A pivotal time for an RNA pioneer

Introduction

0:00You're listening to The Top Line, brought to you by Fierce Pharma and Fierce Biotech. I'm your host, Ayla Ellison.

0:212026 is a pivotal year for RNA therapeutics pioneer, Ionis Pharmaceuticals. With a key FDA decision ahead and major phase three data expected this year.

Ionis Pharmaceuticals

0:34On this week's episode of The Top Line, Angus Liu speaks with CEO Brett Monia about the science behind antisense oligonucleotides, the significance of those readouts, and what it takes to turn a 30-year-old discovery platform into a full-fledged commercial biotech. Let's get into it.

0:58So, Brett, I can imagine you must be busy these days. We just saw the data at the American Academy of Neurology of self-nursing in a rare neurodegenerative condition called Alexander disease. And it's shown stabilize the gait speed as assessed by a 10-meter walk test. This is a condition with no approved therapy.

Antisense Oligonucleotides

1:26So, Brett, could you explain just briefly how your platform science, the antisense approach, is able to address the disease? Absolutely, Angus. We're very excited about the Zilga Nurse and Alexander Disease Program. Let me take a half a step back and set the stage here for what we're going to talk about with respect to Zilga. Ionis is not only a pioneer in the creation of the field we refer to today as RNA-targeted therapeutics,

1:57you know, a real paradigm shift in clinical medicine that has led to so many breakthrough treatments, but also pioneers of CNS disease, right? It was Ionis who conceived, discovered, and he actually even developed, before licensing to Biogen, as you pointed out, Spinraza. The first nucleotide-based treatment for any neurological disease and the first FDA-approved medicine for spinal muscular atrophy. Spinraza was truly transformational for the SMA community.

2:30SMA, before Spinraza, was the number one genetic cause of infant death in the world, and that has changed. It really changed SMA to be a manageable condition because of that breakthrough. And then following this was the breakthrough in ALS that we created, which was CalSati, the first ever disease-modifying treatment approved by the FDA for a cause of ALS, a genetic cause of ALS. And although this addresses a segment, a rather small segment of the ALS community, that is, different causes of ALS,

3:05this being due to mutations in the SOD1 gene necklace of ALS, it was transformational for the SOD1 ALS community, which is a hereditary condition to afflicts generations of people and showed, for the first time, the ALS to be a treatable condition. Now, we're moving into Alexander disease. It's our third positive phase 3 result for our CMF platform. Alexander disease is a rare genetic loop of dystrophy that very commonly affects infant death or death in childhood.

3:40Through the mutations in a gene called GFAP, which goes overproduction of this protein, which is in the myelin sheath, in the neurons in the city lab, there are no treatment options available for Alexander disease today. That is until Zilva nursing. We reported top-line data last year of very positive phase 3 data in the 10-minute walk test, as well as several secondary endpoints that favor Zilva nursing treatment in our phase 3 trial. And yes, we reported detailed data for Zilva nursing in Alexander disease patients at the A8N American Academy Neurology Justice Suite,

4:17where we really showed in fine detail the remarkable benefit that these patients in our trial are receiving, both on the primary endpoint of 10-minute walk distance. That is a measure of motor function, which is one of the primary causes of this disease or symptoms of this disease, motor dysfunction. But also in quality of life and in most part of some symptoms in these patients and so on. So not surprisingly, when we submitted our NDA for this drug and for this treatment in January of this year,

4:52the FDA recognized the unmet new year and the remarkable efficacy that we demonstrated and granted us correction therapy designation as well as priority review. So we're looking forward to an approval date, achieving the approval date of September of this year and get you started to the patients as quickly as possible. Right.

FDA Regulatory Framework

5:13Just speaking of the FDA and also kind of an overlay with the technology that IONS has discovered. So we're seeing the FDA recently lean into this plausible mechanism framework to essentially enable approvals of individualized therapies that will do gene tweaking. So I wasn't aware until a recent symposium by the National Organization for Rear Disorders, where Dr. Teresa Baracchio from the FDA mentioned that this idea kind of started with SOs,

5:44where the FDA had a series of guidance to help move these individualized ASO INDs forward. So as a pioneer of this technology, Brad, do you think the regulators are finally catching up on this? And does IONS plan to leverage this opportunity in any way? We're all for, highly supportive of faster regulatory paths to ensure faster access to our medicines for patients. And we have a longstanding, very strong, very positive partnership.

