Good afternoon, everyone. Thanks for joining us. We're really pleased to have with us Brett Monia, CEO of Ionis. Before we start, though, I am gonna read a disclosure. We are required to make certain disclosures in public appearances about Goldman Sachs' relationships with companies that we discuss. The disclosures relate to investment banking relationships, compensation received, or 1% or more ownership. We are prepared to read aloud disclosures for any issuer during the sessions upon your request. However, these disclosures are available in our most recent reports to you with client and our firm portals. In addition, updates to these disclosures are available by ticker on the firm's public website. Goldman Sachs agrees to host this conference on the basis that no third-party speaker will provide confidential or material non-public information.
In addition, by attending the conference, you provide Goldman Sachs the right to re-record or record and redistribute the conference information. The views of third-party speakers do not necessarily reflect those of Goldman Sachs. With that, Brett, very excited to have you here. To start here, you do have a few regulatory and late-stage programs in the clinic, and multiple upcoming commercial launches. Could you just walk us through your near-term outlook here and strategy for these launches?
Sure. Happy to, Salveen, and thank you for the opportunity to be here today. Yeah, we do, we have quite a number of actually upcoming near-term pipeline events, including regulatory events and launches. Today, you know, with the addition of two phase III studies that initiated in the first half of this year, we now have eight drugs phase III development across 10 indications, and those are for rare indications and large indications. About half of those are partnered, the other half are wholly owned by Ionis today. Certainly, our upcoming near-term regulatory action that we're really looking forward to is the FDA action on eplontersen for TTR polyneuropathy. You know, last year, we reported interim data from week 35 from the phase III study.
That was highly positive, very competitive, excellent safety, along with really remarkable efficacy. In April, we reported the week 66 data from the completion of the study. Not only did the data hold, it actually showed continued improvement in which patients, more than half of the patients were actually improving compared to their baseline values. Hit both all three primary endpoints, TTR reduction, mNIS+7, Neuropathic quality of life, and as I said, patients were actually doing better than compared to baseline values. We're looking at a PDUFA date of December of this year, and we and our co-commercialization, co-development partner, AstraZeneca, are preparing and ready for launch as soon as the drug is approved.
That's certainly a near-term event that we're looking forward to. We expect eplontersen to be a second product approved to add to our commercial portfolio this year, alongside QALSODY, which was approved for SOD1-ALS earlier this year. A very competitive profile for eplontersen. We could talk more about that. Olezarsen, phase III asset that's in two indications, at the rare genetic indication, FCS, and the broad indication, SHTG. This is a disease in which patients are suffering from severely elevated triglycerides. They're at high risk for acute pancreatitis as well as cardiovascular disease. The phase III data is due to read out in the second half of this year.
We're feeling very good about, you know, the likelihood for success there. The SHTG, the much larger indication, we phase III data in the second half of next year. That's coming, both of those are coming along pretty quickly. Our prophylactic treatment for hereditary angioedema, donidalorsen. We completed enrollment in the HAE study a few weeks ago, and we're phase III data in the first half of next year. That's another key regulatory and data output action that we're looking forward to. Probably one other drug. I won't go through all eight of phase III drugs, but I think it's worth highlighting pelacarsen too. This is a partnership with Novartis.
This is for a cardiovascular indication, that's due to high levels, elevated levels of a risk factor, cardiovascular risk factor called lipoprotein(a). That study is fully enrolled. It was fully enrolled last year with more than 8,000 patients in a cardiovascular outcome trial. This is a very large market opportunity. 8 million-10 million people globally suffer from cardiovascular disease due to high Lp(a) levels. Based on our profile from phase II, we expect not only pelacarsen to be the first to market with Novartis, for this very large market, but also probably a best-in-class molecule for Lp(a)-driven cardiovascular disease. There's a lot coming from the pipeline and both regulatory as well as data readouts in the next few months.
Let's start with eplontersen and hereditary TTR polyneuropathy here, which is under review. How do you think about where this will be positioned within the landscape, given the other players out there, in terms of where early adopters will come from, and then how you think that'll play out over time?
