardiovascular benefit, but that hasn't been studied. I doubt it will ever be studied. 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 APOC3 inhibitor. TRYNGOLZA will be the first one out there by a long shot to be the treatment to manage sHTG. It will not be in the guidelines for managing cardiovascular outcome because we didn't study that in that outcome as you pointed out. With that said, you know, although the high-risk patient population that we're focused on is primarily patients that are above 84, have a history of acute pancreatitis, there are a lot of patients that have triglycerides well above 500 that have cardiovascular disease. Those are the other comorbidities that round out the 1 million-plus high-risk patient population.
Cardiologists recognize that, having triglycerides that high, puts them, disposes them to cardiovascular risk, and they're gonna wanna get those triglycerides down to the normal range, which we achieve more than 80% of the time in our sHTG phase III trial. We do believe that that's gonna be an added benefit for the sentiment towards prescribing TRYNGOLZA is also those patients that have a history of cardiovascular disease because it's recognized that this is a contributor to cardiovascular disease.
Okay. Then just circling back to price, I believe both you and your competitor have declined to speak specifically about kinda what gross-to-net would look like over time. Can you just maybe remind us about payer mix? 'Cause I imagine with the government plan patients, there'll be some mandatory, you know, rebating that needs to be offered. I'd imagine, like, rare disease and comps and maybe even oncology drugs might be a good proxy for maybe the spread between gross and net. Any high-level commentary that you can offer?
Sure. 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 a net price that we announced of $10,000-$20,000. We were still doing our market research, so we had a lot more work to do, a lot more payer research to do. That was the net price that was 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 WAC price.
That's gonna 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 to be beyond $3 billion. We upgraded it from $2 billion to above $3 billion, and that's because our net price will be higher than that $10K-$20K range. Other than that, we're really not going into more detail about net pricing and rebating at this time.
Okay. Maybe a few questions just on safety. olezarsen and safety looks pretty pristine. Do you think this is going to be easy drug to administer? You know, monitoring requirements can sometimes be add a layer of complexity for drugs. Do you think this will be a drug that has many safety monitoring requirements tied to it in the sHTG setting?
No. I mean, first of all, FCS has no monitoring. It's clean. 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. 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. Right now, all of our discussions with the FDA have been going very smoothly, and that supports my conclusion.
Yep. Yeah, 'cause what I wondered is, you know, there's obviously gonna be blood work done to determine patient's triglyceride level at baseline. I 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. It could presumably be done in the same measurement.
We don't expect hepatic fat fraction 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. 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 sequelae, no clinical outcome, no adverse events or reactions related to that, right? 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 a non-target effect, Jason.
We know this 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 APOC3 mechanism of action are two pathways that are substantially and rapidly lowering triglycerides out of the circulation. One is to break down the VLDL particle, the triglyceride into fatty acids. The second is to clear it through the liver very rapidly. The liver does a very good job of clearing out those, the fat that's being shunted through. There was some residual liver fat that we saw 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 one year, which further continues to get to baseline at two years, and we're going to report that data at a medical congress later this year. We don't expect any monitoring.
Is it crazy to think, I think the way WAYLIVRA, liver fat went down, it was not down APOC3 mediated.
Yeah.
ASO. Is this just noise?
I don't think it's noise. I think WAYLIVRA is a very different class of molecule. 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 that's 50-fold higher than what we use for TRYNGOLZA. That's because it's not a GalNAc. WAYLIVRA is probably affecting APOC3 in other tissue beds, including the GI tract, which if you inhibit APOC3 in the GI tract, you will block chylomicron absorption in other aspects of triglyceride metabolism. We think that it's a different animal entirely in that it's broadly distributed, whereas TRYNGOLZA's distributed precisely to the hepatocyte in that we're getting our effect.
Okay. Lastly, just is the status of your semi-annual APOC3 modulating therapy, you know, when could we get an update on next steps, and how quickly could something like that move through development?
Quickly. It's a high priority for us, and it's focused entirely on less frequent dosing. Semi-annual dosing or once-per-year dosing. That conclusion is supported by the phase I data that we reported last year in patients with mildly elevated triglycerides, where following cessation of dosing, we're seeing a lasting lowering of triglycerides in APOC3 that's approaching a year in duration with very high potency. We're going to start the phase II study in FCS patients very soon. We expect to wrap that study up pretty quickly. We're already discussing next steps to initiate phase III development. We're moving that forward rapidly. The focus is entirely on less frequent dosing.
