Good morning, everyone. Thank you so much for joining us. It's my pleasure to introduce Ionis, and with us we have Brett Monia, CEO. Brett, thank you for being here.
Pleasure, Salveen. Great to be here.
To start here, you've laid out a transition to a more balanced portfolio in terms of your wholly owned and partnered programs, and now have independent launches, as well as several wholly owned pipeline programs. Could you just start with discussing how you've executed on the transition and your key priorities as you look to the outlook into the end of this decade?
Happy to. We are going through a transition evolution. Really, it's the product of a vision that I laid out when I moved into this role as CEO in January of 2020. Really focused on two key objectives. The first was to expand and diversify our technology, really advance new chemistries for antisense technology, to expand into siRNA technology using Ionis knowhow, even some gene editing, really genetic medicine. That wasn't as big a lift as you might think, because we have an outstanding research organization. Really what I needed to do was unleash the hounds, if you will, and we're all over. We have our first new chemistries for ASOs in the clinic, siRNAs in the clinic. We're moving forward with gene editing and so on.
The second objective was a big lift. That was to move Ionis from an R&D organization, and when I say D, I mean early-stage development, which partnered all of our programs to a fully integrated commercial-stage biotech company. That was obviously, there was a lot to do there. All of our programs were partnered, we had to build our wholly owned pipeline in two therapeutic areas, cardiometabolic, two areas we have a proven track record, to build our medical team, build our commercial organization. We wanted to do this to really drive value for the company, to retain the value that we created in drug discovery, but also to control our own destiny, right? Move at our pace and not rely on partners so much. I'm proud to say that we've achieved this. It's still early days, but we've had a great deal of success.
Last year, we launched our first two products, wholly owned products, TRYNGOLZA for familial chylomicronemia syndrome. That launch is off to an outstanding beginning, and it sets us up for a much larger indication, sHTG, and DAWNZERA for hereditary angioedema. We're prepared to launch independently two new programs this year. I already mentioned severe hypertriglyceridemia with a PDUFA date of June 30th coming up, and zilganersen, our first wholly owned neurology drug, to be launched in September for Alexander disease. The company really has evolved. We still have a lot more coming up, but it's really the product of the vision I laid out in January of 2020.
As you think about the 12 to 18-month catalyst path here, what would you highlight as the key updates which we read through to these five-year goals for the company?
Yeah. There's a lot coming up for the company, for Ionis, but I would start with the PDUFA date, the approval of TRYNGOLZA for severe hypertriglyceridemia. This program represents our first launch into a multibillion-dollar product opportunity for severe hypertriglyceridemia. Millions of people in the United States today suffer from the risk of acute pancreatitis, which can be fatal, and cardiovascular disease due to severely elevated triglycerides. We reported remarkable groundbreaking data at the AHA last year. Phase III data showing not only substantial reductions, up to 72% reductions in triglycerides on top of standard of care. More than 50% of patients we were able to normalize their triglycerides, but also an 85% reduction in outcome acute pancreatitis, which is groundbreaking, unprecedented. This multibillion-dollar product opportunity is obviously a big event for the company that sets us up for a lot of success well into the future.
The approval of zilganersen by the FDA in September is a big event, too. Although it's an ultra-rare indication, it's our first wholly owned launch into neurology, and we have seven drugs in our wholly owned pipeline in neurology today. 13 total with partners, but seven, including our Angelman's program. I would highlight the Angelman's program, too, where we expect to complete enrollment this year, and have phase III data next year as well. Those are big events that are coming up for the company, as well as our partnered pipeline, which we could talk more about later, which we have to manage to drive continued success. Our objective is to be cash flow breakeven in 2028 with revenue growth, consistent revenue growth to follow year-over-year, quarter-over-quarter, and ultimately be profitable. Those are some big events that sets us up to achieve that.
In the context of the cash breakeven in 2028, how are you thinking about longer-term margins?
Growing. Growing extensively as we continue to grow. We expect continued growth as these launches take shape. Our wholly owned launches take shape, growing margins quarter-over-quarter, year-over-year, and as our partnered pipeline takes shape. It's a big advantage to have multiple sources of revenue for the company. Our wholly owned pipeline is our priority. However, we have a rich revenue stream from our partnered pipeline as well. SPINRAZA continues to perform exceptionally well. We have a follow-on to SPINRAZA, salanersen, which is coming, which provides really attractive economics to Ionis. We have the chronic HBV drug with GSK, which we expect approval in October, where we have attractive economics. We have four more phase III readouts from our partnered pipeline this year.