6:17And I purposely refer to it as a partnership with the FDA in bringing breakthrough treatments to patients. That includes Spenorov's, that includes Calcite, that includes Olzai can go on and building Erson-Browers, and their disease. We've been working with the FDA for decades and educating them on the advantages of RNA-targeted therapeutics with respect to efficiencies that can be capitalized on to get patients access faster, these breakthrough treatments.

6:51And the FDA has been receptive to our work. All RNA-targeted therapeutics, whether it be ASOs or SIRNAs, the primary mechanism in this class, two mechanisms that we're wholeheartedly pursuing here at IONIS, are very well suited for these types of approaches, one being a plausible mechanism framework. And that is because, well, what's plausible? What makes sense in the eyes of regulated? Well, number one, because of the nature of the platform that we created, we pioneered and created RNA-targeted therapeutics,

7:29most of the time we are targeting the root cause of disease. We are targeting the genetic cause of disease. And that is because RNA-targeted therapeutics can pursue any drug target, theoretically. That is, all targets are drug-borne, unlike traditional approaches like small molecules or monoclonal antibodies. But where they have to often target the disease, because those targets are undruggable with those approaches. Because these targets are drug-borne, we can target the root cause of disease.

8:01I'll give you an example. Well, a great example is Alexander. We know the cause of this disease is the overproduction of the protein GFAB. We're targeting GFAB, right? That's one. Second, we can show that we're lowering GFAB. We're lowering GFAB to approaching normal levels, you know, that should produce a clinical benefit. And then you add to that a clinical benefit. That's entirely consistent with a plausible mechanism. We're targeting the root cause of the disease. We're lowering the cause of the protein that's causing the disease.

8:32And we're showing everybody it's a clinical benefit. So there are many other examples, but whether it be an N of 1, which is being pursued by some charitable foundations like NLORM, or even in populations in the millions, plausible mechanisms is very well suited for an RNA-targeted approach. And it's something we strongly embrace here at Ionis. And we're pleased to have FDA as a partner in improving efficiencies.

Ionis Pipeline

8:58So beyond Zogonersen, 2026 is a year of big reveals for Ionis. We're looking at the Horizon Cardiovascular Outcome Study of CARSEN for liver protein A. And there's CardioTransform for Vinoa in ATTR cardiomyopathy. These are potential multi-billion dollar market opportunities. Brad, talk to me about why these are important readouts. I know people at Carson, the expression potential game changer has been used. And it's possible that Vinoa's data could be differentiated from some existing competitors.

9:32Yeah. Yes, indeed. 2026 is really set up to be a transformational year for Ionis and for the platform of RNA-targeted therapeutics. There are several real game changers that are in the works that are not only addressing rare genetic diseases, but also very, very large patient populations. I would highlight three that are addressing very large patient populations. Medicines that were conceived and discovered here at Ionis. And I would start first with Tringolza.

10:05Generic name is Olazarsin. We anticipate FDA approval for a disease, for this medicine, for a disease called severe hypertriglyceridemia. A disease that afflicts millions of people in the United States. It's more than 3 million people in the United States have very high elevated levels of triglycerides that put them at high risk for cardiovascular disease, diabetes, as well as, and most importantly, a risk of a potentially fatal acute pancreatitis attack, destruction of the pancreas.

10:36This is the second indication for Tringolza. The first indication was approved last year, the first FDA-approved medicine for a genetic cause of severe hypertriglyceridemia called familial fibromicronemia syndrome, or SCS. That drug was approved and then was launched last year by Ionis, and that launch was doing very well in this patient population, which is about 3,000 people in the United States. We are now expanding that to millions of people for non-genetic causes of severe hypertriglyceridemia, SHTG.