It's going to be hard to match, you know, to exceed the data that we've already generated in FCS for TRYNGOLZA. It's really less frequent dosing.
Okay. Maybe shifting gears to DAWNZERA and the HAE launch. This one is exceeding our expectations so far in the early goings. I know you guys have been firm that, you know, you think this is an underappreciated therapy and a big value add to the HAE setting. Maybe early observations in the launch, anything exceeding your expectations? I know this is largely a switch market as you frame it, I imagine the early adoption is primarily coming from switches. Anything you could say to help us better understand what's going on in the early days there?
Yeah. The demand by patients and HCPs has been very high for DAWNZERA as a prophylactic treatment 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. 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. We're really thrilled with execution on free drugs as well as on commercial drugs.
We're thrilled about the demand for the drug and the compliance. Patients are staying on drug. It's reporting very positive experiences. What has really been a surprise to us has been how much the mechanism of action has really resonated with HCPs. They're 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. 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, Takhzyro, because that's the majority of patients that are being managed today is on that medicine. We're seeing switches from all the other prophylactics. We're seeing switches from on-demand treatment.
We're also seeing, newly diagnosed patients, coming on to DAWNZERA. We're really pleased with the launch. It's gonna be a big year for DAWNZERA.
You mentioned the free trial program. What does the conversion rate look like once you're in that program? Do you have a line of sight? Is there a big queue of patients that are entering into the free drug program?
It's very high, the conversion. We haven't reported the specific numbers. We're not gonna do that right now. It's competitive, but it's very, very high. That's because the patients are getting great experiences with DAWNZERA on treatment.
Okay. Maybe, we've got five minutes, so just we'll do some quick hitters here. WAINUA, it makes timely given you published, baseline demographics, I think over the weekend.
Yep.
How would you kind of level set investors now that we have that data out there, key differences that your trial versus HELIOS-B and, you know, what that either portends in terms of added risk or opportunity, a lot of focus on the tafamidis combination data sets, right, to sort of be incremental for the silencer 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 silencer that was approved for ATTR cardiomyopathy just, you know, greatly supports our, you know, 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. We're very well-powered for the primary endpoint. The baseline demographics that we reported this weekend, really not a whole lot of surprises. There's 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 ATTR cardiomyopathy.
We've been saying that we're going to have more patients that on baseline tafamidis that we're going to be adding onto in our study, and that's what we reported, about a 56% at baseline patients on tafamidis. It's not that much more than HELIOS-B, but more. We also have some more, a higher percentage of patients with New York Heart Association Class III, a higher percentage of patients that are hereditary, which are more rapidly progressors. 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's a real-world setting that's gonna generate data that is gonna resonate really well with cardiologists who manage these patients because those are the demographics that patients that these physicians are managing today.
Patients are on tafamidis. They're not doing well. They're progressing. What evidence do you have that combination is going to actually provide further benefit? You know, 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. If there is a complementary mechanism between a silencer that stabilizes or a stabilizer that stabilizes 50% to 70% and then knocking down the rest with a silencer, we're going to have the data to convince HCP that combination usage is the way to go.
If you generate that data, can you talk about that as, like, a Ionis Astra company-specific benefit that could allow you to swing the competitive pendulum and potentially fulfill the bull case on, I think, eplontersen, and you'd be the only company, I think, that could promote, right, this data and presumably gets at least into clinical section fourteen of the label.
That's correct because it is a pre-specified secondary endpoint. We elevated it to that. It's upside. It's significant upside. Our base case, AstraZeneca has reported this as well, is a $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 upside for the program. That'll be a very significant upside.
Okay. Where do you expect, you know, given some of the recent announcement on the prefilled syringe and for Part B, where this market's going to go, right? For you think it's going to be more of a Part D drug, more of a Part B, as in boy, drug?
Let me first start by saying that the self, the ability to self-administer WAINUA by patients themselves once per month has resonated incredibly well in the polyneuropathy launch and will be magnified many, many fold exponentially in the much larger cardiomyopathy indication. The ability to self-administer is a big differentiator. With that said, AstraZeneca felt that flexibility optionality would be very nice to have. They're like those centers of excellence that do buy and bill. They came out as they pushed forward a prefilled syringe that would be administered by a physician as a Part B approach for, you know, using a buy and bill 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's room temperature stable, can be carried around, taken on vacation and so on. That'll still be the main driver.