We refer to this as a revenue accelerator, our partnered pipeline, on top of our wholly-owned pipeline, which of course we own, to really drive those continued growth for those margins for well into the future.
Strategically, what is the role of external business development here and other modalities for advancing your portfolio? Historically, the company was very much focused on ASOs, and we are now seeing you bring in other technologies. Maybe you could speak to those as well as your work on the blood-brain barrier technology.
Yeah. Our research organization is incredibly prolific. I don't see the need for us to in-license drugs at all in the near future. We will always pay attention. If there is something that was really attractive to us, we would be surprised that we couldn't do it better ourselves, but we will pay attention to it. In-licensing drugs is not a priority for us today. We move three to five new drugs into development every year, particularly in CNS and cardiometabolic diseases. Technology in-licensing is something we have done over the last few years since I've moved into this role. In particular, we have in-licensed ligand targeting strategies to open up new tissues and overcome the blood-brain barrier, to your point.
For example, we in-licensed exclusive rights from Bicycle Therapeutics, in which we are using very low molecular weight peptides attached to siRNAs or attached to ASOs that are opening up skeletal muscle therapeutic opportunities, cardiac muscle therapeutic opportunities, and also allowing us to further extend our leadership in neurology by allowing us to not only administer our drugs intrathecally twice a year, once a year, but to now to administer our drugs to the CNS using subcutaneous administration, low volume administration, very infrequent. That is an example of Bicycle. We have other approaches that we have been licensed as well to overcome the blood-brain barrier. For muscle targeting, we are actually in the clinic for cardiac, going after a cardiac myocyte target called phospholamban for heart failure. That is partnered with AstraZeneca. You may wonder, well, if you are prioritizing the wholly-owned pipeline, why is it partnered?
Well, we have a long-standing research collaboration with AstraZeneca, and there was one target slot in the research coverage remaining. They jumped at it. The data was really compelling. We have our own that is now in IND tox studies for cardiac muscle targeting, and we have targets coming for skeletal muscle for neuromuscular diseases. For blood-brain barrier, we are manufacturing our first BBB-targeting drug for CNS diseases, dementia, which will start IND tox studies in the second half of this year, and we hope to be in the clinic next year for our first BBB strategy. I see us continuing to evaluate technology and in-licensing technology when it makes sense to, like we had in the past. Right now, we are in pretty good shape with what we have. We have a lot of opportunity.
Starting here with TRYNGOLZA. You have the June 30th PDUFA for sHTG, as you mentioned. Could you speak to your field team and preparation as you move from the ultra-rare FCS indication to a much larger market here?
Yeah. As I mentioned earlier, this is a big opportunity for Ionis. We're leading the way in targeting this indication, severe hypertriglyceridemia. As I said, millions of people, multi-billion dollar product opportunity, and we're way ahead. And we're creating this market opportunity. The FCS launch, the first indication, just for level setting for everybody, we launched January last year for familial chylomicronemia syndrome, about 3,000 people in the United States, devastating disease due to very high triglycerides. Demand for TRYNGOLZA and growing quarter-over-quarter, week-over-week, actually. That sets us up for a successful severe hypertriglyceridemia launch because we're in the market. Most of the physicians that manage FCS patients manage sHTG. We're out there talking about the phase III data and setting us up to really take advantage of our leadership here. We're ready to launch. We've had our final meetings at Ionis for launch readiness.
We're ready to launch. Our field team, that's approximately 200 or so physician-facing field team, is trained. They're in the field. They're promoting the FCS indication, and they're educating on severe hypertriglyceridemia. And our medical team has been in the field educating on the phase III data from CORE and CORE 2 in severe hypertriglyceridemia. They've been doing that for quite some time. And our drug supply is ready to go, and we're looking forward to an on-time approval on June 30th, and we'll have drug in channel within a few days and ready to launch. The other thing I'll say, Salveen, is that's the starting point. A couple of hundred field-facing teams or patient-facing teams, customer-facing teams, team members. We'll look at how the launch goes, and we could always modify that and upsize it as we need to.
You said a new WAC price of $40,000 for the drug effective April 1st applied to FCS as well as sHTG. Remind us on the rationale behind not waiting until sHTG approval and how the integration into the 2027 payer cycles improves access post-launch.
Yeah. Our $40,000 WAC price for sHTG, again, to level set for folks, we're going from a rare indication, a WAC price of $595,000 down to $40,000. That decision, two years of research, demand research. It was the right time to do this. First of all, we had our phase III data. Our HCP demand research was complete. Now, earlier this year, we completed our payer research, which was extensive. Obviously, what our goal was to do was to retain as much value for our shareholders, for Ionis, while threading that needle to make sure access for patients was optimal, to avoid headaches for prescribers to write prescriptions and get patients access to the drug. In other words, no payer blocks. We believe that based on all that work, we threaded the needle very nicely with a $40,000 WAC price.