11:10We reported very positive phase-through data last year at the American HARC Association, a breaking presentation in the clinical session of the conference, where we showed remarkable reductions in triglycerides, getting a lot of patients to normal levels of triglycerides. But most impressively was the fact that we lowered acute pancreatitis events by more than 85% in that patient population, unprecedented results.

11:40Based on these data, the FDA granted this priority review with a pre-action date for approval of June 30th. So we're preparing to launch into this very large patient population, and this is wholly owned by Ionis. The other two medicines that you referred to that are targeting large patient populations are programs that we are partners with. One of those is Ivalontersin for ATTR cardiomyopathy. This, too, is a medicine. Brand name is Wenua.

12:11That's already approved for an indication that this is indication. That indication is for ATTR hereditary polyneuropathy. That is a co-commercialization, co-development partnership with AstraZeneca. That medicine is done very well in the polyneuropathy population and is now positioned to address a much larger patient population, a half million or more in the United States with cardiomyopathy manifestations of the disease.

12:44That phase 3 data is due to readout in the second half of this year, as I said, and is positioned to be a real game-changer in the patient population. And then the third one for the mega population, if you will, the very large patient population that we're expecting data from this year is pellicarsin. Our partner there is Novartis. This disease is caused by, this cardiovascular disease is caused by very high levels of an independent risk factor called life-approaching little a.

13:17I'll call it LP little a. We all have LP little a, and there's a normal range for LP little a. However, millions of people suffer from cardiovascular disease due to very high levels of LP little a. And what pellicarsin has shown in the clinic is that we can normalize L3 little a levels by targeting the root cause of this disease. And that's based on several clinical trials, but most notably a very sizable phase 2 study, which we published in the Union Journal of Medicine.

13:49That study is now in a cardiovascular outcome trial, in which we'll readout in the second half of this year, in which the objective is to demonstrate that we significantly reduce cardiovascular-related mortality and hospitalization. And that could be a real game-changer, obviously, if there were the LP little a on cardiovascular disease community. Right. Brad, is there perhaps a kind of comparator in the drug development history that we can perhaps benchmark arson against, like the potential, its potential impact on the disease?

14:28Yes, absolutely. I think LDL cholesterol is a great analog. LDL cholesterol, which we're all very familiar with. We're familiar with treating LDL cholesterol with statins and PCSK9 inhibitors. And we're all familiar with the cardiovascular disease that's caused by high LDL cholesterol. LDL cholesterol is an independent, proven cardiovascular risk factor that's addressable with the marketed products that I already touched on.

15:00LDL cholesterol, statins, PCSK9 inhibitors, and so on. Based on the proof that LDL intervention of LDL cholesterol produces positive cardiovascular outcomes and mortality, you can now have an LDL medicine approved by the FDA by targeting LDL alone. You don't need the outcome data. We're not there for LP little a-driven cardiovascular disease because no one's ever proven that if you lower LP little a, you will benefit patients on mortality and hospitalizations.

15:33But the announcement holds. We are in the first stages of proving that intervention of LP little a will benefit patients with respect to mortality and hospitalizations, just like the industry did and was pursuing decades ago for LDL cholesterol. They are both independent of each other. So, high LP little a drives cardiovascular disease independent of LDL, independent of hypertension, independent of diabetes, just like LDL is independent of other risk factors.

16:05So, I think that's a great analogy. It's a mega population and we're targeting the root cause of this disease. It's one of the few remaining independent cardiovascular risk factors that have not been addressed with existing treatments. This is definitely an exciting new area on Fierce Biotech. We actually recently had a feature article just on LP little a. Listeners can check that out as well. So, Brad, back to you. In both of these cases, the TTR amyloidosis and LP little a,

16:38illness, so candidates may need to compete with small interfering RNAs. And there's obviously some much hype around sRNA right now. And they're both RNA medicines. But from both a mechanism perspective and a clinical application standpoint, what advantages do you think the antisense drugs could hold against those small interfering RNAs? So, at IONIS, we have the capabilities and are pursuing those capabilities to deliver medicines utilizing an antisense ASO,