Maybe a two-word answer. What are you most excited about between Tau, Lp(a), and Angelman?
Pelacarsen is a big deal. We're looking forward to the data the second half of this year. We're looking forward to the Tau data in mid-year 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. 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. I'll leave it there. We're excited about all three of them.
All right. Thank you. With that, we're out of time.
Thanks, Jason. It was a pleasure.
If you've ever done something big. I am a large and mid-biotech analyst at the bank. It's my pleasure to have with me our next presenting company, Neurocrine. Sitting up here on stage are a couple familiar faces, Matt Abernethy, who is, of course, Chief Financial Officer, as well as Todd Schlichla. What's your job again, sir?
I'm the current vice president of investor relations.
Okay. Just wanted to clarify.
He did-
Yeah?
He did tell me his new title from you this morning, was his favorite person.
Oh. Yeah.
Can you confirm that?
Yes, that is true. I did say that. I did in fact say that. We'll put that on your card.
Thank you.
Maybe, Matt, for the few people who aren't as familiar with the company, can you just give us a quick overview of Neurocrine, and then we can go into some of the more recent updates that have been happening?
Sure. We are gonna be making forward-looking statements, as you can imagine, so check out the latest SEC filings. I'm sure you're excited about that update. I was reflecting coming out here, Suzanne, eight and a half years ago I joined Neurocrine. In our first conversation, I remember it 'cause you've got, you know, a good perspective on things. If I recall, the conversation was all around elagolix and a little bit around INGREZZA.
Yeah.
When you fast-forward, over the last eight and a half years now, we sit here in a tremendous position. For me personally, I feel like it's quite a fortunate position to be in as a company. There's really three attributes that every company is striving for, especially when you're in mid-cap. How do you get from mid-cap to higher mid-cap to large-cap? You're really looking at your commercial franchise first and foremost. Do you have durable revenue that's gonna continue to grow and deliver? We have INGREZZA. That was actually approved when we first talked.
I think in 2017. It's been on the market for quite some time now. It's for an involuntary movement disorder caused by prolonged exposure to antipsychotics. Unfortunately, they get these hand movements, face movements, trunk movements, and up until 2017, there were no available treatment options, as you know. We continue to surprise to the upside.
Very recently.
Yeah.
At last week.
Guidance this year is $2.7 billion-$2.8 billion. LOE is 2038. We still have a lot of opportunity left there. The second major product that we have is actually CRENESSITY, which was approved in December of 2024. That was for classic congenital adrenal hyperplasia. It was the first medicine in over 70 years approved for CAH patients. The launch has gone great so far and continues, like you said, surprise to the upside. I think it's a reflection of just the great unmet need in the marketplace as well as a drug that is working and working well. We have a little bit over 10% of patients on therapy within the first five quarters. Last in Q1, we had over $150 million in sales.
The third product, which is going to be new for Neurocrine, is called VYKAT XR. We have an announced acquisition of Soleno Therapeutics. I'm not going to be able to speak much about it today because it is in its under offer period. When you think about a medicine that was approved last April, it's a rare endocrine product similar to CRENESSITY, and they've had a great first four quarters of launch, $95 million of sales in Q1. When you aggregate all three of these products together, it's over $900 million sales in Q1 alone. The scale of the company is growing, and we would expect it to continue to grow over the future. On the pipeline side, we have close to 20 clinical stage pipeline programs at this point.
I know people always ask me to choose my favorite kid, and I typically do choose my favorite kid. The two lead programs are the phase III programs. One is, you know, osavampator, a major depressive disorder that reads out in 2027. Also dereclidine, which is a muscarinic agonist that's being studied in schizophrenia that will also read out in 2027 and 2028. Of those two, my favorite is osavampator, for a variety of reasons which we can get into if you'd like later. On the early stage, we actually just announced entering the clinic with 2118, our CRF2 agonist, and that's being studied in obesity. That data in healthy obese people will be read out in late 2027 as well.
And then the last piece, the third piece, so you got your commercial, you got your pipeline, and then last piece is financial. We've been able to drive significant top-line revenue. Profitability is flowing quite well right now. We had $200 million of non-GAAP net income in the quarter, and we would continue to expect that to grow, while at the same time prioritizing investment in R&D at a rate of 30%-35%. That's a mouthful for the company, but we have a lot going on, a lot to be proud of, and, you know, as you said, Q1 was quite good.
