Ionis Pharmaceuticals, Inc. ($IONS)

Great. 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, and great to be here.

So 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?

Yes, happy to. So 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 2 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 know-how, even some gene editing, really genetic medicine. And that wasn't as big a lift as you might think because we have an outstanding research organization. And really what I needed to do is 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, and that was to move Ionis from an R&D organization. And when I say D, I mean like 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. We had -- all of our programs are partnered so we had to build our wholly owned pipeline. [indiscernible] In 2 therapeutic areas, cardiometabolic, [indiscernible] 2 areas, we have a proven track record to build our medical team, build our commercial organization, and 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 2 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. And we're prepared to launch independently 2 new programs this year. I already mentioned severe hypertriglyceridemia with a PDUFA date on June 30 coming up and Zilganersen, our first wholly-owned neurology drug to be launched in September for Alexander disease. So 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 read through to these 5-year goals for the company?

Yes. So 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 or/and cardiovascular disease due to severely elevated triglycerides. And we reported remarkable groundbreaking data at the AHA last year, Phase III data showing not only substantial productions up to 72% reductions in triglycerides on top of standard of care. Nearly -- more than 50% of patients we were able to normalize their triglycerides, but also an reduction in outcome, acute pancreatitis, which is groundbreaking unprecedented. And this is this multibillion-dollar product opportunity is obviously a big, big event for the company that sets us up for a lot of success 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 launch into wholly owned launch in neurology, and we have 7 drugs in our wholly owned pipeline in neurology today, 13 total with partners, but 7, including our Angelman's program I would highlight the Angelman program, too, where we expect to complete enrollment this year and have Phase III data next year as well. So 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. But 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. So 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. We have a rich -- 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, [ sale nursing ], which is coming -- which provides really attractive economics to Ionis. We have a chronic HPV drug with GSK, which we expect approval in October, where we have attractive economics, then we have more Phase III readouts from our partner pipeline this year. So this really -- we refer to this as a revenue accelerator our partner pipeline on top of our wholly owned pipeline, which, of course, we own to really drive those margins -- 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're now seeing you bring in other technologies. So maybe you could speak to those as well as your work on the blood-brain barrier technology.

Yes. Our research organization is incredibly prolific. I don't see the need for us to in-license drugs at all in the near future. I mean we'll always pay attention if there's something that was really attractive to us, we'd be surprised that we couldn't do it better ourselves. But we'll pay attention to it. But in-licensing drugs is not a priority for us today. We moved 3 to 5 new drugs into development every year, particularly in CNS and cardiometabolic diseases. Technology and licensing is something we have done in the -- over the last few years since I've moved into this role. And in particular, we've in-licensed targeted 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 technology, Bicycle Therapeutics, in which we're using very low molecular at 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's an example of bicycle. We have other approaches that we've been licensed as well to overcome the blood-brain barrier. For muscle targeting, we're actually in the clinic. For cardiac -- going after a cardiac myocyte target [ phospho land ] for heart failure. That is partnered with AstraZeneca you may wonder, well, if you're prioritizing the wholly owned pipeline is a partner, well, we have a long-standing research collaboration with AstraZeneca and there was one target slot in the research [ cover ] remaining. They jumped at it. The data was really compelling. We have our own. That's now an IND [ tox ] study 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. So I see us continuing to evaluate technology and in-licensing technology when it makes sense to like we had in the past. But right now, we're in pretty good shape with what we have. We have a lot of opportunity.

Starting here with TRYNGOLZA, you have the June 30 PDUFA for sHTG as you mentioned. Could you speak to your field team in preparation as you move from the ultrarare FCS indication to a much larger market here?

Yes. So as I mentioned earlier, this is a big, big opportunity for Ionis. We're leading the field, leading the way in targeting this indication severe hypertriglyceridemia. As I said, millions of people, multibillion-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, where we launched January last year for familial chylomicronemia syndrome with about 3,000 people in the United States devastating disease cause due to high -- very high triglycerides [indiscernible] demand for TRYNGOLZA and growing quarter-over-quarter, week-over-week, actually. That sets us up for a successful severe hypertriglyceridemia launch because we were 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 [ field ] patient -- physician facing the field team is trained they're in the field. They're promoting FCS in 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 CORE2 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 30, and we'll be -- we'll have a drug in channel within a few days and ready to launch. So the other thing I'll say, Salveen, is that that's a 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 can always modify that and upsize it as we need to.

You set a new WACC price of $40,000 for the drug effective April 1, applied to FCS as well as remind us on the rationale behind not waiting until sHTG approval and how the integration into the 2027 payer cycles improves access post launch?

