Great. I think we can get started. My name is Yanan Zhu. Thanks, everyone, for being here. We are lucky to have the Ionis Pharmaceuticals team here at our conference. And with me for this fireside chat is CEO Brett Monia. Thanks, Brett, for being here.
It's a pleasure to be here, Yanan. Thank you.
Great. So I think for people who are familiar with the Ionis story, you know, they appreciate the company is at a very important stage, today. You're looking to commercialize your first wholly owned product in just a few months, and next year, we'll be hearing about data from a couple of indications affecting millions of people. So those are all big events. I mean, at this juncture, could you talk about the setup of the Ionis story, and what's your vision, for the company in one to two years from now?
Happy to, Yanan. And thanks again for the opportunity to speak on behalf of Ionis and our team. So, you know, we've accomplished a great deal over the last couple of years, specifically, in achieving our vision to become a fully integrated, including a commercial organization of excellence that matches our history of excellence in R&D. And to be fully integrated and to solidify our position in RNA targeted therapeutics. And that vision is. It's not just that, of course. To enable that, it is to deliver a steady cadence of really important, meaningful medicines to patients, to drive value for all stakeholders, including our shareholders. And we're off to a great start.
The approval of Wainua in December of last year, now launched, it was launched in January of this year, is off to a great start, and it was a key step forward to full integration. It's our first-ever co-commercialization partnership in our history. We have a very meaningful role with our co-partner, AstraZeneca, in the launch of Wainua for ATTR polyneuropathy in the U.S., and it's going really, really well. We also had the approval of Qalsody for a genetic cause of ALS last year, with our partner, Biogen, a drug that was conceived and discovered at Ionis, and then licensed to Biogen, as the only treatment today, any...
Or the only disease-modifying treatment for any cause of ALS, let alone the only treatment for a genetic cause of ALS, solidifying our position, the validation of our platform for CNS diseases. Right behind Spinraza is now Qalsody and a whole host of other CNS diseases. We've also had two specifically this year, very positive Phase III readouts, which sets us up for our first independent commercial launches. Olezarsen for FCS now under review with the FDA, very positive Phase III readout, and then donidalorsen as a prophylactic treatment for hereditary angioedema.
Supporting these two programs, olezarsen and donidalorsen, as well as Wainua, is the establishment of a really strong, solid commercial organization and medical affairs organization that's in place and prepared to launch FCS independently in December, assuming approval, and then donidalorsen next year, and then more to come. Those are near-term, such big successes, upcoming launches. We also have one of the richest Phase III pipelines in biotech. A strong pipeline of nine or so medicines for highly prevalent diseases. To your question, millions of people suffering with forms of cardiovascular diseases and so on, and metabolic diseases, and also for severe rare diseases.
And we expect that Phase III pipeline to expand actually next year when we move our Angelman's program into Phase III development in the first half of next year. The Angelman's data that we reported this year from Phase II was remarkably supportive of advancing to Phase III. And this represents well, we believe, our cornerstone of our wholly owned CNS pipeline, so stay tuned for that. And then lastly, I'd say we're very proud and pleased with the advancements we're making in technology to expand and diversify our technology to strengthen our leadership in RNA-targeted therapeutics. Advancing new chemistries for CNS diseases so that we can deliver our drugs intrathecally, but less frequently, semiannually, or even annually, dosing with intrathecal delivery.
And we're also approaching systemic delivery to CNS for CNS diseases. It's imminent. We're expecting our first candidates to come forward next year for systemic approaches for CNS diseases. And then targeted delivery to muscle is coming very, very soon for cardiac myocytes, for heart failure, for neuromuscular diseases, to expand our neurology pipeline. All this is setting us up to achieve our vision, you know, to be the leader in RNA-targeted therapeutics and a leading fully integrated biotech.
Wow! That's a lot on the company's plate.
It is.
Very exciting. Maybe let's just start with ATTR cardiomyopathy. I guess it's a topic on people's mind, given a competitor, Alnylam's presentation of data, Phase HELIOS-B data at the ESC meeting last Friday. Could you share your overall thoughts on that data?