We implemented this on April 1st because our work was done. Secondly, to coincide with 2027 payer budget cycles, which really begin April and May. What we wanted to do was to make sure that TRYNGOLZA with the proper $40,000 was the proper price for a large, highly prevalent disease indication, was on the radar, was in the budgets for payers so that we didn't have any roadblocks in the 2027 budget cycle. It's there. It's getting there. It's getting embedded in the budgets for 2027. Thirdly, it allowed us to talk to payers as we approach the PDUFA date and to talk about what their exposure is, right? How we're going to be able to manage that with them to ensure for a smooth launch from a payer perspective. Really all that came together and has been very well received by the payer community.
It sets us up for a nice, smooth launch.
Could you lay out how you're thinking of quarterly dynamics this year as the volume from sHTG offsets the pricing headwind in FCS?
We have guided toward a $100 million - $110 million revenue goal for TRYNGOLZA for this year, that reflects the significant, what I just took you through, substantial reduction in price right out of the gate. Right now, we have a $40,000 WAC price for FCS, right? That will go right into the sHTG launch. That is going to drive revenue down initially until that volume accelerates in the second half of this year. We're expecting the volume to accelerate pretty rapidly, but still, the volume has to overcome the deficit in revenue that we'll get because of the drop in price. We expect that to really start beginning to take off in the fourth quarter of this year as that volume really overcomes and really takes shape.
Next year is going to be a big year for really accelerating revenue growth for the company as we work towards our $3+ billion peak product sales opportunity in the U.S.
What are you looking to see in competitor Arrowhead's plozasiran phase III data in the third quarter? Is it possible that their construct or use of siRNA could result in different hepatic fat increases versus TRYNGOLZA?
There's so much to take care of to ensure that this launch is as successful as possible. As I said, we're in great shape to make sure it is successful. That's what we're focused on. We're really not looking for any data from any competitor, phase III data or whatever, to influence what we're expecting to do. We expect there to be a competitor in this space, our $3+ billion product market opportunity, peak sales opportunity reflects that we're not the only ones in this space. Our data is groundbreaking, as I said, and we've set a very high bar on the reductions of acute pancreatitis, reductions in triglycerides that I just took you through, all with excellent safety tolerability, and the convenience of self-administration once per month using a simple low-volume auto-injector.
Let me talk about the hepatic fat that you referred to because it is important to discuss. What we reported at AHA last year was a small increase, particularly at the 80 mg dose in liver fat in patients with severe hypertriglyceridemia. I want to emphasize that we are expecting approval for 50 mg and 80 mg. Both were highly efficacious. The 80 mg dose showed a little bit better efficacy, particularly in the normalization of triglycerides down to a certain level, but both were highly efficacious. 50 mg barely moved the needle on liver fat. It was very, very small. 80 mg was small too, but it was higher. The effects were dose-dependent. There was no clinical sequelae associated with that increase in liver fat at 80 mg. There was no correlation with ALT elevations.
All of our demand research, the $3+ billion product market opportunity that I referred to before, assumes that is there. That was included in our payer research. That was included in our HCP demand research. In the eyes of HCPs, they shrug it off.
They do not think it is anything to be concerned about, particularly since there is no adverse events associated with it. It is just an observation, and it is also well-recognized as an on-target effect. We know that a competitor of ours. The competitor program that you referred to, the siRNA, showed in their phase II study a dose-dependent increase in liver fat through this mechanism targeting APOC3. It was not statistically significant, but it was underpowered. It will be underpowered in their phase III study, too, because really, relative to our study, there are very few patients that are undergoing MRI. We think it is comparing apples to oranges.
The bottom line is we are focused on our study. There is no clinical sequelae associated with this. Then the final thing I want to say is that as we continue to monitor these patients long-term in the open-label extension, we are seeing exactly what you would see in an adaptive on-target response, is that a return towards baseline. These patients are continuing to be treated. No adverse events are emerging with long-term treatment, and we are seeing the liver be able to handle this, and the triglycerides in the liver return towards baseline. We are going to present that data at an upcoming medical congress, so stay tuned.
How are the competitive dynamics between both drugs playing out in FCS? Maybe talk to what you are seeing in terms of new patient share and switches, and is there a read-through from that to sHTG?
