All right, good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the Biotech Analysts here, and it's my pleasure to introduce Brett Monia, CEO for Ionis Pharmaceuticals. Just as a reminder, the format for today is a fireside chat. So if anyone has any questions, please feel free to raise your hand, and we'll address your question. But before we get started, I just need to read a quick disclaimer. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." With that, Brett, thanks for joining us today, and maybe to start, I'll just hand it over to you for some introductory comments, and then we can hop into the Q&A.
Thanks, Mike. It's really a pleasure to be here and to discuss the great progress we're making at Ionis. And we've had a lot of success over the last couple of years in working towards achieving our vision to become a leading, fully integrated biotech company and solidifying our leadership position in RNA-targeted therapeutics. You know, over the last less than two years, we've had two very important drug approvals that are now launched. The approval of Wainua in hATTR polyneuropathy in December of last year. It was launched in January, and we're really pleased with the uptake for. That's occurring in the launch. There's a lot of enthusiasm for this drug, and it really sets us up for a highly successful outcome in the much more prevalent TTR cardiomyopathy space.
Mid-year last year, we also had the approval of QALSODY for SOD1-ALS, the first-ever treatment for a genetic cause of ALS, and really the only disease-modifying treatment for any cause of ALS, solidifying our leadership in CNS drug discovery and in drug development. This year, we also reported more positive data, positive phase III data, olezarsen in FCS at the ACC. We're prepared to launch, assuming approval in December, and that represents our first independent commercial launch as we move to full integration for Ionis. And we've also reported very positive phase III data for donidalorsen in hereditary angioedema, and the NDA is now submitted, and we're looking forward to a potential approval around this time next year.
The phase III pipeline is second to none in biotech, with nine drugs in phase III development, all firing on all cylinders. We're looking forward to expanding the phase III pipeline early next year when we advance our wholly-owned Angelman syndrome program into phase III development as early as possible next year, but certainly in the first half of next year. The commercial organization for our independent launches is in place. We're ready to launch. Everything's in exactly where it should be, and we're making tremendous progress in really advancing our technology base, expanding and diversifying our technology, you know, to really advance new chemistries for CNS diseases, cardiovascular diseases, and more, and I'm happy to talk about that.
We're really excited about where we are and the successes we've had of late, and we're very much looking forward to the near term as well as the long-term future.
Yeah. Great, thanks for that introduction. And, maybe we can start with Wainua, as you mentioned, you know, recently launched with your partner, AstraZeneca. Maybe you can just talk about, you know, your responsibilities in the launch and maybe expand a little bit on some of those early, favorable launch trends.
Yeah. So, just to level set, as a reminder, Wainua represents our first step to commercialization for Ionis. You know, we've always been known to be, you know, for excellence in research and development, and we're now building and gonna match that excellence in commercialization. The first step was to do our first-ever co-commercialization partnership in our history. And that's with AstraZeneca, for Wainua, for TTR amyloidosis. The co-commercialization is off to a great start. The roles and responsibilities between Ionis and AstraZeneca have evolved over time as designed. You know, we're running the phase III programs.
We ran the polyneuropathy phase III study, NEURO-TTRansform, and we delivered, and we actually were responsible for the regulatory and get the drug approved in the United States. We're running the CARDIO-TTRansform study as well, so that's a lot of responsibility. We've since passed over the regulatory responsibilities to AstraZeneca to handle ex US approvals for neuropathy and then ultimately cardiomyopathy. Medical affairs, we started. We took the lead in medical affairs. We've since shifted that over to AstraZeneca. And on the commercial side, we're responsible for patient engagement responsibilities. We're the face to the patient community. AstraZeneca is responsible for the sales team in the field, and of course, that's in the United States. Outside the United States, AstraZeneca is responsible for all commercial activities.
We're focused on the US market right now. The Wainua launch is off to a fabulous start. We couldn't be more pleased. The launch is hitting or exceeding all of our. When I say our, Ionis AstraZeneca, all of our preset KPIs, our performance metrics that we set out in advance. The receptivity, the enthusiasm for Wainua has been very strong. We're seeing a real strong liking for the data, of course, the efficacy, but also the ability of patients to self-administer.
Mm-hmm.