I think it's the data is strongly supportive of the silencer class for ATTR cardiomyopathy. The results were very strong on the primary endpoint, the composite of the cardiovascular or all-cause mortality, plus CV hospitalizations. I thought that there were other strong trends favoring the silencer class in secondary endpoints and exploratory endpoints. I think it bodes very well for this class. You know, eplontersen, the version of Wainua that's being developed for cardiomyopathy, it's the same drug. We don't refer to it as Wainua until it's approved. It is being evaluated in the largest, most comprehensive Phase III trial ever conducted in ATTR cardiomyopathy.
So it's set up to provide the richest data set in, not only for the primary endpoint, but the secondary endpoints, the subgroups, combination, monotherapy and imaging studies and so on, that are all underway. So, you know, the success of the first silencer to reach and get through Phase III development, it really, really bodes well for all eplontersen, and we're evaluating all of our options right now.
Got it. Got it. Could you, maybe, you know, talk about based on HELIOS-B data, those initial insights on monotherapy activity versus, you know, combination, or versus tafamidis alone? You know, and then what's the implication for commercialization, and how do you see the silencer class entering the market?
We believe that the silencer class will deliver the most meaningful benefit in all forms of TTR amyloidosis. I mean, we're seeing it in polyneuropathy, right? The silencer class is delivering the greatest efficacy for TTR amyloid buildup that causes polyneuropathy, and we expect the same thing for cardiomyopathy. It's logical to block the production of a toxic protein is gonna show really, really strong efficacy. And I believe that the first silencer class that read out in Phase III last weekend, the full data strongly supports the class. You know, that study was a relatively small study.
We have a study that's more than double the size, so it's strongly powered for not only the primary endpoint, of course, because it was hit with a smaller study, but also the subgroups, as I mentioned before. You know, as monotherapy, there, it looks strong. There was a positive outcome in monotherapy in the extended portion of the study into the open label extension, and there were strong trends in combination usage as well, favoring combination usage. I think, it's inappropriate to compare, however, you know, Kaplan-Meier curves timing to improvement in mortality, which I know many people are focused on.
Compared to drugs that were evaluated 10 years ago, ten, and then looking at timing of separation of a curve from 10 years ago to today, I'm referring to a stabilizer, tafamidis. It's a very different patient population. Patients are being diagnosed much earlier on in their disease, so they live longer naturally. So the placebo group is gonna go longer before it starts to really inflect, and you start seeing a meaningful increase in mortality. So you have to do much, much longer studies or bigger studies to do that, which sometimes are impractical in clinical trial design. We believe that with you know with today's patient demographics, that the silencer class will deliver better data than stabilizers. And I think that that's gonna bear out in the real-world setting eventually.
And we believe that based on the size of our study, we're gonna have a lot of data to support that conclusion when we read out CARDIO-TRANSFORM. As far as market strategy, there's a strong unmet need for better treatments for TTR cardiomyopathy. All patients either get little benefit with stabilizers or they eventually progress within a few years. They need better treatment options. I believe the silencer class will support newly diagnosed patients as a monotherapy in many patients. I believe that for patients that progress on stabilizers will go on to silencers. And that's. And as I mentioned, all patients eventually progress, so that's a big unmet need. And then I also believe that there's gonna be value in combination data.
And as I said, there's, you know, strong trends that combination patients on combination in the study that read out was favorable, and we think that with our size of our study, we're gonna have potentially even stronger data. So I think it's all on the table: monotherapy, combination usage, and progressors.
Great. That's super helpful, and then maybe to follow up on the last point about the trend in combo dataset. That's, you know, admittedly, probably the weakest data from the whole dataset in combination patients. You have a larger study, but I was wondering, you know, what is the benefit? Are you shooting for a statistical significance in that subgroup? Or, you know, it doesn't have to be like with a stat sig to support a combo use.
