Good afternoon, everyone, and thanks for joining us at the Morgan Stanley Global Health Care Conference. I'm Mike Goldsmith, a biotech analyst here, and it's my pleasure to introduce Brett Monia, our CEO from Ionis Pharmaceuticals. Before we get started, I just need to read a quick disclosure statement 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. We really appreciate it. Maybe to kick things off, if you could just give an introduction to Ionis, maybe for people that are less familiar with your story.
Yeah, thanks, Mike. Good afternoon, everybody. It's a pleasure to be here. Ionis, we are a genetic medicines company focused on RNA-targeted medicines, of course, with seven FDA-approved medicines on the market today for severe rare genetic diseases and a pipeline, a deep pipeline that has today nine phase 3 programs that are due to read out this year, next year, and for several years to come. We've had extraordinary progress over the last little bit, last couple of years, especially this year. Really, really exciting results this year from our pipeline, which began with the late December approval of Tringolza, the first ever FDA-approved medicine for familial chylomicronemia syndrome, FCS. This is a genetic disease in which patients suffer from severely elevated triglycerides. They have all kinds of comorbidities, but the biggest risk is the potentially fatal acute pancreatitis. That launch is off to a great start.
It's our first independent commercial launch in our history. Just last week, we reported a second result for a phase 3 program for a second indication for Tringolza, Olzarsen, for a broad patient population, non-rare, prevalent disease called severe hypertriglyceridemia, in which we really had blockbuster, amazing results from that program. We're looking forward to filing the supplemental NDA for that program by the end of the year. Just three weeks ago, we had approval of our second independent launch on a medicine called Donzera for hereditary angioedema. That launch is now underway. We're really proud of the great progress we're making, and it's setting us up for a lot more exciting news to come later in the second half of this year and well into next year.
Great. Thanks for that introduction. Obviously, you've had a lot of success recently, launching your first drug and getting the second drug approved, as you mentioned. I thought maybe we could start with Tringolza and FCS. You mentioned you're off to a strong start there. It's only been two quarters so far, but you've put up numbers ahead of expectations. Maybe talk a little bit about what's behind that, what's driving that.
Yeah. Again, the first ever FDA-approved medicine for this severe debilitating disease, familial chylomicronemia syndrome, FCS. The launch is off to a very strong start. It has really exceeded all external consensus estimations across the board with $26 million in revenue through the first two quarters. We've now increased our guidance for the community to be in the $75 to $80 million range for the year. Pretty remarkable for this rare disease that affects about 3,000 people in the U.S. The reason for the success is, of course, it starts with the drug profile. It's really shown, has shown amazing triglyceride reductions in FCS patients with substantial reductions in acute pancreatitis and substantial reductions in hospitalizations as well for these patients. It's a great drug profile, very well tolerated, very convenient for individuals, the ability to self-administer using a simple autoinjector once per month. It starts there.
The other success that we've had, of course, is with our commercial organization and our medical organization doing really a fabulous job in identifying patients to identify and confirm that they are indeed FCS patients, getting them onto drug quickly, and really having very positive payer interactions, whether it be government coverage or commercial coverage. It's all going very well. Lastly, the team has done an outstanding job in converting patients that were in our expanded access program in the U.S., as well as from our clinical trials, converting them over to commercial drug as well. All that has really contributed to a very successful launch to date. We expect the launch to continue to go well through this year, well into next year, ahead of our expected launch in severe hypertriglyceridemia.
Yeah. You mentioned the groundbreaking results you recently had in SHTG. Before we dig into some of those results, maybe just talk a little bit about where the market opportunity is in terms of the patient population and what the unmet need looks like there.
Yeah. We couldn't be more pleased with the results of the phase 3 trials, CORE and CORE2, in patients with severe hypertriglyceridemia that we announced the day after Labor Day. Like FCS, these patients, these individuals suffer from a whole host of problems due to severely elevated triglycerides. Like FCS patients, their biggest risk is a potentially fatal, almost always debilitating attack of the pancreas, an acute pancreatitis attack, severe inflammation of the pancreas. Unlike FCS, this is a prevalent disease. It affects millions of people in the U.S. who have triglycerides above 500 milligrams per deciliter, which is the definition of severe hypertriglyceridemia. Many of these patients are in the thousands as were in our trial. There are no effective treatment options available for these patients today. Current treatments for FHTG are generic medicines like fibrates, omega-3 fatty acids, statins, what have you.
