Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Okay. Well, Good morning, everybody, and thank you once again for joining us for the 42nd Annual Healthcare Conference at Cowen. I'm Yaron Werber from the biotech team. And it's a great pleasure to moderate the orphan neurology panel with my colleagues, Brendan Smith and Eva Privitera. We really have a terrific session today. We have with us Shoshana Shendelman, who is the Founder and CEO of Applied Therapeutics; Brett Monia, who is the CEO of Ionis; Jeremy Levin, who's the CEO of Ovid; and Ed Kaye from Stoke. Gentlemen and ladies, thank you so much for joining us. Great to see you.

Thanks, Yaron.

Thank you.

So we have a lot to talk about. There's a lot going on in orphan neuro these days, and you're all essentially developing therapies for unmet medical needs. The field essentially is changing. There's new biomarkers. There's -- imaging is getting incrementally better. The FDA is also struggling or trying to innovate and move forward in using biomarkers and potential surrogate endpoints as well.

Maybe, Brett, let me start with you because you have such a huge pipeline targeting orphan neurology, how is the FDA stance changing as you're dialoguing with them?

Sure. Thank you, Yaron. Yes, we do have a big -- a great deal of experience with the FDA's neurology division with 13 neurology drugs now in our pipeline. We have really a great relationship, a very productive relationship with the FDA. They recognize the value of the types of medicines that we're bringing forward to patients with neurological diseases, targeting the root causes of those diseases using the antisense platform. And it really began with the wonderful cooperative relationship we established with SPINRAZA in spinal muscular atrophy, where working with the FDA very closely, we were able to bring forward a medicine for a disease that has never been achieved before, new clinical trial designs, new biomarkers. And that led to the approval of SPINRAZA just a few months after we actually submitted our NDA, which really showed tremendous cooperativity for a drug that really had a meaningful impact on the lives of patients. And honestly, that has really established the foundation with the FDA in neurology, at least for our company that has been incredibly productive. We've had a great relationship with them on other drugs in forging novel efficient paths forward based on biomarkers, including ALS, for TTR amyloidosis and Prion diseases and so on. So we're very pleased with the cooperativity we've experienced with the FDA. And I think if you have a great-looking disease-modifying drug to treat a disease where there's a great unmet medical need, it's a great working relationship to take advantage of.

And Ed, what are you seeing? I mean, both from your experience with Sarepta and now with Stoke as well?

Well, I think I'm not seeing a sea change at the FDA. And I think with Rob Califf in charge now, I think Rob is a big data person. He's very interested in the science, and I think he'll continue with that. I think what I am seeing though is, there is certainly some political forces that are trying to, especially in Congress that are trying to see if there's a way to kind of reduce the impact of accelerated approval in surrogate endpoints. And I think the challenge, I think, came up with aducanumab. And just because it was such a large disease that had an impact on Medicare, there's been more of an economic push. I think what we're -- we and others and certainly the efficacy groups are trying to do is make sure that everyone understands that accelerated approval is really critical for a lot of diseases where it may be very slowly progressive. It may take decades. You don't have an easy to identify clinical endpoints. So having a surrogate endpoint that would allow people to perform a study. And again, surrogate endpoint is likely to predict a clinical benefit. And for a lot of diseases, that's probably the only way that we could easily develop it within a reasonable period of time. So I think the change is not -- the impetus where change is not, I don't see it coming from the FDA. I see it coming from Congress. And I think what we should all make sure we do that they understand that this has really been -- since 1983, the Orphan Drug Act has been an incredible boon to patients. And we can't throw out the baby with the bathwater, and we need to make sure we maintain that for -- especially for rare and orphan diseases.

Yes. And Jeremy, in Angelman, you've essentially worked with FDA a new endpoint, right, for -- with the first study really randomized study for Angelman. And then for -- with OV935, you were dialoguing potentially for an epileptic encephalopathy broad label, which was a novel opportunity as well. Can you discuss your experience with FDA and how flexible they are being?

Yaron. It's -- to me, I take a very optimistic view on the field, particularly with CNS. It's been -- we've seen a number of different things that have played out in a SPINRAZA certainly has been terribly important in it. But specifically with regard to the endpoints, I think things -- as you focus on building a company in the rare epilepsy, you have to -- you can read back on the functions of the FDA and how they're reacting when you try and introduce novel endpoints. Now we were the first ever to introduce a novel endpoint in Angelman's. That took a lot of dialogue with them, education, patient advocacy groups, et cetera. But at the end of the day, we put in place an endpoint, which when we started, there were no other companies at all in this field and now there's something like 20. All are using the same fundamental endpoints. So I found the interaction with the FDA extremely interactive and very, very positive. Now as we look to the future, I think Yaron what one should be thinking about is really very concrete end points that are measurable, plus biomarkers. And in the field of epilepsy, our chosen field, that's something which is extraordinarily important. And I take a very optimistic view of the of the FDA's approach to this. So in summary, and to let everybody else have their say, #1, pioneering a new endpoint is very difficult. But once you've got it, you can open up a field and the FDA is open to that, and I've been very impressed by that. #2, when you go into an area like soticlestat, which is a -- you tackle a rare epilepsy as we have, and we look forward to see the pivotal results first half of this forthcoming year, you have an interaction with the FDA, which says, if you're able to get the endpoint that is defined for this rare epilepsy and you get then a safety profile, which is satisfactory. This can open up a world of opportunity. And as you know, Yaron, it's an $8 billion global market for epilepsy, and it's going to grow 6% per year. So we know that CNS within the FDA is changing, and the stage was set congratulations to Ionis and for Biogen for having done that.