Like all clinical studies, our primary endpoint is where our statistical analysis plan is focused on. We're set up and were designed to achieve statistical significance against the primary endpoint, which is CV hospitalizations and CV mortality, a composite endpoint. Secondary endpoints include monotherapy, combination data and other endpoints, functional endpoints as well. And we have a lot of exploratory endpoints too. So we're not necessarily powered to demonstrate statistically significant benefit in the randomized portion of the trial on a primary endpoint in combination use. That's a secondary endpoint.
With that said, we're gonna have the richest data set, the largest, by far, of combination usage, and we're gonna be evaluating the combination usage of eplontersen with tafamidis in the composite endpoint, in the mortality endpoint, hospitalization endpoint, biomarkers, functional endpoints, like six-minute walk test. And we also have several imaging studies. Large, well-sized imaging studies, MRI, scintigraphy, as examples, in which we have over a hundred patients in those studies, both combination as well as monotherapy. And those studies are gonna be allow us to make, potentially, you know, judgments, claims on how, how's the amyloid, build up in the heart of being affected by monotherapy versus combination. Are we clearing the amyloid faster out of the heart? Is the heart functioning better?
Ejection fraction, you know, those types of echocardiography, those types of endpoints. All that data is gonna, we believe, will provide a compelling case for combination usage, with or without stat sig. It's gonna be very important for cardiologists who are prescribing, are gonna advocate for combination usage if they believe that, patients are gonna do better based on the totality of the data.
Great. Great, yeah, that's super helpful again. So, any thoughts on whether you might read out CARDIO-TRANSFORM early?
It's have been how many days since the data, all the details came out? We and our co-partner, AstraZeneca, are reviewing all the data in detail as much as we can. Of course, we're reviewing our own data, too. The study's gone very well. We're on track with our events in the study. We like what we're seeing. We're still evaluating the data. Our base case remains, base case meaning, you know, the plan still today, as it has been, as we've been saying through this year, has still been to read out, through one hundred and forty weeks, the full duration of the study, which would be around mid-2026.
And that base case, you know, of course, allows us to take full advantage of the advantages we have. One of the big advantages we have is the size of our study and the depth of data that we expect to come out of it. So we're still... But we're still reviewing the data. That doesn't rule out the possibility of an early readout, as we continue to review the data and really get into the nuts and bolts. But that's still our base case. If we did do something different, either in the statistical analysis plan or an early readout from the study, we'd first obviously get regulatory FDA advice and before making any announcements. But it's in process, and it's going well.
Great. Great. And lastly, when we anticipate that data readout and the data, you know, you have articulated all the benefits of having a larger data set and also the differentiated point about imaging studies and what role that might play. But on the efficacy, is your assumption or should our default assumption be that all silencers should be the same, or could there be differentiation?
There's only two silencers that I'm aware of that are in late stage development, so I couldn't speak for all silencers, but I believe that the two that are in late stage development, eplontersen being one of them, are showing equivalent reductions in transthyretin levels that are robust, greater than eighty, you know, slightly above 80% for both, with really good safety and tolerability, so I think the differentiation will come down to other factors. For eplontersen, we're happy to have several that are potentially differentiators. We already touched on the data set that we're gonna get from the largest Phase III trial ever conducted in this patient population, and the subgroups and all of that.
We really like the sustained rapid reduction in TTR, but the sustained durability of the TTR reductions. It's really clamped down at the 80% plus reduction. We're not seeing any waning of TTR. We think that that's gonna really bode well for efficacy long term. We also, the imaging studies I mentioned, I think are gonna be very important to understand the mechanism, what's happening behind the clinical endpoints. You know, what's really resonating well in the patient, in the healthcare provider community, is the ability of patients to self-administer using a simple auto-injector. Not having to rely on a healthcare provider to make an injection that they're perfectly capable of making themselves, as infrequent as once per month. Simple auto low volume, painless auto-injector.
That's resonating really well in the polyneuropathy launch, and we think it's gonna resonate really well in the cardiomyopathy launch. And then the last differentiator, I would say, and it's, it was purposefully why we did this co-co, one of the reasons why we did this co-co, is, you know, the combination of our experience in TTR amyloidosis and in our RNA platform, coupled with the global presence of AstraZeneca commercially as a powerhouse in cardiovascular disease, to reach markets fast, around the globe, will get to patients more, more patients faster. And all that we think will contribute to a profile that I think will be meaningfully differentiated.