That's going very well. We like the mix of prescribers, neurologists, cardiologists, gastroenterologists, and more. And our strategy to focus on newly diagnosed patients versus really focusing on switches is paying off really well.
Yep.
You know, more than 80% of patients today with TTR polyneuropathy are not on treatment, so it makes sense to focus on newly diagnosed patients. And, you know, the team of, you know, Ionis' expertise in our platform and TTR amyloidosis, coupled with AstraZeneca's commercial strength, their omnipresence around the globe is really paying off to find patients. So we're seeing, and in addition to newly diagnosed patients, we are seeing switches from other treatments and combinations, too.
Mm-hmm.
But mostly it's newly diagnosed patients, and that's exactly what we set out to do.
Yep. Great. And maybe just sticking with Wainua, you mentioned the ongoing CARDIO-TTRansform study in ATTR cardiomyopathy. Maybe you can just give us, you know, some update there on how that progress is going, and then, you know, any updated thoughts on potentially stopping that study early?
Certainly. The study's going very well. As you know, Mike, this is the largest study ever conducted in ATTR cardiomyopathy. It is the largest to account for the fact that the patient demographics has shifted from years ago, when patients were being diagnosed very late in their disease. Today, they're being diagnosed earlier in their disease because of better disease awareness and better methodologies to diagnose the disease. Therefore, you need to do bigger studies to have the best data sets. That's exactly where we are. We think the size of our study is very well designed to provide the most comprehensive, the richest data set in this patient population, and the study's going very well.
We're pleased with, you know, we fully enrolled the study earlier this year, and you know, the whole tracking of events and conduct, and safety, and tolerability, and adherence, compliance is going exceptionally well. So we're really looking forward to the readout. Our base case remains full completion of the study, which is through 140 weeks, which was the original. You know, which was our design.
And, we're continuing to assess the possibility of an early readout, but, you know, the new data that came out at ESC this weekend, we were all waiting to see, and certainly we're analyzing that data, we and AstraZeneca, very carefully, as well as our own data, from the ongoing CARDIO-TTRansform study. And we'll decide whether, at some point, whether it makes sense to read the study out early. But in no way do we want to compromise the, you know, the real big advantage we think we have with eplontersen, Wainua, in cardiomyopathy, in having the, potentially having the richest data set because of the size of the study.
So we're anxious to get to the market as fast as possible, but not at the cost of compromising our rich data set that we expect.
Yeah. Maybe can you talk a little bit about the process you're going through in order to make that decision? And, you know, how long could that take? And, you know, I guess, what- you know, if you disclose anything, you know, if no news means you continue to completion, or do you make some announcement that you won't start?
Yeah. You know, it, it's a very competitive space. You can't get into the details too much about what specific types of data we're looking at and how that's gonna factor into an early readout or not. We're looking at all the traditional endpoints that you would look at in a cardiomyopathy- cardiovascular outcome trial. You know, mortality events, in our own study, hospitalizations, nature of those events, and comparing them to competitors and how we fit. We're comparing demographics as well, and we like what we see, so far, and you know, if we, if we make a decision to read the study out early, we're certainly gonna get FDA input first before doing that, and then before we, we can make any, any announcements.
All I can say is we're working through it, night and day, with our partner, AstraZeneca, and we like how it's going.
Yeah. Makes sense. Maybe just based on some of the data you've seen so far, you know, internally for your program or even externally with the HELIOS-B data, just where do you think the silencers fit in relative to stabilizers? Are they frontline? Are they combo? Both? Any thoughts there?
We think all that. We were really pleased with the results that came out this past weekend. It was a real positive readthrough for the silencer class, the first readout for the silencers class, and TTR cardiomyopathy is a highly prevalent disease indication. You know, we also believe that because of the design of our trial, we're in a position to have an even richer data set. You know, obviously, the study was very positive with respect to the primary outcome, the composite of all-cause mortality and hospital CV hospitalizations, and we're certainly very well powered there. We have the same, essentially the same primary endpoint. It's really the subgroups, the secondary endpoints, the exploratory endpoints.
Where we're looking to really take advantage of the size of our study to have the richest data set there. We think that that will position us to be a treatment of choice for all forms of TTR amyloidosis, based on the comprehensive nature of the data. We're really looking to your question, we believe that silencers will be the first choice for many patients with TTR cardiomyopathy. We believe that it'll also be the number one choice for patients that are progressing on current stabilizers, right?