17:11antisense oligone nucleotide ASO approach or a siRNA tied approach. Both target RNA. Both are very similar to each other, but they do have unique differences today. It depends on the application. It depends on the target you're going after. It depends on the indication. There are circumstances where an antisense oligone nucleotide approach would be, has several advantages over an siRNA approach and vice versa. For example, we know that antisense oligone nucleotides primarily exert their effect,

17:44their action in the nucleus, right? So, based on that, as an example, an approach to correct a splicing defect, which is common in genetic diseases like in Duchenne's muscular dystrophy or spial muscular atrophy, For other nuclear-retained targets, an antisense approach is superior to an siRNA approach. And approaches may have other advantages over anisense oligone nucleotides. One of them being durability. So, you may be able to dose less frequently, particularly in the liver,

18:17compared to anisense oligone nucleotides. There are advantages and disadvantages depending on the circumstances, and we at IONIS bring forward the best possible medicine, whether it be ASO or siRNA, to address a particular disease. For ATTR amyloidosis cardiomyopathy, there are two classes of treatments today to address this disease. One are referred to as TTR stabilizers, small molecules that prevent the protein from unfolding that causes amyloidosis.

18:50There are two marketed products today that are stabilizers. And then there's the silencer class, ASOs, siRNAs. They block the production of a disease-causing TTR protein. So, we ran it from ever getting made. There's no need to stabilize it. We block the production. There is a siRNA already on the market today that was just approved last year for cardiomyopathy, and we're expecting our phase three data this year. How might we differentiate? Well, we firmly, first of all, firmly believe that the silencing mechanism

19:23will be superior in efficacy compared to the stabilizer. We already saw that in polyneuropathy, the first indication that they were superior to a stabilizer that was actually rejected by the FDA for that indication. So, we believe in that class. However, with respect to the two silencers that are approaching, the one that's on the market today and ours that's approaching the market, do you think that we'll be able to provide data that no one else has been able to provide before, which is going to be very important? And that's because our study is the largest study that's ever been conducted,

19:56even more than double the size of any study that's ever been conducted in TTR cardiomyopathy before. We have a great drug, an eclonturcin, that silences the protein beyond that that anyone's really demonstrated to date. And we think that that's going to produce meaningful benefit, not only in the primary endpoint, which is cardiovascular mortality and hospitalizations, but in secondary endpoints. In our study, we will be the only study that will have meaningful data that will address the potential added benefit of combining a silencer,

20:32eclonturcin, with a stabilizer, the famidus. We're going to have a very large beta set, and that's very important because these are two classes of medicines to treat ATTR cardiomyopathy, and physicians want to know if they combine them, will they provide added benefit? Stabilizers were first to reach the market. They provide benefit to patients, but still these patients are progressing. They're all progressing. Some progress fast. So if having that data to show that we can provide added benefit

21:03and combination will go a long way in differentiating eclonturcin from other medicines out there and also providing comfort for those prescribers who want to deliver added benefit to their patients. Yeah, I know analysts definitely said about that. They are very excited to see the combination data, obviously.

Partnerships and Commercialization

21:23Now, Brett, in both of these two cases, as you mentioned, IONUS have partnered out with AstraZeneca and with Novartis. And partnering everything with large pharma was kind of IONUS' business model for more than 30 years. But I think beginning with Trangosa, started to own and sell drugs by itself. Now, we're kind of familiar with the argument that the company gets more value this way. IONUS gets more value. But my question is, why now? Like, was it a decision of let's do it as soon as possible?

21:55Or was there a particular timing element to it that this is the right time for IONUS to kind of fully integrate a commercial company? Historically, IONUS had the business model that was to focus on creating this new platform for drug discovery on antargeted therapeutics and to partner our programs and let our partners conduct the riskier phase 3 studies as well as to commercialize their products. The rationale was that we needed to focus

22:28on developing this platform, optimizing this platform, and to invest the precious dollars we had into doing that. While large pharma companies could invest in the late stage development, which can be very expensive, of course, as well as for commercialization. When I approached moving into my role as CEO, I felt the time was right for IONUS to take it to the next level. to drive far greater value for the company,