Yeah. Eplontersen is in development for polyneuropathy, hereditary polyneuropathy. As I mentioned, and you just asked about, it's also phase III development for the broader indication, TTR cardiomyopathy. Regarding polyneuropathy, I think it's first, it's very important to recognize the fact that well over 80% of patients with TTR polyneuropathy are not on treatment today. This is a market development opportunity. This isn't a switch market. Nobody owns this market. The objective will be to find those patients and get eplontersen to as many patients as possible. We think we have several advantages. First, we have great efficacy, and great tolerability and safety from phase III study. Very competitive profile.
Another significant advantage is the route, the mode of administration. eplontersen is administered by the patient themselves. Self-administered using a simple, low-volume, painless auto-injector once per month. Very convenient and very easy for the patients to use. It does not have to be administered by a healthcare provider or any complicated setting like that. This is a key differentiator from the competition that's out there today. In addition, we, of course, have a very complementary relationship with AstraZeneca. We know TTR amyloidosis very well from our earlier generation work within inotersen. We know this space, we know the KOLs, we know the communities, AstraZeneca brings with it global commercial strength to reach as many patients as possible.
As I said, this is a market development opportunity, so finding those patients, not just in the United States, but globally, we think AstraZeneca brings great value there. That's, you know, this is a very competitive drug, and it's a drug that we think will do very well on the market once we get there.
You spoke to the share of the market currently taken by the existing players. Why do you think that it's not a greater amount? What have the hurdles been to adoption here?
Diagnosis. These patients, you would think that since this is a progressive, potential, ultimately fatal, form of polyneuropathy, that all these patients would present in the same setting, a neurology setting, neurologist. That's not the case. In fact, even in a neurologist's office, this disease is often misdiagnosed for some other causes of polyneuropathy, like CMT or other things. This diagnosis in the neurology office is still poor, but these patients suffer from all kinds of problems. They suffer from heart disease. Sometimes they present in a cardiology office, and the disease is not understood there. They can present in a nephrology office because of renal involvement or GI. These patients have severe GI problems. They go to GI docs. Diagnosis is the biggest challenge today.
These patients generally go years before they're properly diagnosed and then can be put onto a therapy. That's our goal, that's our challenge, is to find these patients and build this market out.
How does the out-of-pocket or kind of reimbursement dynamic play out for your asset versus the others?
We think this bodes very well for eplontersen. You know, the Inflation Reduction Act got, in our opinion, got a lot of things wrong. For, you know, it's really gonna, we think, it could potentially hinder the rapid development of drugs, novel drugs for multiple indications. One thing it did get right was the elimination of the donut hole, if you will, the loophole in which patients that are on Part D drugs had very high out-of-pocket expenses that they had to pay. That was eliminated by the IRA now.
In fact, for Part D drugs like eplontersen, which are self-administered by the patient themselves, they don't have to go to a healthcare provider, the maximum out-of-pocket expenses annually is $2,000 in totality for the disease, not just for one drug, for the, in totality. Easily manageable. Well over 10-fold reduction in out-of-pocket expenses. You know, this, coupled with the at-home administration, we think represents a significant path forward advantage for eplontersen.
Moving over to your cardio TTR or T transform.
CARDIO-TTRansform.
TTR cardiomyopathy study here. Remind us on your confidence in trial design and treatment effect, in the context of kind of the modern patient population and what you've seen play out with other programs?
This is a very important question. This is a very important aspect of our trial design. We think we have the right trial design for this very large patient population. You know, TTR amyloidosis, in totality, is estimated to be a market opportunity that's greater than $10 billion, driven, of course, mostly by the cardiomyopathy. Broad indication, up to 500,000 patients are estimated globally. You know, when we first started, designed our phase III trial, the CARDIO-TTRansform study, as well as everyone else that is evaluating investigational medicines for TTR cardiomyopathy today, the powering assumptions were all based on the Pfizer tafamidis ATTR-ACT study, right? At that time, very little was known about TTR cardiomyopathy.