Okay. Nobody can see us 'cause we don't have video, but you've been smiling the whole time. I'm gonna take that as a sign that you're pleased with the way things are going so far this year. Let's just do one question on Soleno. I know you're limited on what you can say, but how does this sort of fit in, sort of with the other drug launches that you guys are doing? Obviously, you've demonstrated the ability to have outsized launches, and you're taking over someone else's launch here. What was it, I guess, that you thought would be particularly synergistic?
Well, these are both products between VYKAT XR and paltusotine are both rare endocrine products.
As we look in our portfolio and pipeline over the future, we would expect to have a full business around this segment. There's a lot of valuable synergies from the sales side, not necessarily focused on the cost side right now. To be able to go into these clinicians and be able to share about CRENESSITY and also then have another sales force being able to hear about VYKAT XR, it was something that, you know, was a great strategic fit for us. The team is quite motivated. They care a lot about the Prader-Willi syndrome patients, a lot of talented people. We're looking forward to getting this closed, and we'll be able to provide more color once we get that behind us.
It is gonna be a durable, a durable asset for us that goes into the 2040, from an IP perspective, and it's a great strategic step.
It's not because Eric doesn't have enough to do.
Eric is very good at developing markets in rare disease.
He would say that the number one most difficult market he's ever seen or underdeveloped market is actually tardive dyskinesia. 'cause when you think about nobody being diagnosed in that marketplace, it's something that, you know, has taken a lot of effort to get from diagnosis all the way to a prescription being written. The good thing about the Prader-Willi syndrome is that there's a specific ICD code that allows you to know who the patients are, where they're at.
That differs from paltusotine in that there isn't a specific classic CAH code. I think there's some good things that come from a medicine like this for Vykat. Both Vykat, PD, and paltusotine, there was no approved other medications for these patients prior to the launch of these three medicines. It's gonna be quite special on our hands.
Okay, great. On the topic of INGREZZA, what quarter of the launch is it now?
We're 9 years in.
Nine years in.
Nine years in.
At 9 years in, you still manage to beat expectations on 1 key sale. Can you talk to us about where you think the, you know, unmet demand is and how we should generally think about what to expect on uptakes, not just for the rest of the year, but for the next couple years?
Yeah. I would just give another kudos to our sales team and our medical team, to be able to get record numbers of new patients in the first quarter when the first quarter is typically challenged with seasonality.
Yeah
is a testament to the work that they did, but it's also a reflection of how many people with tardive dyskinesia continue to need help. It's debilitating to take an antipsychotic for your mental health, get your mental health in check, and then ultimately develop a movement. That movement, even if you remove the antipsychotic, it still stays there. The big basic blocking and tackling that we have underway, it's gonna sound boring, because it's the exact same things we've been doing for quite some period of time. It's really ensuring the HCP is aware and thinking about tardive dyskinesia. These prescribers are primarily psychiatrists, they're thinking about the underlying mental health condition of the patient, not necessarily thinking about tardive dyskinesia.
We see the more the call frequency is or the higher the call frequency, the more likely a clinician is to see the TD and to prescribe Ingrezza, and that's what we're seeing so far. That's like one basic blocking and tackling item. The second is the direct-to-consumer advertising in that we know patients have these movements. They may not know what they're from. They're definitely not thinking about talking to their psychiatrist about a movement disorder. That'd be like asking a dentist to look at your ankle, right? It just doesn't happen. We have direct-to-consumer advertising campaigns that are putting a name to this movement and encouraging them to talk to their doctor about whether Ingrezza could help them. A lot of room left to go. Around 50% of the market has been diagnosed at this point.
Only 1 in 10 patients with tardive dyskinesia are currently on a VMAT2 inhibitor, so still a lot of room for growth ahead.
There was a lot of discussion towards the second half of last year on a couple of items. First, you know, the competitor gaining share, and then secondly, what type of negotiation you'd have to make with payers in order to have coverage. When do we start to hear, I guess, on the second point about how your discussions for 2027 are going?
Yeah. Once we get closer to 2027, we of course expect our product to be have strong access still.