22:58for patients, but also to control our own destiny. No longer should we rely on partners, partners who sometimes don't move with the urgency that we want them to move at or change priorities and that can damage our drugs. There have been too many instances, in my view, in our past where partners have read us down. I felt that it was the right time based on our financial strength, but also based on validation proof that the technology is validated,

23:30which is now delivering medicines and was positioned to deliver a title rate of new medicines for patients, that it was the time to control our own destiny. That is to build a commercial organization that matched really the excellence that we've always had in research and in development. And that's where we are. Of course, when I moved into the role of CEO, most of our, if not all, of our pipeline products that were in development were partnered. So it took us time to develop the wholly owned pipeline,

24:01which is now really robust, strong, and to build our commercial organization to launch our own products. As you mentioned, last year was a transformational year for the company as we launched our first two products and both of those launches are off to fabulous starts. And more importantly, the feedback we're receiving from the patient community that's just been overwhelmingly positive for Trangolza, for familial chylomicronymia syndrome and Donzera for hereditary and your hema.

24:31So we're off and running, but we've only scratched the surface. As we've discussed, we expect two more launches this year, Alexander disease and severe hypertriglyceridemia. Severe hypertriglyceridemia represents our evolution to moving and delivering our products through commercialization for now a large patient population, moving and expanding beyond rare diseases to include large patient populations. So given this, will partnerships still play a role in Iona's future,

25:03I'll still partner drugs with large pharma companies? Yes, absolutely. But it'll be a lower priority. In addition, we will do different types of partnerships, right? For example, today, we are commercializing our programs, our products in the United States only. This is a path that other biotech companies have taken in the past to build the commercial organization, if you will, to get the legs, the commercial legs under you to ensure success before going global.

25:34So the types of partnerships we're doing today to make sure that our medicines reach patients globally are to have commercialization partnerships outside the U.S. We have excellent partnerships, commercial partnerships for Tringolza, for OU.S. commercialization, for Gonzera, for OU.S. commercialization. We'll soon have one for Sylga Nursum for Alexander Businesses. We will also decide on whether or not a program might be a better fit for a large pharma than to out-license

26:04this program entirely and let them take it through the late stages of development and the commercialization. If we think that it makes sense for IONIS, for example, we still need to, of course, live within our resource constraints and if we have more programs to bring forward and that can be the case because our research engine is highly prolific, we may choose and prioritize certain programs to out-license outright. But that is not the top priority.

26:35The top priority is to build the holding of the pipeline and to deliver our medicines ourselves. Secondarily, we may out-license but that is not the primary mission. Yeah. Now, I think I mentioned at the beginning that, Brett, you're part of the founding science team at IONIS. So now, why was it important for a scientist to remain at the helm during this pivot? I think it's common practice here in the biotech world for kind of the scientific founder of the firm to step aside and hire someone with commercial experience

27:05to take the firm commercial. So why do you think it's important that leading the company? That's a great question. You know, when I was moving into my role as CEO during a one to two year transition period, you know, following, you know, at the time in which I was running research and many programs in clinical development and some of the business relationships with partners and so on, I was recognizing the need to take control of our destiny as I mentioned before

27:35and to deliver our medicines that we conceive and discover directly to patients. That was not the plan, you know, by our board of directors when they selected me to be the incoming CEO. It was something I had to sell to them and they understood the rationale and they were 100% behind me in transforming and taking a lead to transform the company to become a fully integrated company. Now, they also recognized that I wasn't an expert in commercialization, but they valued

28:05the fact that I was with the company from the beginning. I understood the culture of the organization and how precious the culture is to continue to strengthen the organization as the company would grow in size as well as grow in value as a commercial organization. They also recognized the tremendous value that I brought in understanding the science, the technology, the research, drug development, what has succeeded in the past, what has failed in the past

28:36and building off of that. And they also, and I really appreciated this, they also recognized that I appreciated the fact that although I wasn't an expert in drug commercialization, that I would find the right people, that I would hire experts and bring them into the organization. People that not only had tremendous experience in building a commercial organization as well as launching, successfully launching products, but also people that would understand

29:06the mission, the central mission of the company, which is to grow and transform the lives of patients and clinical medicine and the importance of the culture of the organization. I mean, you know, I was maybe a little naive, honestly, I mean, how hard could commercialization be after creating a branding platform and paradigm shift for joint discovery? but it was hard and we persevered and we were able to bring in really, really great people.