Great. Great, thanks. I was going to ask about the at-home administration's, you know, that convenience factor. How has that borne out in Wainua launch? So I think you just mentioned it resonated very well.
It has resonated extremely well. I mean, obviously it starts with efficacy. Wainua has shown remarkable efficacy in reversing polyneuropathy, improving quality of life as well as neuropathy progression, with excellent safety and tolerability. The auto-injector has resonated very well, not just with patients, but also with healthcare providers who are very busy. Staffs and physicians that don't need to have to see their patient to do a subcutaneous injection that takes 10 seconds. But it's not at home that's most important, Yanan. That's nice. What's really most important is the ability of the patient to self-administer. Anybody can invite a healthcare provider to their home and ask them, and schedule an appointment to have them do a subcutaneous injection. What's the point?
The ability of the patient to self-administer at home, at work, on vacation, while they're hiking, I mean, really, with a simple pen in their backpack, is what's really resonating with the healthcare providers and the patients.
Got it. Great. So let's move on to olezarsen for FCS and also for SHTG. So Arrowhead just presented also at the ESC meeting their Phase III data for FCS. Could you share your thoughts on the data? How should we compare their triglyceride reduction and acute pancreatitis benefit with olezarsen?
As a reminder, recall that we reported highly detailed results for olezarsen in FCS at ACC in April, and published in the New England Journal of Medicine, two publications, actually. And what we reported was really substantial, remarkable reductions in triglycerides in FCS patients. Essentially, elimination of acute pancreatitis in patients treated with olezarsen versus placebo. I think there was one event that happened a year after starting olezarsen. One event of AP a year after treatment started in the treatment group, and versus eleven that were starting within a few weeks after in the placebo group. It was a real shutdown of acute pancreatitis, all with excellent safety and tolerability. Greater than 80% reduction in hospitalizations.
These patients don't feel well, whether or not it's an AP event that drives them to the hospital or they're just feeling awful. 86% reduction in hospitalizations compared to placebo and other advantages. The results we saw this week on a competitor program, you know, does not in any way reduce our excitement, our confidence that olezarsen will be the standard of care for FCS and eventually SHTG. When comparing the data, it is really important, as we all know, to compare apples to apples, placebo-adjusted reductions, not versus baseline, but placebo-adjusted reductions across different programs. Of course, you know, the caveat of the risks associated with cross-trial comparisons, understood.
But let's just compare placebo-adjusted reductions in triglycerides at similar time points, at the same time point, like at 12 months, for example. What we're seeing is that olezarsen is producing equal or even slightly better triglyceride reductions when you look at placebo-adjusted reductions or levels. We're also seeing greater reductions in acute pancreatitis and a faster onset of action of producing reductions, eliminating acute pancreatitis attacks in our study, all with excellent safety and tolerability, and with the added advantages and convenience of a self-administered auto-injector that I already highlighted. So we're thrilled that olezarsen was accepted for priority review by the FDA, with a PDUFA date of December nineteenth of this year.
I'm also pleased to say that our commercial organization is in place and ready to launch as soon as we get approval for olezarsen, representing our first independent commercial launch for Ionis.
That, that's great. So, I guess you also have the SHTG data next year and then launch, but, you know, of course, I think the competitor product, you know, also had the data obviously are positive and will be also launched into FCS. How do we think about the commercial launches of all those indications?
... Well, I can't speak for a competitor program on what their strategy is or so on. You know, I do wanna emphasize that we're first to market. For FCS, we're 9 to 12 months ahead of the leading competitor program, and we don't see any advantages in that program, you know, from a differentiation standpoint. So a year ahead, and in SHTG, and as a reminder to everybody, SHTG is not a rare disease. It's millions of people in the United States alone that suffer from the same things that FCS patients suffer from, which is, you know, severe abdominal problems, pains, cognitive deficits, but mostly a high risk for acute pancreatitis that puts them in a hospital for a week plus at a time.