They have very mild effects on reducing triglycerides in severely elevated conditions. The results we announced last week were groundbreaking, validating all kinds of hypotheses that have been in the medical community for decades that if you lower triglycerides enough in this patient population, you can actually reduce the risk of acute pancreatitis. It's been believed, never been proven. We proved it. Not only did we achieve substantial reductions in triglycerides, a 72% mean triglyceride reduction on top of standard of care in our CORE trial, we also demonstrated an 85% statistically significant reduction in acute pancreatitis events in the trial, all with favorable safety and tolerability. Really groundbreaking results that we couldn't be more pleased with.
Can you just talk about acute pancreatitis and the analysis you did there and how you would have combined the two studies and how unique that was?
Yeah. We really took an innovative approach, a highly innovative approach to the clinical trial design to maximize the probability that we would be able to see at least favorable trends in reducing acute pancreatitis, let alone statistical significance in reducing it. There are two pivotal trials, CORE and CORE2. Both were 12 months long. In total, a little over 1,000 patients with severely elevated triglycerides. 13% to 22%, depending on the trial, had a history of acute pancreatitis in the last 10 years. The primary endpoint in both CORE and CORE2 was at six months, and that was on triglycerides compared to placebo. We evaluated two doses, but I forgot to mention that: 50 milligrams, 80 milligrams, and placebo. The primary endpoint on triglycerides was at six months. That's where we achieved the 72% mean reductions in CORE that I mentioned before.
However, to maximize the probability of a successful outcome in acute pancreatitis, we wanted to power the study as strongly as possible. We let the studies go out for the AP endpoint, the key secondary endpoint, at 12 months. We combined CORE and CORE2 treatment arms, Olzarsen, versus the combined CORE and CORE2 placebo. That really innovative design allowed us to really demonstrate highly statistically significant reductions in acute pancreatitis. That, of course, was all pre-specified and agreed to with the U.S. Food and Drug Administration. That was an appropriate endpoint in the trial.
You shared a lot of the top-line results, but you plan to share some detailed data, I think, later this year at some point. Maybe talk a little bit about that. If there's other additional analyses you plan to include in that or any other things we should be looking out for there.
Yeah, we're looking forward to it. We're really looking forward to sharing the full data set at a medical meeting in the second half of this year. There are some obvious meetings to target. We're hoping to get late-breaking clinical trial opportunities to present the data. Also, we'll look to present a simultaneous publication as well for the full data set. What we're looking to present, of course, are the details, not just on triglyceride lowering, on acute pancreatitis, including the number of events in the trial, events in CORE versus CORE2, 50 milligram dose versus 80 milligram dose. It all looks very good, and we're looking forward to sharing that. The time course for reductions of acute pancreatitis compared to placebo, history versus non-patients without a history of acute pancreatitis, all that will come. The other secondary endpoints will be important too, right?
Not only will we share what I think is very impressive, reductions in APOC3, the target for Olzarsen, APOB100, a risk factor for cardiovascular disease, REML cholesterol, and so on. We're also going to share results on % of patients that we actually got below 500 milligrams per deciliter, which means that we got them below the definition of severe hypertriglyceridemia. Also, the % of patients we got below 150 milligrams per deciliter, which now means that you have normal triglycerides. The results are impressive. All those secondary endpoints will be shared along with a good update on, of course, the favorable safety and tolerability.
I guess there's more to look forward to from the data. If you could talk about next steps from here on the regulatory front and what are the pieces of the puzzle to get that moving forward.
The team is actively, they actually started preparing some of the NDA materials, supplemental NDA materials ahead of the data readout to get the submission completed as rapidly as possible. We'll get that done by the end of the year. Our base case right now, we're assuming a standard supplemental NDA review of 10 months, which puts us in an approval and launch in the early fourth quarter of next year. In addition, we're working to the presentation, of course. Very importantly, our commercial organization has already begun building the commercial team to launch SHTG, building off of the FCS commercial team. All that will be in place by the first half of next year.
In terms of adding to your commercial infrastructure, maybe give a little bit more detail around that in terms of what needs to be done and how big a lift that is from here.