Patients were being diagnosed very sick, far along in their disease. Obviously, the powering assumptions are very different for a disease that's, in which patients are presenting with very severe disease versus a setting in which patients are presenting with milder disease. Well, thanks to the great work Pfizer has done in building out this market, better diagnostic techniques for diagnosing this disease, better patient awareness. Patients are actually being diagnosed much earlier on in their disease, milder disease in general. Well, we responded to that. We upsized our study to make it really a landmark study, the largest study by far ever done in TTR cardiomyopathy. 1,400 plus patients when we complete enrollment, we expect to complete enrollment very soon in this cardiovascular outcome trial.
Our powering assumptions are based on today's demographics, not yesterday's demographics that were based on the tafamidis ATTR-ACT study. We think this not only gives us a much higher probability for a successful study, but also a much better opportunity to have the richest data set to compete in this market. In addition, in our study, we're gonna have a very large subset of patients in which we're evaluating eplontersen's benefit on top of tafamidis, as well as eplontersen as a monotherapy. We believe that this is a big advantage for the cardiomyopathy indication because, you know, cardiologists are treating, a lot of... Most of the patients are on tafamidis today, certainly in the United States and in certain countries outside the United States. You know, tafamidis is a safe drug. It provides benefit.
There's a lot of room for improvement, but it does provide benefit. Cardiologists are gonna wanna know: What data do you have that your drug on top of tafamidis is gonna add benefit, provide further benefit? We believe that we're gonna be the only ones that really have that data because of the size of the study and the design of our study. Based on the size of the study, we are also gonna have a very significant percentage of patients with hereditary TTR cardiomyopathy as well, which is important because these patients actually progress faster. They have severe disease than the wild-type patients based on the rate at which they progress. In fact, tafamidis had demonstrated better benefit, higher benefit in the hereditary population versus the wild type.
Both received benefit, but the hereditaries did better. These advantages in our trial design, coupled with our co-commercialization partner, AstraZeneca, who's a leader in commercialization of heart failure drugs globally, we think all of this represents a very significant advantages for eplontersen to reach this, as many patients as possible globally for this very, very large market opportunity.
Is there a target for tafamidis, naive versus experienced patients or hereditary versus wild-type patients?
For tafamidis versus naive, we're targeting around equal amounts, 50%, tafamidis patients and about 50% non-tafamidis patients. I'm pleased to say that we're just about there.
Mm-hmm.
The team's done a great job at Ionis on prioritizing sites where tafamidis is not readily available to increase the product, the amount of patients that are naive, not on tafamidis, and we're just about equal, 50/50. On the hereditary side, we haven't stated what percentage there is, but our goal is to have about the same percentage of patients that have hereditary cardiomyopathy that Pfizer did in the ATTR-ACT study, and we're getting there.
Is there the ability to make changes if need be, or, you know, could there be learnings that play out from BridgeBio? If not, if, let's just say, you're very confident in the overall situation, is everything on track for first half 25?
Yeah. We don't see the need to make any additional changes to the CARDIO-TTRansform study. We think we got the right study, the right demographics. Like I said, we're coming close to completing enrollment. We have quite a number of patients already rolled over into the open-label extension. Really good safety tolerability. No, we don't see any need to make any changes. As far as readouts from ongoing studies, like BridgeBio, you asked about specifically, it's a much smaller study, Savine. You know, I think it's estimated to be 500 patients. You know, based on what I just said, the changing demographics in TTR cardiomyopathy, we think it's gonna be, it's gonna be a challenge to show a positive outcome in that study.
We think if the demographics are what we think they are, and I think they've reported that the demographics are exactly as we said, and we believe a milder patient population, it's gonna be difficult to see an outcome there. We don't see readthrough to our study. It's also a different mechanism of action, a stabilizer versus a silencer. We like the silencing mechanism of action. What will be interesting is how the event rates play out, right? Does the milder population for TTR cardiomyopathy today really manifest in what we would expect, fewer events in the placebo group? We'll be very, very much focused on that.
Remind us how the responsibilities on the commercial side will be divided between yourselves and Astra?
