Good afternoon, everyone. I hope everyone's doing well. Great to see the packed rooms. Great to see the attendances this year. My name's Akash Tewari. I'm a pharma and biotech analyst here at Jefferies. I have Brett from Ionis. Brett, why don't I hand it over to you for some brief introductory remarks, and then we'll get started with questions.
Sure. Happy to, Akash. Good afternoon, everybody. Thanks for the invitation, Akash, to be here. It's really a pleasure. We're really excited about the progress we're making at Ionis today. We've had a great deal of success over the last two to three years from our pipeline and some of the launches that we initiated recently, and this momentum we feel is just going to continue in many important ways. We're on the cusp of a real change for the company. Four or five years ago, we set out on a vision to deliver new medicines, innovative medicines that we conceived, discovered, and developed directly to patients ourselves. What I'm saying is to become a fully integrated biotech company and to commercialize drugs for our own.
And of course, by doing that, not only do we control our future by controlling the drugs that we bring forward through to deliver to the market, but that also, of course, brings great value to the company, brings great value to shareholders, and brings much greater value to all stakeholders. We're on the cusp of doing that. Our upcoming first independent commercial launch is just a few weeks away. And then we're looking at a steady cadence of new Ionis-controlled launches for the next several years. Four launches in the next three years are anticipated with more to come. And we can jump into any one of those launches or phase 3 readouts that are coming, Akash.
Actually, Brett, I'm going to start with another angle. So I think it's interesting. Obviously, with the RFK announcement, everyone is sitting here worrying about what's happening from a regulatory perspective. When I look at Ionis, and I particularly look at rare diseases, I'm going to be co-hosting a panel with Peter Marks tomorrow. We talk about the potential negatives. I don't think enough people are talking about the potential positives about accelerated approvals for rare diseases. And you guys are a leader in that field right now. So I'd love to get your take. You've operated in different administrations, but where's the puck headed in terms of accelerated approvals with rare diseases, and where could there be potential upside with your portfolio?
Yeah. So a change in administration is obviously coming in the U.S. and potentially a change in healthcare leadership as well. It's a rapidly evolving process. Obviously, we're going to need to understand what the policies are going to be, what the priorities are going to be with the new administration. But we're not terribly worried about any changes to healthcare control or regulations in the U.S. that are coming. And it's mainly because of the fact that at Ionis, we are 100% laser-focused on delivering innovative, first-in-class molecules, medicines for diseases where there's a severe unmet medical need. Not me-too drugs in which we're just trying to provide incremental benefit to patients and drive high costs. We are delivering innovative medicines for both rare and broad disease indications.
That's reflected by the fact that we've had a lot of success with accelerated approvals too in our history, including the accelerated approval, for example, of Qalsody for SOD1 ALS. We have very strong relationships with the FDA because of the types of drugs we're bringing forward, and we expect that to continue regardless of changes in administration.
Understood. And I feel like that's a good bridge. We initiated on your company earlier this year. And I feel like when we were looking at Ionis, obviously a lot of work on ATTR, because that's what everyone was talking about. I think we completely missed the ball on Angelman’s. And that went from a program that I think a lot of investors weren't paying attention to to now. It's probably one of the most important products in your portfolio. Can you talk about the study design that you recently announced and really the endpoint selection you chose? Because to me, it seemed like the inclusion of expressive communication was not something that the FDA was requiring you to do. It was something that you chose. You made a very conscious decision to make that as a part of your primary endpoint.
Can you talk about that?
Yeah, that's true. So let me just level set for a second, Akash, and make sure everyone appreciates this. At Ionis, we have pioneered and led the way in the development and the validation of a new platform for CNS diseases, right? Oligonucleotide therapeutics, whether it be antisense oligonucleotides or siRNAs that are delivered to the CNS for devastating neurological diseases. Examples of that are Spinraza, the first ever approved treatment for spinal muscular atrophy. The second is Qalsody, the first ever approved medicine for a genetic cause of ALS. Both of these drugs are now on the market. We have 11 drugs for CNS diseases in development today for both broad indications like Alzheimer's and rare indications like Angelman syndrome. Our Angelman syndrome is a wholly owned program for Ionis, and it's probably our most important CNS wholly owned program today.
Angelman syndrome is a neurodevelopmental disease that afflicts about 100,000 people in major markets today in which there are no effective treatments. It's a devastating disease. People with Angelman syndrome live pretty much normal lifespans. However, they develop an intellectual capability of about a two to four-year-old. They never go beyond that. And obviously, living a normal lifespan with that level of intellectual capability provides an enormous burden on the healthcare industry, let alone families. We were the first to come up with an innovative strategy to treat Angelman syndrome by targeting the root cause of the disease. That is to replace a protein that is lacking due to the genetic defect in the UBE3A gene. The mechanism is novel and is set up to really deliver a potential breakthrough treatment for this disease.