Yeah. Right now, we have about 30 sales members in the field for FCS. That will grow to somewhere around 200, maybe above 200, for the severe hypertriglyceridemia to cover about 20,000 HCPs in the U.S. that are currently managing SHTG patients. These are your lipid specialists, cardiologists, endocrinologists. We're also building our omnichannel. We have omnichannel capabilities in place already. We're expanding that to make sure we reach as many HCPs as possible. We're conducting extensive market research on pricing. Currently, Tringolza is priced at a rare disease price for FCS. That will come down to match a prevalent disease, and we have all that work to do. We'll share those conclusions when we're getting ready to launch next year.
There's a lot to do between now and next year to ensure that we fully take full advantage and maximize our success for this blockbuster opportunity in which we have the first drug ever to really meaningfully address severe hypertriglyceridemia.
Yeah. You mentioned pricing, and I just wanted to get your maybe updated thoughts there if you have any. In the past, you sort of suggested a range for SHTG, but obviously, now you have very strong AP reduction as well. How does that impact your thinking on where you can price it?
Yeah. We have a lot of work to do now that we have the data. Now comes the time to roll up our sleeves and really get the work done. Obviously, having such strong triglyceride reduction with outcome data in acute pancreatitis gives us meaningful leverage to optimize the price in the U.S. as well as in Europe where outcome data is critically important. The AP data in Europe for pricing and reimbursement is going to be absolutely very helpful. We will settle on a price to maximize access for the patients, to maximize the number of patients that have easy access to Olzarsen, while also making sure that we receive the full value that this drug is really providing. A lot of work to do there. Some of the numbers that we put out there in the past were before we had data.
Now we have the data, so now it's really time to refine our pen, or sharpen our pencils and really refine our conclusions on pricing. A lot of work to do there.
Okay. Great. Maybe we can shift to your second independent launch, Donzera for HAE, approved a couple of weeks ago now. Maybe talk a little bit about the market opportunity there and some of the challenges that these patients with HAE are currently facing.
Yeah. Unlike Tringolza for FCS, where we're the first FDA-approved medicine, Olzarsen for SHTG, we're the first meaningful treatment for SHTG that we expect to be approved by the FDA next year. HAE prophylaxis is an indication where there are several prophylactic treatments already on the market. It is very different. With that said, we believe that Donzera has the profile to be the treatment of choice for many patients who suffer with hereditary angioedema. What we know is, despite the fact that there are prophylactic treatments on the market today, patients are substantially, significantly underserved. They're unsatisfied with current treatments. They're unsatisfied with the efficacy. They're still getting attacks, unpredictable, debilitating attacks that can happen anytime without any known triggers. They are unsatisfied with the tolerability profiles of current prophylactic treatments and the convenience. They're unsatisfied with the inconvenience of current treatments, at least some of them.
Donzera, now the launch of the brand name Donzera, checks all three of those boxes. We have shown really remarkable efficacy that's far above 80% reductions in HAE attacks in our phase 3 study that grew into the 90% reduction of attacks in our long-term open-label extension studies out to a year. Very durable efficacy, excellent tolerability, and the convenience of using a simple autoinjector self-administered once every four weeks or once every eight weeks. It's up to the patient and the HCP to decide what treatment algorithm they prefer. Not surprisingly, with current prophylactic treatments, what we're seeing and what's been published is that around 20% of patients are switching treatments in the U.S. today because they're unsatisfied. We think we can take advantage of that.
A recent Harris poll that was conducted showed that 9 out of 10 patients with HAE are very much willing to try another treatment option if it becomes available that they think could satisfy their unmet needs: efficacy, tolerability, or convenience. In fact, to that end, recognizing that patients are unsatisfied with their current prophy treatments, we set out to address that directly by conducting a switch study, another innovative trial design that we implemented. We invited patients from the three main prophy treatments that are on the market today in the U.S. to come onto a clinical trial in which they got to switch over to Donzera and did so. What we found was that patients enrolled and signed up for the clinical trial very quickly, not surprisingly, since they're unsatisfied. We had phase 2 data that they saw already, and I assume they were impressed with the data.
What we found in that trial was not only were we able to prevent any gaps in protection when we weaned them off of one treatment and weaned them onto Donzera, we were able to reduce their attack rate further compared to their baseline values of 64%. At the end of that trial, they were asked to fill out an independent survey, a questionnaire on how they felt about their current treatment versus the previous treatment. 84% of patients concluded that they preferred Donzera over their previous treatments for various combinations of efficacy, tolerability, and convenience. We think this drug, although we're coming into a market that has other treatments there already, has the potential to be a preferred treatment of choice for many patients. Our team, we got approval three weeks ago.