And for SHTG, a really big, highly prevalent disease, we're two-to-three years ahead with first mover advantage. So our strategy for Ionis is to get FCS launched, to strengthen our position in this field of endocrinologists who treat patients with high triglycerides, to establish our foundation there, for this rare disease. And then with the SHTG Phase III data expected in the second half of next year, with a submission expected next year as well for approval, then to transition into the large, highly prevalent disease, SHTG, rapidly. And again, first mover advantage, we think here is a key differentiator. The SHTG Phase III trial was fully enrolled this summer, and we're expecting, and everything's going really well.
Great. Maybe switching gears again to donidalorsen for HAE. Mainly the question is: How close are you to filing that NDA into FDA?
We have submitted. So, it's in. It's been in for a little while now, and as soon as we get acceptance in the U.S. with the FDA, we'll put out an announcement, and we wait for acceptance before we make announcements for submissions. And as a reminder, we have an ex-U.S. commercial partner for donidalorsen as a prophylactic treatment for HAE, Otsuka. Otsuka is planning to submit for approval in Europe soon. And we expanded this year our partnership with Otsuka for donidalorsen for Pan-Asia. And they're working on submissions for Japan as well as in other territories as well later this year. You know, we presented the Phase III program for donidalorsen in HAE at EAACI in July.
And we were very pleased with the comprehensive presentations we gave, both the primary endpoints, the Phase III trial, the long-term open label extension data, which showed continued improvement for donidalorsen, up to 90% plus reduction in HAE attacks with long-term treatment, and then the switch cohort. Patients that are on current prophylactic treatments, who switched over to donidalorsen, in a prospective trial that we conducted purposefully because the U.S. market is a switch market. We wanted to gather the data, and we wanted to know patient preferences. We had a very successful study. We saw more than 60% further improvements in reductions in HAE attacks versus standard of care in the U.S. market today, Takhzyro or Orladeyo or Haegarda.
And patient preferences at the end of the study, which do you prefer, your previous treatment or donidalorsen? More than 80% of the patients said that they prefer donidalorsen versus their previous treatments. And I'm pleased to say that all these patients continue in the switch cohort, eventually, essentially all these patients in the switch cohort, which will continue to a potential launch, as well as our open label extension study. So we're really pleased with the overall profile for donidalorsen.
Got it. Got it. If we may touch on pelicarsen. This is your partner program with Novartis, targeting Lp(a). I think there's more and more interest as we're getting close to that data. So mainly people wanted to know what does success look like for this first-in-class study? And what's the threshold for clinically meaningful change on the primary endpoint of CV event rate?
Yeah, pelicarsen is set up to be a first in class. It actually first in any class.
Right.
There are no treatments for Lp(a)-driven cardiovascular disease. This is a disease that, caused by an independent risk factor, high levels of lipoprotein(a), that cause atherosclerosis and pro-inflammatory effects in the vasculature, causing heart attacks, strokes, and et cetera, and which, there are no treatments available. This is a disease that afflicts, tens of millions of people around the globe who have normal cholesterol, non-diabetic. This is the cause of their disease. What we showed in Phase 2 development was that, we were able to normalize, 98% of patients with this indication, we drive their Lp(a) down to normal levels. This is a threshold effect, right? So lower is not necessarily better for Lp(a). If you get them below the threshold of risk, they should be fine.
And we think that we're gonna replicate in Phase III, Novartis will, our data in Phase II, which was very strong. Success with no treatments out there today, we want statistical significance. I know it sounds obvious, but the treatment group patients with, this is secondary prevention, patients with cardiovascular disease, with high Lp(a) levels above 70 mg/dL. We want statistically significant benefit in CV mortality and hospitalizations versus placebo. With that said, typical, you know, benchmarks for cardiovascular outcome trials are usually 20% or so outcome risk reduction, which is, you know, which of course, would be very nice to see.
Got it. Great, thanks for that insight. And then perhaps on Angelman syndrome. I think this is, you know, a very interesting topic. You reported positive data in July, but then before that, partner Biogen decided not to opt in. There's been a lot of questions around that. Could you talk about, you know, your, you know, what's surrounding that Biogen decision, and your excitement level for this program?