Yeah. You know, Ionis, we're really undergoing through some really exciting transformational changes. Today, we're moving. We're now a fully integrated biotech. We're preparing for our first commercial launches. Our first launch will be eplontersen in a co-commercialization partnership with AstraZeneca. Come our independent launches soon thereafter, olezarsen, donidalorsen, and others. We think this step is a key value driver for Ionis, retention of more value for the drugs we bring to the market directly. For the co-co with AstraZeneca, our co-commercialization arrangement is for the US only. They're responsible for ex-US commercialization. In the US, even globally, we have an equal seat at the table with them in setting brand strategy, commercial launch strategy. Certainly for the US market, where we are responsibility.
We're sharing medical affairs responsibilities today. We're in the field preparing the market for neuropathy and cardiomyopathy. We have the lead in patient services for the launch and communications as well. AstraZeneca is responsible for the field force in the U.S. and globally. That's the arrangement, and as I said earlier, we're prepared for launch, assuming eplontersen gets approved in December.
Jumping over to olezarsen in FCS and severe hypertriglyceridemia. How are you thinking about the launch trajectory here, or just even just the initial kind of launch outlook? You know, just given your history with this space, but also what we're seeing with some of the buy and bill aspects in, you know, cardiology.
Yeah. olezarsen is projected to be our first independent commercial launch. We're developing olezarsen for two indications, the rare genetic indication, FCS, and the broad indication, SHTG. FCS has a prevalence of a few thousand estimated, SHTG is in the millions in the United States alone. As I said earlier, these are patients that are at high risk for acute, severe acute pancreatitis that can be fatal. They also have cardiovascular disease, what we're really focused on is improving the outcome or prevention of acute pancreatitis events in this patient population. Very large unmet medical need here. The existing therapies are not adequate. They don't lower triglycerides nearly enough, not even close. Our mechanism, targeting APOC3, another LICA medicine that's like eplontersen.
We're expecting profound reductions in triglycerides based on all of our experience, phase two data, as well as our predecessor, WAYLIVRA, where we showed remarkable reductions in triglyceride. This is basically a better version of WAYLIVRA, more potent, and really well-tolerated with an excellent safety profile. olezarsen, well, let me before I get to the buy and bill, that question, part of your question. You know, this is a really attractive market opportunity. This is a market where patients and physicians are really waiting for a drug like olezarsen. There's like a segment of this SHTG community we refer to as early adopters that have had one, two, three pancreatitis events already. They've landed in hospitals. Their pancreas is degenerating from this. They're developing diabetes. They're desperately searching for a drug like olezarsen.
These are endocrinologists that are primarily prescribing, not cardiologists, although some cardiac cards do this. This is the endo population, and this early adopter population, this segment of these millions of patients with severely elevated triglycerides, represents a $1 billion-plus market opportunity by itself in the United States. Blockbuster. We're gonna be first to the market, substantially or earlier than any competitors out there. We're planning to build this market out ourselves. Olezarsen, nor eplontersen or any of our LICA medicines are positioned as a buy and bill with a buy and bill strategy. These drugs will not be administered by a healthcare provider, a Part B drug, if you will.
They will be, you know, prescribed naturally, normally, as non-buy and bill drugs are prescribed through specialty pharmacies. Patients will be administering the drug themselves at home with a simple auto-injector, self-administered very easily every month or so, administration. Buy and bill, you know, has worked well in certain therapeutic areas like ophthalmology. Cardiology is a new area for this. It's gonna be a tough road to convince cardiologists that they wanna buy highly, very expensive medicines, store them, and then go through all that logistics associated with this. I mean, we'll see what the future brings, but we were never big fans of the buy and bill strategy for this, for these types of indications.
Jumping over to hereditary angioedema, where are you getting the sense from physicians that they, you know, want to use this drug, or how the uptake's gonna play out?
Yeah, this is an interesting. This was really an interesting journey, how we got phase III development for donidalorsen. Another LICA medicine like eplontersen and olezarsen. You know, this is a different type of market than olezarsen, where we're first to the market, eplontersen, big untapped market, where we're coming in really alongside competition. This is a market that's established, particularly with Takeda's TAK-743. It's TAK-743 is mostly administered most frequently, but mostly administered as an every two week administration, subcutaneous. It can be administered every four weeks, but you lose a lot of efficacy if you administer every four weeks. Even every two weeks, there's still a big unmet need there for better efficacy. You know, when we went into the phase II study, we went in with our eyes wide open.