We got drug in channel within a week, and prescriptions have been written and drug is with patients already. Really a really nice operation. We've estimated in the U.S. market peak sales of $500 million for Ionis.
You mentioned only sort of approved a couple of weeks ago. You've got a product in the channel already. Any sort of early feedback you're hearing that you can share there?
too early on the launch to add any color to that. What I can tell you is that the sentiment in the HAE community has been very positive, very complimentary. We've been working very closely with the HAE Association and other patient groups. We've been actually very much moved, overwhelmed at times with the positivity that we've received from the community and how excited they are about Donzera. We think we're going to leverage that sentiment and execute on our launch, but it's a little early to comment on any color in the launch.
Got it. Maybe we can shift gears a little bit now to Waynua, and maybe start with TTRPN first and just talk a little bit about some of the recent trends you're seeing there.
Yeah. Just to level up to that, Waynua, the brand name Waynua, was developed by Ionis in our first-ever co-development, co-commercialization partnership that is with AstraZeneca. We're developing it for two indications: the hereditary polyneuropathy indication, TTR polyneuropathy indication, and the TTR cardiomyopathy population. 50,000 patients polyneuropathy, upwards of 500,000 plus in cardiomyopathy. The polyneuropathy indication was approved at the very end of 2023, and the launch has gone well. We believe that based on the overall drug profile, which has been shown, we're actually not just halting of disease, but actually a reversal and improvement of disease in many cases, coupled with the convenience of a self-administered autoinjector once per month using a low-volume painless injection, has resonated very well with the patient community. The launch is going well. We're seeing really substantial demand for Waynua for hATTR polyneuropathy.
We think that the benefits that we're seeing there, the positive sentiment we're seeing there for polyneuropathy is going to resonate and translate very well once we get to the cardiomyopathy indication, not too far down the road.
Maybe we can continue on just the cardiomyopathy there. There are a couple, two approved products there, one recent or multiple, three, sorry, with two recently launched earlier this year. Just any thoughts on the market opportunity a year ago versus how you're thinking now? Is it more optimistic than in the past, potentially?
It is. It's a growth market. It's clear that the size of this market continues to grow with new entrants coming into the market. It's been estimated to be $20, $30, $40 billion and growing. We believe that Waynua, eplontersen, will be a treatment of choice and do very well in this market once we get there for cardiomyopathy. There are two classes of mechanisms. There's a silencer class, like eplontersen, and then there's the stabilizer class. Both have shown great promise. Obviously, Tafamidis as a stabilizer is proven to be successful on the market. We believe that the silencer class is going to do very well. We believe the mechanism will be superior to other mechanisms and will be the preferred treatment of choice as first-line treatment, as well as for patients that progress on stabilizers. All patients eventually progress on stabilizers.
That's been shown, as well as for combination usage with stabilizers. The mechanisms can be, and should be, complementary to each other. Our cardiomyopathy phase 3 study is the largest study by far that we've ever conducted in TTR cardiomyopathy, with more than 1,400 patients in that study. We have a very strong mix of combination with Tafamidis, as well as monotherapy in the study. We believe that when we read this study out the second half of next year, we're going to have the richest data set, a compelling data set, not only in the overall population, which is CV mortality and hospitalizations, but in the subgroups that include combination usage with Tafamidis, which is very important because Tafamidis is the treatment of choice today in the U.S. market and globally, really.
Having that data for physicians to see the benefits of combination usage is going to go a long way. We're going to be the ones in the best position to have the best data show potential benefits of combination usage.
Got it. Later this year, you're also planning an Innovation Day, I think in October, if I remember. Maybe just talk about what we should expect to hear.
Yeah. In October, we're going to have what we used to call in the past R&D Days, give people a flavor for what this is, but we're more than R&D. Now it's a fully integrated commercial-stage biotech company. We rebranded it as Innovation Day. We're going to provide a really meaningful update on the pipeline, new pipeline products, actually, new pipeline programs that we're going to discuss that are in the cardiometabolic space and the neurology space, our two main franchises. We're also going to share some of the remarkable progress we're making in the technology, including the efforts we're making in medicinal chemistry that is allowing us to dose much less frequently, so increased durability in different programs.