29:37Speaking of culture, Brad, I was watching this video by the Audit View Nuclear Tide Therapeutic Society naming you the 2025 Lifetime Achievement Award winner and Dr. Richard DeGuerre who recently retired as IONS Chief Development Officer called you and I quote him, PhD nerd with an IMD heart. So just thinking about that, what has been the biggest culture shock for you moving from that position, a science position, an R&D position to thinking about commercialization?

30:09You know, honestly, Angus, I don't really feel like we went through a culture shock. It was my biggest fear when I was moving and trying to transform the company into a fully integrated biotech was that the culture was going to erode and in fact, that was one of the driving reasons not to become commercial by my predecessor because of the potential for science to take a back seat. Science is the center of everything we do here at IONS. It's our strength. It's our differentiator. But also that the culture

30:39could erode as the company went through. I also was concerned that our long-tenured employees at IONS, and we have a lot of them. I'm not the only one. We have many people that have been here for decades who would not be pleased with the decision to move to full integration. I was pleasantly surprised that I didn't need to worry about that. The long-tenured employees at IONS fully embraced the decision for full integration because they felt that IONS could do a great job in moving forward the medicines that we can see

31:10and discover more quickly and more effectively to patients because they're our babies, if you will. They are the drugs that we came up with and we worked on around the clock to create. So, you know, I was pleasantly surprised that I didn't need to, although I was worried about it, I don't need to worry about it. It is something that you have to continue to nurture, and we do that at IONS, but the culture really has not suffered a bit. If anything, it's been made stronger because people are seeing the benefits,

31:40the rewards of seeing those medicines for each patient directly, you know, now that we're fully connected to the patient community. I would say, if anything, the biggest surprise is the sticker shock that I experienced. Although I was confident we could do it, I was a little idea on how expensive it would be, but we've been able to do it. We've been able to strengthen our financial position and be able to manage the expenses that are associated with these launches. we're right on track

32:10to achieve profitability with breakeven cash flow expected the year after next with growing profits to follow. So I think we're in really good shape.

Biotech Industry Outlook

32:20Yeah.

Biotech Industry Outlook

32:20So Brad, to close things up, looking at the reality of the biotech market in 2026 and the vision that the team had when you founded IONS, did the market force you or the team in a direction that you didn't expect? And what do you think is the biggest uncertainty facing the biofarmament industry today? Yeah, there's nothing in the biotech that has influenced us or caused us to change direction. It was really all about understanding and optimizing

32:51the RNA-targeted therapeutics platform and understanding where our drugs work the best and capitalizing on that. That's what led to our leadership in cardiometabolic diseases and in neurology. Those are areas where our drugs work the best and it took time to optimize the medicines and to understand that. Nothing else has really driven us to a particular disease or indication, rare, large populations

33:21or so on. So it's all been science-driven. With respect to the future of biotech, there I am very concerned. I am very concerned about new policies that are being put in place or at least trying to be put in place to control drug pricing with respect to the impact it will have on innovation. You know, social drug controls, pricing controls are not favorable to innovation in biotech. Of course, we do everything

33:52we can to control drug pricing and maximize access to patients, but we also have to understand and appreciate the fact that now after 50 years of biotech's existence, we've created something that's incredibly special that the United States has led. And I feel that we need to do far more to embrace biotech to ensure that the next 50 years are even more productive for patients, more productive with respect to innovation and delivering

34:22being-changing medicines for patients going forward. It's an industry that has proven its value and it's an industry that we need to embrace and to continue to cherish and to maximize its potential well into the future. Brett, it's been a fascinating look behind the curtain of Ionis business. Thanks for joining us on The Top Line. Thanks, Angus. It was a pleasure.

34:50That's it for The Top Line. I'm your host, Ayla Ellison. You can find out more about this topic in our show notes at fiercepharma.com. Look for podcasts. And that's the bottom line from The Top Line.