It was like: Hey, this is a market that's established. We're gonna have to have a great-looking drug. donidalorsen hit on all the aspects that our market research said we needed to hit on for this drug to be competitive. Efficacy. Better patients, physicians want better efficacy. We're cheap. We're obtaining in our phase II data now, in our long-term, two-year open-label extension data, reductions in HAE attacks on the order of 95% or so. Second, patients want better convenience. As I mentioned, standard of care is every two weeks, mostly. Our drug is in development phase III now, as a once per month or even once every two-month dosing regimen. Less frequency and better convenience, with the convenience of a simple, painless auto-injector, self-administered.
We have a great tolerability, which patients want. We have great convenience, and we think we're gonna have great efficacy when phase III data reads out. For a market that's not the size of olezarsen, not the size of eplontersen, but still an attractive market that doesn't require substantial investment to reach, you know, specialty centers where patients are being seen. We're looking forward to phase III data, which will read out in the first half of next year. We're gonna be prepared to launch, assuming the data is positive.
What do you think the peak opportunities could be from these three assets?
In totality, multi-billion dollars. Obviously, eplontersen is a total market opportunity of, in excess of $10 billion. As I mentioned earlier, we expect to be very competitive and have a very substantial market share there. Blockbuster for eplontersen. As I said earlier, olezarsen also, we expect to be first to market. Blockbuster potential, $1 billion-plus in the United States, even with that early adopter group. Keep in mind, those early adopters are just the start, right? We get to those early adopters for olezarsen, for severely elevated triglycerides, and then it's market build, then it's market expansion to get to additional patients that have triglycerides that are above 500, that we think will further add to the market.
Donidalorsen for HAE is smaller, probably won't reach blockbuster potential, but still a very attractive market opportunity for Ionis.
Jumping to the pipeline here, your neurology portfolio, where you've seen, you know, a good amount of activity. What pipeline programs are you most excited about? Has the recent approval by the FDA for your drug in ALS, impacted your view on, you know, biomarkers in the regulatory landscape here?
Yeah, we're very proud of the approval in April of QALSODY for SOD1-ALS. You know, this is a drug we partnered, we licensed to Biogen, but it was, you know, like all of our ALS drugs today, SOD1-ALS was conceived and discovered and developed at Ionis, and then licensed to our partner, Biogen. This is the first ever drug approved for a genetic cause of ALS. I think when, at the end of the day, once we get real-world, a lot more real-world experience with QALSODY, I think it'll be the first-ever disease-modifying treatment for any cause of ALS. QALSODY represents now our second CNS drug for, that's on the market for severe neurodegenerative disease. The first, of course, being SPINRAZA.
I think QALSODY's not only is a breakthrough for the ALS community and for SOD1-ALS patients in particular, but is really transformational for the whole field. First, the accelerated approval of QALSODY lays a path for potential accelerated approvals in the future for ALS, based on neurofilament light chain as a biomarker. NfL is a now validated. QALSODY validated NfL as a biomarker to monitor and potentially discover, monitor progression and to develop drugs and get them approved based on reductions in this biomarker that predicts disease course in ALS. Second, I think it also reflects the fact that the neuro division is flexible.
They're willing to bring drugs forward when you look at the totality of the data, including a biomarker like NfL, along with all the clinical evidence that we had, that QALSODY was helping these patients for an accelerated approval, you know, with demonstrating that willingness and that flexibility to bring these drugs forward. We, today, right behind QALSODY and SPINRAZA, we have 12 medicines in clinical development for other causes of neurodegeneration and neurodevelopmental disorders, and more coming. We expect to start two new clinical studies in CNS diseases this year and more next year. QALSODY is important. It's further validation of our leading, industry-leading, I believe, CNS platform, and further validation, and really bodes well for the rest of our pipeline of CNS drugs that are coming.
You have an extremely deep and broad pipeline. If you were to focus the investor base on, you know, some of the key programs with whether their data reads over the next 12 months or that you think longer term are just gonna be key drivers for your future, where would you, where would you direct?