Mm-hmm.
And all patients eventually progress, and they progress fairly rapidly within a few years, so basically that. And we also believe that if there's data to support the combination of a silencer with a stabilizer, there will also be a lot of use in combination, too, because patients are progressing.
Yes
And on stabilizers, and they're complementary mechanisms. It makes a lot of sense, and if you have the data, and we think we're gonna be in the best position to have you know, convincing data that combination provides added benefit. There'll certainly be that segment as well. You know, this is a dynamic market. Treatments today are not adequate, and cardiologists are gonna advocate for the very best medicines, whether it be a monotherapy, switches, or combinations, and we think that the silencer class will ultimately be the treatment of choice.
Yep, makes sense. And how do you view that market sort of changing when tafamidis potentially goes generic?
It'll be easier to do combination.
Yeah.
What I was referring to before, I was really talking about, you know, today's branded medicines, tafamidis, before it goes off patents. But certainly that will also provide a challenge, but with challenges that I think will be overcome in many cases. But certainly when tafamidis goes generic, that bar gets lowered, and it'll be much easier to, you know, to be able to prescribe and have payers pay for combination usage.
Yeah. Where do you think the bar is for combination use before it goes generic? Is it, you know, you need to show some statistical significance, or is, or strong trends enough, or just any thoughts there?
Yeah. I absolutely do not believe that we need statistical significance for combination usage, whether it be branded pricing or generic pricing for stabilizers. You know, if you have convincing data that combination usage is going to provide greater benefit, whether it be secondary endpoints or, you know, biomarkers or imaging studies. You know, we have a lot of imaging studies in process, which we're actually gonna be looking at amyloid burden by PET imaging or MRI, and scintigraphy, and so on. If you can show that you're clearing amyloid faster in combination usage, you know, physicians are smart people. They know that that's gonna result ultimately in better outcomes, whether or not you have.
Mm
Statistical significance or not, and they will advocate for combination usage, as they should, and payers will do what's right.
Makes sense. Maybe we can shift gears to olezarsen, FCS.
Mm-hmm.
You're currently under FDA review. You've got a PDUFA date coming up later this year. Maybe just.
Mm
You know, remind us, you know, what was so exciting about the data you showed and kind of where you are in preparing for, for the launch.
Yeah. We were thrilled with the data we presented at ACC. You know, to just level set, olezarsen is a wholly owned product that is in development for patients suffering with severely elevated triglycerides. And we're in development for olezarsen tackling a severe rare indication called FCS, familial chylomicronemia syndrome, and severe hypertriglyceridemia, SHTG. FCS is rare. SHTG is highly prevalent, millions of people suffering from this disease. And what they suffer most from, in addition to body aches and pains and brain cognitive disorders, and so forth, from these severely elevated triglycerides, their number one risk is severe acute pancreatitis, which can be fatal, and if it's not fatal, it almost always lands an individual in an ICU for up to a week or so.
We were thrilled with our first phase III readout in FCS, which showed substantial reductions in triglycerides, and remarkably substantial reductions in acute pancreatitis. And in fact, we essentially eliminated pancreatitis events compared to placebo in the treatment group that's now under review by the FDA, the dose that's under review, which was never demonstrated before in history. It was always postulated that we can do that potentially, but to do that in such a small trial was remarkable. We also demonstrated greater than 80% reduction in hospitalizations in the treatment group versus placebo, and that was mostly not AP. That was actually patients just not feeling well. They're worried that they're about to have an AP attack.
Mm
They're having other problems, and they go to the hospital, and we reduced that almost 90%, greater than 80%. And overall, the safety profile was great. So, the drug, ol ezarsen, was accepted, rightly so, for priority review by the FDA, with a PDUFA date of December 19th. And it is, we're looking forward to the, you know, expected approval late this year. To your question, we are ready to launch. And this represents the first in our history, the first independent commercial launch for Ionis. The first of many, but still a real landmark achievement for the company. And we're very much looking forward to it.
How important is educating patients, you know, and identifying the patients, you know, since you'll kind of be the first to market here?
We have a long-standing presence in the field in the FCS community, dating back many years. We have first mover advantage in FCS. We have done a great job in working with centers of excellence that manage these patients and with the patient community. Our medical affairs team has been in the field for three years now, you know, building the momentum.