We shared data at the Angelman Foundation meeting in mid-year this year showing that we were able to improve all aspects that we measured of this disease. That includes communication. These individuals cannot communicate effectively. That includes cognition. That includes motor function. That includes seizures, sleep patterns, quality of life. That caused us to make the decision that this program needs to go to Phase 3 development to prove and to get this drug to the market. We decided that our primary endpoint should be expressive communication. And we did that for two main reasons. The first is that although we showed very meaningful benefit in all aspects of the disease that we measured, the greatest magnitude of benefit was in expressive communication, the ability of the individual to communicate with a caregiver or a family member more effectively. The greatest impact was there.
That was true in children as well as adults with neurodevelopmental disease. The second and equally important is that this is a very tight community, a very well-established community that takes care of the people living with Angelman syndrome. And they have said, they have shown, and they have published that the most demanding, the most challenging aspect of this disease is the lack of their family member to not be able to communicate, to not be able to expressively communicate and say what's bothering them, if something's helping them, what's working for them. It also has benefit on intellectual improvements and those sorts of things. Based on that, we went to the FDA with a primary endpoint of expressive communication as our primary endpoint in this study.
This is a study in which we're going to be examining two dose levels, not only in children, but also in adults, so a very broad patient population, two doses that we showed that were effective in our Phase 2 study. We're going to be using a placebo control in our study. It'll be a gold standard for a Phase 3 clinical trial, placebo-controlled trial. We have an excellent relationship with the neurology division with the FDA. We're very proud of that. We delivered Spinraza, Qalsody, Wainua for polyneuropathy, TTR polyneuropathy. We're pleased that the FDA agreed with all of our recommendations, including the placebo control group, primary endpoint trial design, and so forth. We're looking forward to getting the phase three study started in the first half of next year.
Understood. I wanted to dig into that a little more. One part about, I think, expressive communication is really how do you control placebo response? Why is expressive communication maybe a better endpoint when we're thinking about placebo, especially as we get to further time points?
Yeah. I mean, we chose expressive communication for the reasons that I just laid out primarily, but also, expressive communication is also considered one of the most objective, not subject to placebo effects or noise, if you will, in the readouts. The assessments are done using an instrument called Bayley-4, which is considered to be the best approach for measuring improvements in neurodevelopmental diseases like Angelman syndrome, and expressive communication is considered to be the most objective response, limiting any potential contribution of a placebo effect. The conduct of the measurement is done by a trained independent neurologist that has nothing to do with the trial execution, so all that taken together, we think that minimizes any impact of a placebo effect.
Understood. Now, biologically, I think the question that my team and I are trying to understand is just on EEG assessments, right? We've seen, whether it's the Roche data, your program, what I think the one question I get from investors is, like, Akash, why isn't there more of a durable signal shown on EEG? How does your team think about the durability of EEG signals, why there might not be that right now, and why you still feel confident on developing your program?
What matters most, of course, are the clinical endpoints. I'll come to EEG in a second, but our clinical endpoints are durable. The improvements that we're seeing in communication, motor function, cognition are durable, long beyond that of EEG. EEG in Angelman syndrome has been shown to be abnormal, right? We have these wide delta and theta waves that are associated with Angelman syndrome. And that's been studied by several different investigators. And attempts have been made to correlate aberrant EEG patterns with the progression of the disease. With that said, there's very little that's understood about whether EEG is a predictor of disease progression and how sustainable that is, how meaningful that is. It's really an exploratory biomarker, if you will, and really very little is known about it.
What is known about it is that the aberrant EEG patterns are much more persistent and much more dramatic in children than it is in adults with Angelman syndrome. But beyond that, it's really a poorly understood biomarker. What matters most, of course, in durability is continuous benefit clinically, which is what we're seeing.
Understood. Maybe moving on to your polyneuropathy launch, and I think everyone's so focused on ATTR because you have Alnylam, you have Pfizer, but I feel like your polyneuropathy launch is a really important proof of concept about outpatient administration and really the patient convenience angle playing out. Talk to me about what you've seen from a new patient start perspective. Obviously, you're competing with Alnylam in that population, but you've been coming from behind there and with AstraZeneca's help, so what are the advantages you're seeing in the real-world setting about outpatient administration, and how have new patient starts trended as we get into 2025?
Yeah. The medicine here is called Wainua. Wainua is being developed for two indications, both related to TTR amyloidosis. One is a rare indication called ATTR polyneuropathy. It's a hereditary genetic form of TTR amyloidosis, and then there's the much broader population, TTR cardiomyopathy, hundreds of thousands of people with TTR cardiomyopathy. The Wainua, our phase 3 data was extremely strong. We have a great molecule, a great drug. It was approved in December of last year for TTR polyneuropathy, and we launched it in our first ever co-branded co-commercialization partnership in our history. It's with AstraZeneca, and we launched in February of this year, so a partial year, just through the third quarter of this year, we reported sales. The launch is off to an outstanding start. We couldn't have been more pleased with the launch of Wainua and TTR polyneuropathy.