Yes. So our $40,000 WAC price for sHTG, again, level set for folks, we're going from a rare indication, a WACC price of $595,000 down to $40,000. That decision [Audio Gap] 2 years of research [Audio Gap] 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. And 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 on 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, and we believe that based on all that work, we threaded the meal very nicely with a $40,000 flat price. We implemented this on April 1 because our work was done. Secondly, because to coincide with 2027 payer budget cycles, which really begin April and May. And what we wanted to do was to make sure that TRYNGOLZA with the proper $40,000 with the proper price for a large highly prevalent disease indication, was on the radar. It was in the budgets for payers, so that we didn't have any roadblocks in the 2027 budget cycle. So it's there. It's getting there. It's getting embedded in the budgets for 2027. And thirdly, it allowed us to talk to payers as we approach the PDUFA date and to talk about what their exposure is, right? And how we're going to be able to manage that with them to ensure for a smooth launch from a payer perspective. So really, all that came together and has been very well received by the payer community. So that 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?

Yes. We -- so we have guided toward a $100 million, $110 million revenue goal for TRYNGOLZA for this year. And that reflects the significant of what I just took you through substantial reduction in price right out of the gate. So right now, we have a $40,000 WACC price for FCS, right? And 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 will 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. And then next year is going to be a big year for really accelerating revenue growth for the company as we work towards our $3 billion plus product U.S. peak product sales opportunity in the U.S.

What are you looking to see in competitor arrowheads [ redemplo's ] 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. And 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. I mean we expect there to be a competitor in this space. And our $3 billion plus product market opportunity, peak sales opportunity reflects that, 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. But let me talk about the hepatic fat that you referred to because it's important to discuss. So what we reported in -- at AHA last year was a small increase, particularly at the 80-milligram dose in liver fat in patients with severe hypertriglyceridemia. I want to emphasize that we're expecting approval for 50 milligrams and 80 milligrams. Both were highly efficacious the 80-milligram dose showed a little bit better efficacy, particularly in the normalization of triglycerides down to a certain level, but both were highly efficacious and 50 milligrams barely move the needle on liver fat, it was very, very small. 80 was small too, but it was higher with the effects were dose dependent. There was no clinical sequelae associated with that increase in liver at 80 milligrams. There was no correlation with ALT elevations. All of our demand research, the $3 billion-plus product market opportunity, that I referred to before, assumes that is there. That's based on -- that was included in our payer research, I was included in our HCP demand research. It's -- and in the eyes of HCPs, they shrug it off. They don't think it's anything to be concerned about, particularly since there's no adverse events associated with it. It's just an observation, and it's also well recognized as an on-target effect, right? We know that our competitor -- a competitor of ours -- the competitor program that you referred to, the siRNA, showed in their Phase II study, dose-dependent increase in liver fat. By knocking through this mechanism targeting APOCIII. It wasn't statistically significant, but it was under powered. And it will be underpowered in their Phase III study, too because it's really relative to our study, there are very few patients that are undergoing MRI. So we think it's comparing apples to oranges. The bottom line is we're focused on our study, there's no clinical sequela associated with this. And 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're seeing exactly what you would see in an adaptive on-target response is that a return towards baseline, right? So these patients are continuing to be treated. No adverse events are emerging with long-term treatment, and we're seeing the liver fat -- the liver to be able to handle this and the triglycerides and deliver return towards baseline. So we're going to present that data at an upcoming medical congress. So stay tuned.

And how are the competitive dynamics between both drugs playing out in FCS maybe talk to what you're seeing in terms of new patient share and switches. And is there a read-through from that sHTG.

The FCS launch continues to go great. I mean, as I said before, the demand is -- continues to accelerate. Each week, my team tells me that this week was better than last with new patients coming out of TRYNGOLZA. And that, again, sets us up really well for severe hypertriglyceridemia it really reflects the product profile. I mean the efficacy and the feedback we're getting from the patient community and HCPs has been overwhelmingly positive. That's great. I can't speak in detail about our competitor because I am not that familiar with it. But I'm sure that the vast majority of patients that they're identifying like us, our newly identified patients. I mean this is -- we've just scratched the surface in FCS. And this, we had the first FDA-approved medicine for FCS. So it's all about patient identification and getting patients onto new drug, I think, for both programs. I mean we're seeing a handful of patients switching from theirs to ours. And I think they said the same thing back and forth, but this is almost all newly identified patients for both programs. But TRYNGOLZA continues to go really well with respect to patient demanding 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 is due to the change in price, which could insinuate increased volumes?