It's a great product and a great market. From a pricing perspective, we're competitively priced relative to AUSTEDO XR. You know, I would expect access to be strong. The specifics around it, we'll be able to give more color as we get later in the year. To the previous question about Teva or AUSTEDO XR gaining share, if you rewind back to 2024, we hit a period in the second half of that year where new patient additions were slowing. At that point, Teva were accelerating, not just in prescriptions, but also in revenue dollars because of their titration schedule. Last year, we also had a sales force expansion. We had record numbers of new patients in Q2, Q3, flattish in Q4.
Through that period of time, we actually gained two share points back. We feel quite good on a NRx, on a market basis, but we're in a sort of gain share mode right now.
That's quite attractive. When you think about how is the market doing right now, because their results are a little bit difficult to interpret, because of their inventory fluctuations and also their pricing schema. I think we would both agree that the market right now from a TRx perspective is growing in the low to mid teens, and that's quite strong nine years in, so on.
I had brought up the question about 2027 because last year you said that you had started negotiations a little bit earlier.
Yeah
than you normally would for 2026. I think people remember that, and they'll be thinking about when you start talking about it only because people wanna know about pricing.
Yeah. I think there was an element of that we brought it up because the plans were asking for us to have an incremental discount in the current year that we were in-
Yeah
which was unusual. The trade-off was worth it to go from 45% covered Medicare Part D lives to 70% and just seeing that flow through with the new patient starts. We would not expect to add any other lives on.
In terms of our coverage status for 2026. We like where we're at. We're around 70%, and we'd expect similar levels as we look ahead.
Okay. Maybe let's move on to paltusotine. That's also had an outsized launch. Can you just talk about the dynamics there? Obviously, a much newer launch than Ingrezza. It's also a more, I guess, technically smaller opportunity for a disease. What are the differences in how the commercial team is looking into gaining share there versus what needed to be done for Ingrezza?
Yeah. There's really three things that it takes to be, have a successful drug launch. One is there has to be a high unmet need.
The second is the drug actually has to work. The third, there has to be a level of tolerability that allows them to stay on therapy, and we're checking the box on all three. There's never been an improved medicine outside of high dose hydrocortisone for these patients with classic CAH until paltusotine was approved. I think what we can see, both in our clinical data as well as our open label extension, data that we continue to put out, the benefit is significant to these patients. The second piece is I think anecdotally we hear feedback that the medicine is working at least as good as what was in the clinical trials, if not, if not better.
My anecdotal experience with my own son, on paltusotine is it's much better than what was shown in the clinical trials. It's been quite a benefit for him and my family. The third piece is that the tolerability side of the equation. It seems as if patients are staying on therapy. Right now, from a persistency and compliance perspective, it mirrors or looks very similar to what we saw in the open label extension study, which is, you know, over 80%.
We had done a survey before the quarter, and it indicated everything that you just mentioned. You had indicated, you've now moved away from providing, let's say, script numbers. Intra-quarter, how reliable, though, do you think it is to be looking at the vendors that provide scripts?
Well, first of all, I would caution.
When you have very low numbers, it can be skewed a lot. I think many weeks where I would see those numbers being quoted externally, it wouldn't align with what we were seeing internally. I don't know much about the data sources. I also had people talking about patients not being reauthorized on therapy and getting insurance claim data. We've not seen anything like that. I would caution you on over-reliance on some of the third-party data. Maybe at some point it will get more accurate, but right now it just wouldn't be something that I would recommend.
Now, as it relates to Q1 performance, you know, last year as we went from Q2 to Q3 to Q4, you had this steady step-down of number of enrolments, which were quite significant, but they were a trend down from 600 to 500 to 400. I think there is the concern that we've tapped out the market. You know, everybody who wanted it at the KOL, you know, got it, and now it's gonna be quite low. What we saw from Q4 to Q1 is very consistent enrollment forms from what we saw in Q4.
You know, I think as those new patients continue to roll on medicine, and by and large, many of the patients are staying on therapy, there's a compounding benefit that, you know, we would expect to continue.
Just as a reminder, there isn't the same seasonality for CRENESSITY as there is for INGREZZA, right? For 1 Q?
That's right. There is on the gross-to-net side an element where the commercial patients have their co-pays reset, and then we cover that. In terms of reauthorization, because 70% of these patients are commercial, they go through their reauthorization that's more mirrored to how long their plan had approved them to be able to continue to get CRENESSITY. Typically, we see it as a 6-month initial cycle and then it's a 12-month approval thereafter. We've not seen anything that would lend itself to thinking that reimbursement would become more challenging. That's been one of the upsides in the early stages of launch, is that we've had over 80% of our PRXs are actually reimbursed PRXs.