What is resonating with people, patients that have this disease, as well as healthcare providers, is the fact that, first of all, the efficacy is remarkable. We're seeing reversal of disease, so improvements, not just halting of disease in many cases. We're seeing excellent tolerability. And what's really also resonating is the fact that a patient does not have to schedule an appointment and have a healthcare provider administer the drug through a subcutaneous injection. Our drug is the only silencer for TTR polyneuropathy, the only medicine for TTR polyneuropathy that a patient can self-administer conveniently at home by themselves once per month. That is really resonating with patients because they don't want the inconvenience of scheduling an appointment with a healthcare provider, having to go to a clinic and have that administered. It's very comforting for the families and patients. And that has really resonated well.
We're seeing there's about 50,000 people in major markets with TTR polyneuropathy today. More than 80% of those patients today are not on treatment. They either have not been identified and diagnosed properly, or they're not on treatment for whatever reason. Therefore, we in AstraZeneca have been focused on identifying those patients because that's where the biggest unmet need is, is patients new to treatment. We're thrilled that the majority of our patients are new to treatment, and we're getting those patients on, and they're staying on, and they're very pleased with the performance of Wainua. We're also pleased by seeing switches from other medicines that are on the market today for TTR polyneuropathy, and the reasons why we're seeing patients switch and stay on Wainua are for the reasons I said. The efficacy has been very strong and consistent, and also the convenience of self-administration.
Understood. Now, maybe going into ATTR, and I think a lot of us on the kind of investor side are. The HELIOS-B data came out. Your team takes, you and AstraZeneca, you guys take your time. You are processing the data. You have talked about, hey, there will be potential modifications to our current phase 3 design. I think there are a couple of points that I think are important. Number one, okay, your current endpoint is out to 33 months. But you have talked about the ability to include open label extension data at a longer time point as a part of the FDA label. And you have pointed to the fact that Alnylam has done that. When you look at the HELIOS-B data and the extension, right, it certainly seemed important for them to go out to 40 months.
Is that a reasonable assumption for us right now that we should expect an open label extension from 33 to 40 months with the Ionis AstraZeneca program? Yes or no?
Before I go to yes or no, let me just remind everybody. What we're conducting in the Cardio-TRansform study is the largest study by far ever conducted in TTR cardiomyopathy. This is an enormous unmet need, very large market opportunity, up to 500,000 plus patients with TTR cardiomyopathy. The only treatment that's approved today is tafamidis which is a stabilizer. So it's not a silencer. It's a very helpful drug, of course, for patients with TTR cardiomyopathy, but these patients continue to progress. There's a need for more effective treatments available. The results for the first silencer that came out earlier this year lend great confidence that we're going to have a highly successful outcome. Our study is more than double the size of that study. So we are very well powered with a very good drug for this indication.
That alone, we believe, is not only going to ensure for a highly successful positive primary endpoint outcome, but also subgroups, right? It's going to help us have the richest data set in combination with tafamidis, monotherapy, imaging studies that we're doing, a whole host of subgroups that just the sheer size and the powering of our study is going to help us achieve. Our study is well powered, based sheerly on size and the effect size that we predict for our drug. Our study is 33 months long, so it's a very long study. We are not going to extend the study beyond that because we have so many patients in the open label extension today, so it just wouldn't make sense to do that.
Whether or not we choose to increase the length of the assessment somewhat into the open label extension is a decision that has not yet been made. It's a conversation we continue to have with our partner, AstraZeneca. When should we make that decision? Our data isn't due till the second half of 2026, so we have time to make that assessment. We continue to monitor the events in the study. The events are accumulating on track. So we like what we're seeing. We'll make that decision, and we'll make that announcement in due course. But today is not. We're not ready to do that yet.
Always worth trying. Maybe the other two points on Transform. A, it does seem like all-cause versus cardiac mortality. There might be reasons to think that all-cause might be a better endpoint. I'd love to get your thoughts on that. And then number two, this is something that we've been fiddling around with: background SGLT2 use, right? Because SGLT2 use is obviously starting to accelerate. I actually think it's shocking how little it's used just generally in cardiovascular health. But from the Alnylam study to the Novo study, we're starting to see the rates go from kind of the 20%-30% to even 40% or more. I'd think that for your trial, you may also have pretty substantial uses of SGLT2. How does that kind of affect your event rate assumptions, given your trial is going to be reading out in 2026?