That's a question for Biogen. I don't... You know, Biogen is a great partner with Ionis. They've been a great partner for 10 years plus. You know, we developed, we discovered, conceived, and developed Spinraza. They've done a great job in launching Spinraza. It's a standard, it's a standard of care for SMA. Today, I don't know if you saw, an announcement came out. We now evaluated high-dose Spinraza in the DEVOTE trial. The high dose of Spinraza has shown even greater benefit in patients with SMA, evidence of benefit compared to the commercial dose. So we're really excited about what Biogen is doing for SMA. Qalsody, they're doing a great job of launching Qalsody for SOD1 ALS, our tau program, et cetera.
Angelman’s program, Biogen chose not to license the program, and really I would leave it to leadership at Biogen as to why they didn't do that. Obviously, it didn't meet their internal metrics to go to Phase III. Recognizing that people would have the exact question you just asked me, Yanan, one thing, what we wanted to do, because we conceived our ION582, our Angelman’s drug, and discovered it and developed it all along, what we wanted. So we were in control of all the data. What we wanted to do was get that data out there so people can see it, to show how compelling the data is. And that's what we did at ASF. We presented a comprehensive review of all the data.
The clinical data, the biomarker data, various ways to measure progression of Angelman syndrome disease, Bayley-4, Vineland assessments, ORCA assessments, SAS-CGI assessments, they're all favoring benefit across all subdomains: communication, cognition, motor function, with excellent safety and tolerability. And we also had experts there to speak about the importance of this potential importance of this medicine for Angelman syndrome, key investigators in this area. That's a question for Biogen. The data is out there. It's very-- we believe it's very impressive. We are looking forward to having our end of Phase II meeting with the FDA soon, and then to launch into Phase III development first half of next year.
The Angelman’s program represents the cornerstone of the wholly owned Ionis CNS pipeline. A pipeline that's validated with Spinraza, Qalsody, tau, and so on, so we're really excited about it, and we're looking forward to sharing updates on the program as we go forward.
That's great. That's great. So, you know, we didn't have time to really touch on any of the earlier stage programs. I think you have MsPA backbone for longer duration. In your neurology program, you have siRNA, maybe for a heart failure indication. You know just in general, as you mentioned, CNS, muscle, also, those are kind of new areas for ASOs. Maybe just, you know, give us a overview, a preview of what's to come in the new technology front.
Absolutely. As I said in my opening, you know, when I moved into this role as CEO of Ionis in 2020, I focused the company on two key objectives to really drive value. One is to be fully integrated and to hold on to our medicines ourselves and deliver them to the market, and that's in place, and we're about to independently launch olezarsen, with more to come. And then to diversify and expand our technological capabilities, and we've done that. We're on the verge of initiating our first Ionis discovery, using Ionis medicinal chemistry and screening methods capabilities, siRNA, into clinical development this year for a target that we think is better suited for SI versus ASO.
We're also about to initiate our first new backbone chemistry called MsPA in a clinical trial for CNS disease that allows us to dose, we think will allow us to dose semiannually, maybe annually, intrathecally for CNS diseases. In addition, as I mentioned in my opening, we are making great progress in strengthening our leadership in CNS diseases to deliver our medicines potentially systemically, subcutaneously, or intravenously, using platforms that we in-license, such as Bicycle and vectors and other capabilities, to overcome the blood-brain barrier for CNS diseases. We're really pleased with the progress we're making in delivery of ASOs, siRNAs to skeletal muscle to expand our neurology pipeline for neuromuscular diseases, as well as for targeting cardiac myocytes directly for heart failure.
And we have two of these muscle-targeting programs in either IND-enabling toxicology studies right now, or the first one, and then the second one about to reach IND-enabling toxicology studies very soon. Stay tuned for that. It's the investments we're making that are panning out, paying off, and we're looking forward to getting them into the clinic really shortly.
Great. Great. With that, I think, we're out of time. Thank you, Brett, for your time and insights.
Thanks, Yanan. It was a pleasure.
Great.