The FCS launch continues to go great. As I said before, the demand continues to accelerate. Each week, my team tells me that this week was better than last, with new patients coming onto TRYNGOLZA. That, again, sets us up really well for severe hypertriglyceridemia and really reflects the product profile. The efficacy and the feedback we are getting from the patient community and the HCPs has been overwhelmingly positive. That is great. I cannot speak in detail about our competitor because I am not that familiar with it, but I am sure that the vast majority of patients that they are identifying, like us, are newly identified patients. We are just scratching the surface in FCS, and we had the first FDA-approved medicine for FCS. It is all about patient identification and getting patients onto the new drug, I think, for both programs.
We are seeing a handful of patients switching from theirs to ours. I think they said the same thing back and forth, this is almost all newly identified patients for both programs. TRYNGOLZA continues to go really well with respect to patient demand and new patients getting on drug and reauthorizations and prescribers expanding to more and more patients because of their positive experience.
Overall, what gave you the confidence here to raise your peak sales estimate from $2 billion to greater than $3 billion? And how much of this raise was due to the change in price, which could insinuate increased volumes?
In January of this year, we increased our peak product U.S. sales for TRYNGOLZA to be $2+ billion. That was based on the HCP demand research. How many patients do you have? How aggressive are you going to treat? How excited are you about the data? That was based on the phase III data, which we then have. More recently, we have upped that peak product sales to more than $3 billion in the U.S. That is because of pricing. The HCP demand and the data is now in hand. Once we finalize the pricing that I referred to earlier of a $40,000 WAC, that gets us into expectations for a net price that is meaningfully higher than what we were projecting in January. That really is what drove that second increase in peak product sales for TRYNGOLZA to $3+ billion. It is about pricing.
Moving to WAINUA. Clearly addressing ATTR cardiomyopathy, which is a large blockbuster opportunity here. We're going to see data in the second half of the year with your partner, AstraZeneca, and you've disclosed that CARDIO-TTRansform has 57% of patients on a stabilizer. I guess, A, speak to how you're thinking about the overall success of the study, but also in the context of the combo arm here and a really large N there. Do you expect statistical significance on top of tafamidis in the context of that trial?
Like TRYNGOLZA, we've developed WAINUA for two indications. A rare hereditary indication called ATTR polyneuropathy that's approved, and that launch has gone very well. The feedback from the patient community and physicians has been very, very positive for the drug. The second indication, we can call it rare, but we all know it's much more prevalent, the ATTR cardiomyopathy, which includes hereditary but also wild type patients that don't have a mutation in the TTR gene. CARDIO-TTRansform, our phase III study, is the largest study ever conducted by far in ATTR cardiomyopathy, and that sets us up for the richest data set for not only the primary endpoint, but secondary endpoints. We're expecting phase III data, as you said, second half of this year, and everything is going very well in the conduct of the study and execution. The study is reasonably de-risked for its primary endpoint.
We're excited, AstraZeneca's excited to get that data, to get the NDA submitted, assuming positive outcome by the end of this year, and to get that drug launched next year. Because of the size of this study, we also have the potential to show benefit in secondary endpoints, right? The one that people are most focused on is the combination with tafamidis, a stabilizer. First, let me make sure we're all aware that nobody has ever tested the hypothesis that a silencer and a stabilizer will cooperate and show additivity, right? We're going to be the first to test that hypothesis. If that's the case, and it's reasonable to assume that it will cooperate, we're in the best position to generate the strongest data set to reflect added benefit in combination. We're powered for the primary endpoint.
Of course, all secondary endpoints have some powering associated with it, but our powering for the combination isn't very high. It's a secondary endpoint, and it's down in the hierarchy. We've presented the statistical hierarchy already. We believe that if they cooperate together, the mechanisms, that we're going to have the strongest data set that could be convincing to prescribers that for patients that are being treated with stabilizers today, and we know that all patients on stabilizers are progressing, right? This doesn't reverse the disease. They're progressing, which means heart failure, heart attacks, strokes, that they're going to advocate for combination usage with a silencer. We're going to be in a position to have that data and convince physicians that combination is worth doing to help patients. Our $5+ billion peak product sales guidance that we and AstraZeneca have stated does not assume combination benefit.
That's an upside to that. We're very much looking forward to that data and like you said, we'll have the data in the second half of this year and everything is going well for the study.
Noting that you have an auto-injector for the Medicare Part B channel, do you still expect most of WAINUA-treated patients to go through Part D? Within Part D, how are you thinking of pricing relative to the stabilizers? And is this an avenue to compete against vutrisiran, the Medicare Advantage segment?