Mm-hmm.
Virtually all the patients in our phase III study have stayed on drug in the open-label extension. We've opened up an expanded access program. Finding patients will always be the greatest challenge for rare diseases. But I think we have a really good handle on this, you know, and that'll be the biggest challenge, but we think we're very well positioned. The other thing is, you know, the success we're having in FCS and the presence we're building for Ionis in this field is gonna set us up really well for SHTG.
Yeah.
You know, we fully enrolled that study earlier this year. This is a big study. Overall, more than 2,000 patients for this, because it is a highly prevalent disease. Two pivotal studies, core and core two, plus a safety study to round out the safety base that is necessary for approval. This, the drug, the program is going exceptionally well, and we are very much looking forward to the phase III data for that drug around this time next year, second half of next year. And that is only about 2 years behind the rare indication, FCS. So olezarsen is really a big and very important program.
Yeah. For the SHTG studies, can you talk about, you know, the potential of showing a benefit on pancreatitis and how important that is or isn't?
Yeah. So the US definition guidelines are SHTG is defined as triglycerides 500 and above. In Europe, it's 88 and above. The higher the triglycerides, the higher the risk of AP. The higher, the faster you know, the greater the rate of AP, the higher the triglycerides. FCS patients are in the several thousands always. So they have a very high rate of AP. SHTG patients, certainly many of them are in the multiple thousands, but they can be pushing a thousand, 88 above, so forth. So the rate is lower. However, our study is ten times the size of our FCS phase III trial, so we're accumulating AP events. And I can tell you that in a blinded manner, we're seeing a lot of AP events.
If the olezarsen FCS data is indicative of what to expect for SHTG, the vast majority of those AP events should be in the placebo, not achieving group. So, you know, you don't know until you know, but, we're pretty high. Our confidence is pretty high that we're gonna see a meaningful benefit in AP.
Makes sense. Then maybe just last question on olezarsen before we move on, is just, you know, competitive positioning. You could potentially have a competitor in the market maybe sometime next year or the year after. Just how's your, w hat's the differentiation?
We have not, we don't see anything on the competitive landscape that gives us pause.
Yeah.
Our efficacy is second to none, including AP, triglyceride lowering, the hospitalizations and FCS that I referred to earlier, and we have a very importantly strong presence in this community, as I mentioned already, and first mover advantage.
Yeah.
In FCS, anywhere from nine to 12 months, in SHTG, two to three years, to get to the market first. And really, there are no treatments for either of these. And there's nothing approved for FCS in the U.S. And for SHTG, these patients are treated with fibrates and fish oils, which have meaningless impact on triglycerides. So, I would say great overall profile, nobody has matched us, and we have first mover advantage.
Makes sense. Maybe we can shift gears to donidalorsen, HAE. You presented some promising data earlier this year. Maybe just highlight some of the key takeaways there.
Happy to. So we presented a comprehensive review, presentations at EAACI in Valencia, Spain, in July. And in that meeting, we presented three outcomes from three independent trials. The first was the phase III trial, which we showed substantial reductions in HAE attacks with two dosing regimens. Monthly dosing, as well as every two months dosing compared to placebo. Reductions in the mid-80% range or so with great tolerability and so forth. The second trial, it was really part of the first trial, but we call it OASIS-Plus, was the open label extension, in which patients were treated up to a year in totality, in which the reduction in HAE attacks got even better.
For both monthly and bimonthly, we got into the 90% plus range of HAE attack reductions, which are as good or better than anything that's out there today on a prophylactic landscape. Good safety, good tolerability, and good adherence. Essentially everyone was staying on drug. So it bodes very well for long-term safety and efficacy for donidalorsen. The third study was a study that we conceived that would be very important to get into the U.S. market successfully, and that study we referred to as the Switch Study. The U.S. market is. Most patients with HAE today in the U.S. market are on prophylactic treatment. So when we get to the market, we're gonna want to switch patients to donidalorsen.