It's a testament to, you know, our specialty pharmacy partner. They do a great job with this. Then also our field payer team. I think there's also an awareness of the impact of CAH and high-dose steroids on patients that cause the plan to want to cover it.
What is consensus sales peak? You know? Okay.
It's growing every quarter.
Yeah.
It's probably now $1.3, $1.4.
Yeah
million zip code.
How does that kind of compare to the, to the market data research that you guys have done?
We've clearly said that this could be a blockbuster.
medicine. I think that, you know, it tees itself up given the price point. If you do get to the range of rare disease launches, if you look at what could peak penetration be for a medicine that's a chronic medicine that's treating more or less the symptoms or controlling the underlying disease itself, you see a range of 30%-50% overall adoption within the marketplace. I think if we ever get into that level of zip code of 30%-50%, I think that you can see your way to some fairly large numbers that you're referring to. And I think that it's really up to us and the clinician community to continue to help as many CAH patients as possible.
Well, you tack on that the patent goes into the 2040s as well.
You're looking at the commercial base of business that we have or will soon have is, this has got a durable commercial revenue stream.
Yeah. I think our first peak sales number for Ingrezza had been like $1 billion, and some people thought that was too high. It is a bit of a tradition that people up their numbers on-
INGREZZA's still trying to find its peak.
Yeah. On the point of, like, having a long runway, how do you see the competitive landscape evolving in the next several years?
Well, I do think going back to the runway piece, the path to peak is much quicker in a rare disease medicine like this as compared to we're still nine years in for Ingrezza. I think it's about a five-year period of time.
You think about the progress that we can make between the time we launch to that 5-year mark relative to competition, I think we're going to have a very dominant position in the marketplace. As we look at any competition's going to have to cross a very high bar to get patients to switch therapy, let alone disrupt the standard of care. We'll be, of course, keep an eye on competition, but when you have a medicine that's working, a medicine that's safe, and data that supports your claims that are going to be multiple years, multiple patient lives ahead of competition, we like that position.
Well, it's setting a high bar, not just for competition, but also for our own internally.
developed molecules that we're trying to take the next generation, like, 1435 is the name of the product.
Across efficacy, safety, and tolerability has given us something to gun for, but it's not gonna be easy to beat it.
Okay. Let's talk about, other aspects of the pipeline. 2027 is gonna be a big year for pipelines for Neurocrine.
It's gonna be the first of many data-rich years for the company, the way the pipeline is set up.
Yeah. Maybe, let's start with difelikefalin. How are you thinking about Well, remind us when that phase III is set.
This is the selective M4 agonist that differs from COBENFY, which Bristol has, which is a combination of a pan muscarinic agonist and a peripheral antagonist, and different than emraclidine, which is a positive allosteric modulator, and requires endogenous acetylcholine to work. This is a first-in-class, best-in-class approach. The phase III studies for schizophrenia are enrolling. I was just texting Samir, he's at a site visit, making sure that we're conducting well-run trials.
There's two main studies in schizophrenia. The first one is set out to read out in 2027, the second one in 2028. We also have a program in Bipolar Mania for the same drug in phase II.
The two phase III studies, the first one that's gonna read out next year, how much of a read-through would it be for the one in 2028?
For schizophrenia, the way the trials are typically designed, you need to win on one out of two. We'll see.
Okay.
Yeah. In psych, it's always difficult to predict the outcome and so that's why companies like ourselves, even if the regulatory guidance saying
Yeah
You only need one positive, which, you know, here I think combined with the phase II and all the safety data we have with difelikefalin, I think one would be sufficient. You would still, as a company, want to run two, because there are so many dynamics at play in terms of trial quality and clinical site quality. We'll see. We like the setup. We like what we think that the muscarinic can bring to the class of medicine for psychiatry and, you know, one that's safe, tolerable, easy to use. That's going to be one that we're going to look forward to launching.
One question about FDA interactions. It does look like there's gonna continue to be some staffing changes there. Does that impact any of the conversations that you're having?
I think, actually, the FDA has been, you know, quite positive and productive on all of our programs and even had some recent correspondence as of last week on our Friedreich's ataxia program that was quite positive. You know, I wouldn't foresee there to be much disruption, but, you know, of course, instability brings opportunity or moments of crisis. I think that's something that all of us in the industry are getting used to at this point. It's always disappointing to see change, but I think we're resilient and we'll be able to manage through it.