We expect that the vast majority of patients on WAINUA will be going through the Part D route, self-administered using a simple low-volume auto-injector. That's a big differentiator for WAINUA, which does not have to be treated by a healthcare provider in a clinical setting, what have you, using a pre-filled syringe. We and AstraZeneca felt that there could be value in the physicians that prefer to be able to administer the drug themselves, maybe go through the Part B route for WAINUA to provide dosing flexibility, an option for physicians to do that if you want to do it. The vast majority of patients, and this has really resonated in the polyneuropathy launch, self-administration has been very well received.
The convenience, especially when you get into the much more prevalent cardiomyopathy indication, which we're going to be getting into not just centers of excellence, but rural settings and global settings, that it's going to be the primary driver for the value of WAINUA. It does provide dosing flexibility. As far as pricing, the price for polyneuropathy is out there. We haven't disclosed the pricing for cardiomyopathy yet. That'll come when we get approval.
Right. On the neurology side, you mentioned Angelman. What gives you the confidence in your primary endpoint here and ability to manage the heterogeneity in this population and essentially result in a positive outcome? Could you discuss your decision to remove the 40 mg cohort from the phase III study and any impact there to data timing?
We're very proud of our success in neurology. Three approved medicines today, including polyneuropathy for ATTR, but for CNS diseases, SPINRAZA and QALSODY for SOD1- ALS. We recently reported positive phase II data for our tau program in Alzheimer's disease with Biogen, zilganersen we expect approved for Alexander disease in September. Right behind that is our Angelman's program, obudanersen, which we expect to complete enrollment this year with phase III data next year. Confidence, proven platform. This is the same platform that produced those FDA approvals that I referred to earlier. Our phase I/II data, where we showed really, really what we believe is highly clinically meaningful benefit across many different clinical measures, including communication, cognition, motor function in Angelman syndrome, using various different instruments. The study is looking to complete enrollment later this year.
Execution-wise gives us confidence too, but it's really the platform and our phase I/II data. We chose expressive communication as our primary endpoint because that's where we saw the greatest magnitude of benefit in our phase I/II study. Although we saw benefit in cognition and motor function, it was expressive communication that really stood out. It was dose-dependent. Also what's very important is that we know the natural history, which is very well established in Angelman syndrome. The natural history for progression of expressive communication is essentially zero. The signal-to-noise in showing benefit compared to placebo on expressive communication should be highly advantageous for us. We're not going to see a lot of noise in that endpoint.
Of course, we have secondary endpoints on cognition and so forth, and so on, but that gives us a lot of confidence too, and that's why we chose that as the primary endpoint. We removed the 40 mg dose because we didn't feel like we needed it. The phase I/II long-term extension data, which we reported some new data from last year, showed that 80 mg was outperforming 40 mg. Let's just go 80 mg. It's well-tolerated, it's safe, long-term treatment, and it allowed us to get to the phase III data faster. We can enroll the patients quicker. Patients that were on 40 mg were moved into the open label extension for the REVEAL phase III study. They moved them up to 80 mg. It didn't really have much impact on our trial. It was only a handful of patients at the time.
You've partnered neuro pipeline assets with Biogen, notably the tau targeting BIIB080, and the next generation SMA asset, salanersen. Can you remind us of the economics to Ionis and your thoughts on the recent data releases for these assets, particularly the phase II tau data?
Very quickly on salanersen, that's a follow-on to SPINRAZA that we provided to Biogen once per year intrathecal dosing with even greater efficacy on SPINRAZA. The economics goes from the mid-teens to the mid-20% range on royalties and about more than $500 million in development and commercial milestones. The tau data, we're very excited about that we reported with Biogen. That data is going to be presented at AAIC in July, what you're going to see there is unprecedented improvements in cognition by targeting tau. You're also going to see reversal of tau pathology. The neurofibrillary tangles that people are all aware of, we're actually reversing that by PET imaging. Of course, tau reductions. All good tolerability, no ARIA, of course, the antibodies produced.
The economics, they are SPINRAZA-like, low to mid-teens in royalties and a few hundred million dollars in development and commercial milestones. We believe tau is a breakthrough for Alzheimer's disease. Obviously, we desperately need new mechanisms to tackle in addition to A-beta approaches. We think tau is the solution. We actually are also developing a blood-brain barrier approach to tau at Ionis that we expect to move into IND supporting tox studies later this year.
Great. With that, Brett, thank you so much. Really appreciate the time today.
Thanks, Salveen. It was a pleasure.
Good luck with all these datasets.
Yep. Thank you.