We felt that it would be very important to understand patient preference, as well as how to safely switch patients from one treatment to another, and be able to instruct physicians to maybe even get that in our label, how to safely do that. The study was wildly successful. Not only were we able to enroll the study fairly quickly, demonstrating that patients are looking for better options, and they're willing to go into a study like this to try another treatment. Patients came in from prophylactic treatments across the board. Takhzyro, Orladeyo, Cinryze. We had good sampling of all of them. They stayed on treatment. We were able to achieve our goal of protecting against HAE attacks with no slippage, no gaps in protection.
When we read the study out, not only were we able to switch them safely over, we were actually able to reduce their HAE attack rates or HAE attack rate even greater than what they came in from their previous prophylactic treatment. By more than 60% further reduction in attacks for all the drugs that came in, that they came in from. In addition, patient readouts, patient surveys that were done independently resulted in greater than 80% of the patients strongly endorsing or strongly saying that they preferred donidalorsen versus their previous treatment. That was the dataset that we presented.
We published in The New England Journal that data, and you know, we think that positions us very well for the U.S. market, which is, like I said, a switch market. NDA has been submitted, and we're looking forward to, you know, the acceptance soon, and when we do, we'll make an announcement.
Should we be anticipating standard review or priority review there?
With other prophylactic treatments already on the market in the U.S., we would expect standard review.
Makes sense. A lot to talk about here. Maybe we can switch, you know, to another pipeline asset. You recently shared some Angelman data earlier this year and decided to move that forward. Maybe just, you know, touch on that.
Yeah. Our Angelman’s program is a very important program for Ionis. You know, we have a solid position as leaders in CNS drug development. Spinraza, Qalsody, I touched on before. So many drugs that, you know, 11 in clinical development, many of which have already shown clinical proof of concept. Angelman’s is a wholly owned program that is tackling a disease with an enormous unmet need. This is a neurodevelopmental disorder that, you know, afflicts approximately 100,000 patients or so in major geographies, and what we came forward with really the first concept of target tackling a mechanism to replace a protein that's missing in this disease. It's a genetic disease.
And what we reported at the ASF meeting, the Angelman's meeting in July, was data from an ongoing study in which we demonstrated that we were able to improve essentially every aspect of the disease that afflicts these individuals. We showed improvement in, t hese individuals have major defects in communication, cognition, motor function. And across the board, no matter how we measured it, whether it was you know, various different instruments to measure these aspects of the disease and all the subdomains, they were all favoring improvement, benefit to patients across the board with really, really excellent safety, tolerability, and adherence in the study. So we are moving to phase III development. This is wholly owned, as I mentioned.
We are looking to get end of phase II advice from the FDA on our phase III trial design very soon. Provide updates down the road on the ongoing long-term extension, and also to initiate phase III development in the first half of next year. We really, really have prior- this is a top priority for Ionis.
Maybe I'll just ask a broad question: anything else in the pipeline that, you know, you think you want to highlight?
Yeah, sure. Absolutely. I would start with pelacarsen. Pelacarsen is another first, you know, for Ionis like, first treatment potential first treatment for a highly a disease with a high unmet need that Ionis came first with. This is tackling a CV risk factor called lipoprotein(a). We all have Lp(a). It's an independent CV risk factor. If you have high levels of it, you're at high risk for cardiovascular disease. We developed pelacarsen. We conceived it and developed it, and we showed in phase II that we were able to normalize Lp(a) levels in patients. The study was about 300 patients, normalized almost 100% of those patients, get their Lp(a) levels down to normal levels. It's like taking LDL cholesterol down below 70.
It's the same thing, only it's a different risk factor with great safety and tolerability. Based on that, Novartis licensed the program and initiated a landmark study, another landmark study called HORIZON, which is more than 8,000 patients enrolled in a cardiovascular outcome trial. Has gone exceptionally well. Very, you know, great, obviously good safety along the way. And that data, that study is gonna read out in next year, in 2025. So, you know, next year, I mean, we had a lot of phase III success this year. We also had phase II success, Lp(a) driven, Pelacarsen for Lp(a) driven cardiovascular disease.
We also have another drug for a CNS neurodevelopmental disease called Alexander disease, which we're expecting to read out next year as well, and that's another wholly owned program. So, those are, you know, next year, this year's been a really, really great year for Ionis. Next year is shaping up to be even better.
Yep. Sounds good. Looks like we're just about out of time, so why don't we end it there? Thanks so much, Brett. Appreciate your time.
Thank you, Mike.