Yes. And so in January of this year, we increased our peak product U.S. sales for TRYNGOLZA to be $2 billion plus. And that was based on the HCP demand research, how many patients do you have, how many -- how aggressive are you going to treat, how excited are you got the data, that was based on the Phase III data, which we then have. More recently, we've upped that peak product sales to more than $3 billion in the U.S., and that's because of pricing. The HCP demand and the data is now in hand. But once we finalize the pricing that I referred to earlier of a $40,000 WACC that gets us into a net expectations for a net price that's meaningfully higher than what we were projecting in January. And that really is what drove that second increase in peak product sales for TRYNGOLZA to $3 billion plus. It's about pricing.

Okay. 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-TTR transform 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 end there. Do you expect statistical significance on top of tafamidis in the context of that trial?

So like TRYNGOLZA, we're developing -- we've developed a new for 2 indications, right? 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 have been very, very positive for the drug. The second indication, we can call it rare, but we all know it's very -- it's much more prevalent, the ATTR cardiomyopathy, which includes hereditary but also wild-type patients, patients that don't have a mutation in the TTR gene. Cardio transform 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 end points. And our -- 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 derisked for its primary endpoint. We're excited. AstraZeneca is 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 the study, we will also have the potential to show benefit in secondary endpoints, right? And the most -- 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 show the -- 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 our powering for the combination isn't very high. It's a secondary endpoint. It's down in the hierarchy, we presented the higher -- statistical hierarchy already. But we believe that if they cooperate together, the mechanism is that we're going to have this strongest data set that could be convincing to prescribers that patients that are being treated with stabilizers today, and we don't 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 the science. 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 plus product peak product sales guidance that we and AstraZeneca have stated does not assume combination benefit. That's an upside to that. So 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.

And noting that you have an auto-injector for the Medicare Part B channel, do you still expect most of when you are treated patients to go through Part D? And within Part D, how are you thinking of pricing relative to the stabilizers? And is this an avenue to compete against [ Aventura ] in the Medicare Advantage segment?

Yes. So our primary -- 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 health care provider in a clinical setting or what have you, using a prefilled syringe, we and AstraZeneca felt that there could be value in the physicians that prefer to be able to administer the drug themselves and 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 is -- 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 to 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. But it does provide dosing flexibility as far as pricing, the price for polyneuropathy is out there. We haven't disclosed the pricing for cardiomyopathy. That will come when we get approval.

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 results in a positive outcome? And could you discuss your decision to remove the 40-milligram cohort from the Phase III study and any impact there to data timing?

Yes. We're very proud of our success in neurology 3 approved medicines today, including polyneuropathy for ATTR. But for CNS diseases, SPINRAZA and [ Calstore ] we recently reported positive Phase II data for our towel program in Alzheimer's disease with Biogen. And Zilganersen, we expect to prove for Alexander's disease in September. Right behind that is our Angelman's program, [ olezarsen ], which we expect to complete enrollment this year with a Phase III data next year. Confidence a 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 measures of clinical measures, including communication, cognition, motor function in Angelman using various different instruments. So and the study is we're going to complete enrollment later this year. So execution-wise, gives us confidence, too. But it's really the platform in 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 a benefit in cognition and motor function, it was expressive communication that really stood out. It was dose dependent. And 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 0. So the signal to noise in showing benefit compared to placebo on expressive communication should be highly advantageous for us. We don't 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-milligram 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 milligrams was outperforming 40 milligrams, right? So let's just go to 80. It's good. It's well tolerated. It's safe, long-term treatment and allowed us to get to the Phase III data faster, right? We can enroll the patients quicker. Patients that were on 40 milligrams were moved into the open-label extension for the REVEAL Phase III study, and they move them up to 80 milligrams. Didn't really have much impact on our trial. But there's only a handful of patients -- a handful of patients at the time.

You've partnered neuro pipeline assets with Biogen, notably the tow targeting BIIB080 and the next-generation SMA assets Zilganersen. Can you remind us of the economics to Ionis and yourself on the recent data releases for these assets, particularly the Phase II tau data?

Yes. So very quickly on Zilganersen, that's a follow-on to SPINRAZA that we provided to Biogen once per year intrathecal dosing with even greater efficacy of SPINRAZA, the economics from the mid-teens to the high 20 -- 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. And 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, so the neurofibrillary tangles that gets -- people are all aware of, we're actually reversing that by PET imaging and of course, tau reductions, all good tolerability, no area, of course, the antibodies and abilities to produce. The economics there are SPINRAZA like low to mid-teens and royalties and a few hundred million dollars in development and commercial milestones. We believe tau is a breakthrough for Alzheimer's disease, obviously, we need desperate 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. Well, with that, Brett, thank you so much. Really appreciate the time today.

Thanks, Salveen.

Good luck with all these data sets.

Yes. Thank you.