Okay. Let's maybe talk about osavampator since, Matt, you mentioned that's one of your favorites. Why are you excited about that one?
Well, first of all, I think the efficacy in phase II was significant. osavampator, for those who aren't familiar, it's an AMPA potentiator. It is a mechanism that many people have tried to explore in the past, but nobody has been able to drug it without causing some untoward side effects. Thankfully, our partner Takeda developed this medicine tremendously well, we're testing this in adjunctive therapy for major depressive disorder. This is a significant unmet need, needs new mechanism beyond D2, I think that this has an opportunity to do that. Number one, on the efficacy front, we had two doses. Both doses worked, 1 mg and 3 mg.
1 milligram worked a little bit better than the three. We, from a risk, reward perspective, chose the lower dose. We've taken that lower dose into. We have three active phase III trials. We have one randomized withdrawal study. We also have an open label extension study. A lot going on behind osavampator. Why am I excited beyond the efficacy? Financially, it gets you to a major market quickly. I think this major market, if you have a new mechanism and people are and it's safe, I think it's something that people will be trying quite quickly and with the goal of being second line.
Our team is up for the challenge to get this enrolled and to get quality data, we'll see where we take it from there. It could be quite transformative in a quick period of time for the company within our psych franchise. You have your rare endocrine franchise that we've talked about. We also have our INGREZZA psych franchise, that's how the company is developing right now.
You also have obesity.
Mm-hmm. Yeah.
Your focus on that seems to have evolved. I think initially you started talking about metabolic disorders and then it kind of went to obesity.
Yeah. We had a coming out party in December at R&D Day.
Yeah. It went to obesity adjacent, and now we're full on obesity. Why does it make sense? I guess similar questions to what we had been talking about with CRENESSITY. How do you see the competitive landscape evolving there? Because it does seem like there's gonna be a lot of options for folks.
Yeah, I think there's gonna be a lot of options in terms of mechanism, in terms of administration and in terms of, you know, the frequency of how often you take it. There's gonna be a lot of opportunities for others to play in this space. There is a new mechanism that we're, you know, exploring, CRF2 agonist. This is, you know, obviously using the heritage that we have on the CRF pathway, from when we were, when we were, I guess, born by Kevin Gorman. We were talking about Kevin earlier today. I do think that this is a natural evolution to be able to look at the other side of CRF. We also hired an expert team.
Jude Onyia, our Chief Scientific Officer, led large molecules at at Lilly, and we also have a handful of others who are experts in some of the other obesity assets. I think that it makes sense because of our core capability, also the market. There are pockets of need, and this is likely something that will be combined with our own proprietary triple G over time that will give it even more potency. Our view is, let's explore it.
Financially, it's not a big investment, to get to phase I data. Actually, in phase I data, it can inform what your phase II or phase III data might end up looking like, as compared to site is much more risky.
Right.
You really don't know until you get through phase III. Obesity, you can get a quick read within your phase I trials for a little amount of money. You can figure out strategically where you take it from there. I'm proud of the team and what they've been able to develop. I'm still personally getting up to speed on the obesity space because it's so much going on.
It could be a full-time job.
Yeah
to keep up on everything. We do like the exploration of this pathway, and I personally like to know we're gonna have data next year that will tell us if there's a there there.
Okay. The last question, I think people were waiting for years and years for you guys to decide what you were gonna buy. Now you've bought Soleno or buying Soleno. What is your thought about business development in the nearer term now that this is gonna be integrated?
Well, this is one that we can handle financially with our cash on hand and is also EBITDA accretive immediately and non-GAAP EPS accretive immediately. From a financial position, you could practically still do some M&A, but for us, our focus is gonna be on integrating.
Yeah
integrating it very well, reestablishing our cash, position. If the right acquisition is out there, we'll of course, look carefully at it. When you think about INGREZZA, paltusotine, VYKAT, osavampator, dereclidine, obesity, we have a lot on our plate right now.
Yeah
It's not a necessity that we do anything. I personally so thankful we were able to come to agreement with Soleno. Provides a great foundation combined with INGREZZA and CRENESSITY for us to grow off of for many years ahead.
Okay. With that, we're out of time. Thanks, guys.
Thank you.
From San Diego, and thanks everybody for joining.
Thank you.