What matters most is collecting the accumulating events that our powering assumptions were based on when we designed the trial. Yeah, of course, we're going to have drop-ins using SGLT2 inhibitors in our study. The drop-in rate is probably going to be similar to what we just saw in the Helios- B results that came out. We're not alarmed by it. We're seeing the accumulation of events on track to what we had powered the study based on. We don't think it's going to have a significant impact on the study. We're monitoring it.
Understood. And just on all-cause and cardio?
Oh, yeah. You can make a case for all-cause. You can make a case for CV mortality as the primary endpoint. Again, just like what I said earlier about the open label extension, we have time to make a decision within our statistical analysis plan. If we think all-cause is the way to go versus CV mortality, we can make that adjustment. And it's pretty easy to do that. Right now, our primary endpoint is based on CV mortality and CV hospitalizations. You can make a case that CV mortality is a pure measure of CV mortality in a cardiomyopathy indication. You could also make the case that you may miss some CV-related mortalities if a physician ascribes a death due to pulmonary dysfunction, pulmonary failure, which is related to the heart function. So you might lose those events. We're looking at all that very carefully.
We could also look at causes of events as the study progresses, and we have time to make the right choice to do what's right for Wainua when we read this study out, but it's an ongoing discussion with Ionis and AstraZeneca.
Understood. I actually wanted to hit on that. I feel like a lot of times we just think, oh, it's Ionis's program versus Alnylam's program. But in reality, there are structural advantages that you have with partnering with AstraZeneca, A, from a commercial side, but B, and you and I have talked about this, the depleter program that they've started to show data on. I thought it was quite interesting. You're seeing a pretty remarkable drop. I mean, it's one of the first programs where you're actually removing the plaque. And you're seeing a very quick proBNP signal. I mean, something I don't think I've seen before. I can't help but think if there's any shot to kick Tafamidis off standard of care, it would be a combination of a depleter and a silencer program.
And I would almost think it would make sense because you would treat patients. You would have that initial depletion, and then you get patients on a silencer long-term. And that might be the best clinical profile from a safety and efficacy perspective. Talk to me about how your team looked at that data. And could we see a potential combination strategy between you and AstraZeneca with a depleter and a silencer?
Yeah. The mechanisms are so complementary. It makes complete sense. As you said, gosh, Wainua is blocking the production of the toxic TTR protein. A depleter, of course, when you diagnose a patient and you put them on a treatment, they already have amyloid in their heart and in other tissues. So to clear the amyloid more quickly, you would come in with a depleter that basically clears out the amyloid from the heart, but it's not affecting the production of the toxic TTR protein. So you can see why a combination makes complete sense to do such a thing. We have a long-standing partnership, wonderfully successful partnership with AstraZeneca that goes back 10 years for this program and other programs as well. They have moved. We are not part of the depleter program. That's an AstraZeneca, Alexion program. We're responsible for Wainua. But it makes sense.
Both teams have had preliminary conversations on when or what would make sense to do a combination approach in the future and how would you develop a drug such as that. But beyond that, I just can't get ahead of our partner on that. But it certainly is in the conversation. And theoretically, it makes great sense.
Understood. Now, maybe just going on to olezarsen. Again, I feel like it's important to talk about structural advantages that you kind of have in this space. You're going to have your FCS approval and then hopefully SHTG after that. You have competitors in this space that I think have a competitive profile with what you've shown. But I think the question is, what are the structural advantages for being able to come out in FCS first and then SHTG a few years after that from a prescriber-based perspective and then also from a marketing perspective that maybe investors aren't appreciating right now?
FCS, we're developing olezarsen for diseases related to severely elevated triglycerides. And the biggest concern for patients with severely elevated triglycerides is not just the abnormalities they have in cognitive function and body pain and those sorts of things. It's risk of a potentially fatal acute pancreatitis event. We're developing olezarsen for a rare genetic disease called FCS and a much larger blockbuster opportunity, millions of people with severe hypertriglyceridemia, SHTG. FCS is a genetic disease, probably 2,000-3,000 people in the U.S. And we're going to be first to market. We're under review right now in the latest stages with a PDUFA date of December 19th. So we're looking forward in the next few weeks to get another approval, FCS for olezarsen, and then to launch later this year.
Our SHTG phase three study is due to read out in the second half of next year and will submit for approval next year, assuming it's positive. Our phase three data in FCS was remarkably strong, very strong data in triglyceride lowering, very strong data on acute pancreatitis reduction, and we expect that to translate, so it's very de-risking for SHTG, and we expect a very strong label in FCS, and we expect to be first to market by at least a year over a competitor and first to market in SHTG by several years because of the timing of our phase three readout and our submission and our anticipated approval. It's a blockbuster opportunity. It's wholly owned by Ionis, and it represents our first independent commercial launch in our history.
Understood. With that, because I know I'm over time, I will stop. Thanks so much, everyone. I really appreciate it.