Well, certainly eplontersen is a big one, for the reasons we already covered. I mean, this is a really big market, and everybody's, there's the unmet need in neuropathy and in cardiomyopathy is enormous, and we have a very competitive drug, and we're expecting our first approval by the end of the year. olezarsen, for the reasons I've touched on, untapped market, blockbuster potential, big market opportunity. We have a great-looking phase III data, second half of this year. Thirdly, I would say pelacarsen. I touched on that briefly earlier. Another big market opportunity in cardiovascular disease. You know, again, eight to million-10 million people suffer from cardiovascular disease due to high levels of Lp(a), a risk factor that causes, that promotes thrombosis, atherosclerosis, and pro- and inflammation in the vasculature.
There are no treatments for this disease indication, and we are well on our way for phase III outcome trial to read out in 2025. That's another big, non-rare, big patient population that's coming. If I could just add a couple others that we didn't touch on. We're excited about the Angelman syndrome program that's coming. You know, this is a partnership with Biogen, a neurodevelopmental disorder, a market that's, it's projected to be even larger than SMA, significantly larger than SMA. We love our drug. We think we have the right chemistry, and the study is, you know, coming to a conclusion. We may have, we may be able to wrap up the study by the end of the year or sometime first half of next year.
That's a big opportunity. I know a lot of people are very excited about that program. The other things that I would draw attention to is, you know, SPINRAZA continues to perform like a blockbuster. Despite emerging competition, there's quite a bit of post-marketing studies that are in progress today, and some of those studies are gonna start reading out soon. These include, and the purpose of these post-marketing studies is to demonstrate, further demonstrate the added value, the tremendous value SPINRAZA brings to patients with respect to primarily efficacy. Really tremendous efficacy. We have two studies in progress, which are to... SMA patients are being switched over to SPINRAZA, who are not doing well on gene therapy or on the oral medication, Evrysdi.
They're now being switched over to SPINRAZA, that data is gonna start coming out really soon, in which we think patients are gonna show benefit. In addition, SPINRAZA is now in a post-marketing study called DEVOTE, in which we're looking at higher doses of SPINRAZA. SPINRAZA is really well tolerated. It allows us to go to higher doses and test for even greater efficacy in the clinic. You know, I expect that data will be coming out in not too far down the road as well.
Any questions from the audience? Maybe one last question from me. You talked about how Ionis has changed in terms of its strategy, now you're co-developing. I mean, you're involved in developing with partners, but you're commercializing assets here. You've also started to bring in other technologies-
Yeah.
like your partnership with Metagenomi. Where do you go from here? I guess, how do you think about where you could further evolve and, you know, Like, I guess, who is Ionis on the forward?
You know, when I moved into this, the CEO role in 2020, I laid out that we needed to really drive the greatest potential value for the company, for shareholders as possible, is to bring products to the market ourselves, commercialize them, markets we choose to focus on for the market. We're doing that, and we covered that. The second was to extend our leadership position in oligonucleotide therapeutics and expand our capabilities to be the leader in genetic medicine someday. We have the right people. We just needed to pull that trigger, honestly. In 2021, one step along that way was we did a strategic partnership with Bicycle Therapeutics. We in-licensed exclusively Bicycle Therapeutics for targeting the transferrin receptor 1 for opening up new tissues like cardiac myocytes and skeletal muscle.
We've now moved into preclinical development, indeed, enabling tox studies, our first Bicycle siRNA molecule, actually, for targeting heart failure, a new indication, and we expect more coming there. Second, last year, we did a new partnership, as you asked about Metagenomi.
Mm-hmm.
for DNA editing. There's a lot of complementarity between oligonucleotide therapeutics and DNA editing. The medicinal chemistry toolbox we've developed over the years, our knowledge on experience in delivering nucleic acid payloads to different organ systems. Not just the liver, but the CNS, the lung, and other organs, too. We think we bring a lot to the table. The Metagenomi partnership gets us into DNA editing, next generation DNA editing as well. It accelerates our step forward into DNA editing. That's why we did the partnership, was to expand. The partnership is going great. We're making great progress. We hope to provide some updates on some of the progress we're making later this year.
Great! Well, with that, Brett, thank you so much.
Thank you, Sally. Great.