An example I'll highlight is the recent data that our partner Biogen shared for our SMA program, Solanderson, using Ionis' novel chemistry that is supporting once per year intrathecal dosing for SMA. That phase 3 study is going to start next year. We have other programs that are designed to do similar things as Solanderson is doing with IT delivery for CNS diseases once per year. We're going to talk a little bit about that. New targets for technology advancements for targeting neuromuscular diseases, skeletal muscle, heart failure, cardiac myocytes, and delivering our drugs across the blood-brain barrier to the CNS.
We'll also talk quite a bit about our commercial success to date with Tringolza, the work we're doing with Donzera and our strategy for SHTG and our strategy for one of our one of the leading neurology franchises of anybody, what the strategy will be for upcoming launches for expected launches for Angelman syndrome and Alexander disease, to name just two of many. Of course, our financial strategy and our financial expectations. We are very much committed to be self-sustaining, cash flow positive with continued revenue growth year over year in the near term. We will also share our plan to get there and what it will take to get there in the near term. Very much looking forward to it. I hope folks can join us.
You have a very sort of robust pipeline that you're going to highlight. Maybe just a big picture strategy question. How do you balance deciding whether to sort of advance some of these programs on your own versus partnering? You know, how do you think about that going forward?
We take a very proactive, aggressive approach to prioritizing our pipeline that starts back in research. Drug discovery prioritization is happening in a formal, active way. We take that all the way through, and we check in on all those programs as they're progressing through IND supporting tox studies. Are they still the priorities that we set? Phase one, phase two, phase three, and so forth. Today, our prioritization process is very different than what it used to be many years ago when we were a company that was focused on partnering our programs. Today, our top priority in prioritization is what are we going to keep? How are we going to build our, continue to build our wholly owned pipeline? What are the top priorities? Where can we build the synergisms, synergies, I should say, with like our neurology franchise, synergies, vascular cardiometabolic franchise, follow-on programs?
You'll hear a little of that at Innovation Day too. We're using some of the new chemistries and mechanisms we're developing at Ionis. We have follow-on programs to ensure that the investments we're making in our lead program launched or to be launched are going to have a lot of longevity for years to come with new chemistries, new molecules against those targets and programs. Those are a part of the prioritization exercise. At the end of the day, there will always be programs that we feel aren't worth the resources. Everybody has limited resources, and we have, we're no different. If we don't believe that a program will make the cut, we will choose to partner to make sure that the drug is available for the patients and brings additional revenue and upside to Ionis.
In other situations, we may learn something new during the course of drug development that we may deprioritize a program and increase priority. The take-home message is the number one, the top priority is to build a wholly owned pipeline to ensure we're really generating the greatest value for shareholders, for patients, and for Ionis.
Yes. If you could ask, we've got a few minutes left here. Maybe just Alexander disease, you're going to have some data coming up later this year. Maybe talk about what to expect and sort of the market opportunity around that.
Yeah. Another example of our leading neurology franchise, you know, in addition to, it's a proven platform for the work we've done over the years in CNS diseases. It started with Spinraza for SMA and Calcade for ALS, SOD1 ALS, a Tau program for Alzheimer's disease, all really shown remarkable benefit in the clinic. It's one of 13 drugs in development for CNS diseases for rare, like Huntington's, broad, like Alzheimer's, more than half are wholly owned today. This is Alexander's disease, is an ultra-rare leukodystrophy genetically caused by overproduction of a protein called GFAP. We've developed a drug that lowers GFAP, normalizes it in preclinical models, and has really remarkable preclinical data. We took on another example of a very innovative trial design that we came up with at Ionis. Recognizing the ultra-rare nature of this disease, we felt that it was appropriate to do one clinical trial, right?
Not to do a phase 1, 2 study and then a phase 3 study, but to go right in there, utilize the natural history data to our benefit that we've developed over the years, conduct a trial that we think could show benefit in patients by targeting GFAP in this trial. It's a very novel design. The primary endpoint, it's about 70 patients or so, placebo controlled, single dose level. The primary endpoint in the study is a 10-minute meter distance, walk distance. These patients suffer from major motor function disorders, cognitive disorders, other problems that can be typically fatal, and also massive seizures that are continuous throughout life. Our primary endpoint is a motor function test, a 10-minute walk test. We're going to have that data in the second half of this year. We're hopeful the data will be strong enough to support an NDA submission early next year.
Great. Looks like we're just about out of time. When we wrap it up there, thanks so much, Brett. Appreciate your time.
Thank you, Mike.