And Shoshana, maybe to you on galactosemia, I mean, you're literally -- your tires are hitting the payment as we speak on AT-007 looking at surrogates, looking at biomarkers, looking biology and intersection of clinical activity. What are you finding with FDA so far?

So to be candid, we're having a mixed experience with the FDA. And I think that's where different divisions and different leadership sometimes come into the mix. So we have 2 different Phase III rare disease studies ongoing with the same drug in different divisions, right? So AT-007 is in a pediatric Phase III study for galactosemia, that's being reviewed by the Rare Disease division. And we also have a Phase III ongoing in SORD deficiency, which is under review at the neurology one division. And the views on accelerated approval are different. And we all like that to not be the case. I think at the FDA, right? There should be a uniform view on accelerated approval, especially when it applies to rare diseases across the entire regulatory agency. So I do think that -- I'm hopeful that there's some leadership from the top down moving forward on how to interpret the reasonably likely to predict clinical benefit status, and that, that will help to provide more clarity to companies and also its uncertainty that if you meet that standard that you will have accelerated approval open to you. But I do think that specifically with regard to CNS rare diseases, and I think we have a lot of precedent for accelerated approval and biomarkers and innovative end points with the neurology division, and that definitely has led to a lot of the progress that we're seeing on this panel. And I'm pretty hopeful that, that will move across the FDA to other divisions as well, because to Ed's point, in rare diseases, if you are unable to access a biomarker endpoint or some kind of alternative, it's very unlikely that you'll be able to demonstrate clinical outcomes in a period of time that's meaningful to patients. And when there's nothing available to treat these diseases as is the case, I think, in a lot of indications that we're all working in, there is an urgency to treat and the need to move drugs quickly and effectively through the clinic is really present. So I think that probably to be candid, there's a lot of uncertainty for companies and for patients right now at the FDA sort of looking at what's happened with out-of-home and sort of is this going to influence things in a positive way, in a negative way. And I think that it's important that we maintain the importance of accelerated approval to rare diseases and that we all ensure that the FDA understands how important that subpart H policy is to rare diseases, in particular.

All right. Great. So if I could actually jump in here. I just have a few questions for a few of you here. I know we touched just a little bit, not just on actually kind of these innovative endpoints, but I want to drill in specifically a little bit more into Angelman syndrome. So I guess, Brett, if I could just start with you really quickly. I know the program is really just kind of getting into the clinic. I know it's been -- they've really been working on it for a while here. So obviously, a lot of excitement behind it. So as it kind of relates to the FDA conversation we've really been having, I guess, how is your experience specifically within Angelman kind of developing these endpoints? I know early stages as well. And I really kind of want to get your thoughts really as it relates kind of your broader platform and kind of moving the clinical development of those 4 as well.

Sure, happy to. So we're developing a range of drugs for this neurological disease indications, orphan and broad. In most cases, penetrating a patient population for the first time and trying to uncover and establish a development path forward with the FDA, biomarkers, as have already been mentioned, bringing in natural history studies to support our path forward for diseases like that have really -- have not had any meaningful medicines today, like Huntington's, ALS, SMA before SPINRAZA and so on. And Angelman is the same sort of situation where the cause of this disease has been known for quite some time, but the development of therapies has been lacking. And as I mentioned in my opening, it's important to establish a strong cooperative foundation with the divisions. I completely agree with Shoshana that different divisions are different leadership and the openness of neurology division, for example, is quite different than cardiorenal and so on. But we have found that there's been tremendous openness to novel, clinical trial design, accelerate paths to accelerated approval based on surrogates and based on surrogates that have a meaningful connection that predicts a reasonable probability that the patients will benefit clinically. And that's been the case for Angelman's as well, very productive partnership. And we're well on our way. We're initiating -- we've initiated the Phase I/II study, and we're enrolling patients nicely with our UBE3A targeted antisense and very comforted by the preclinical data that we've generated to date, which is also very supportive of it. The other thing is we've been impressed with the willingness of the neurology division to weigh preclinical data, much more than I think in the past, especially for these orphan diseases where you need as much ammunition as you could possibly get to make a case for accelerated approval. And the preclinical data for Angelman has strongly supported our path forward has been good. But even for diseases like prion disease, where the unmet need is tremendous, especially for symptomatic. And they've been very willing to look at our preclinical data and establish biomarker strategies for potential accelerated approval down the road. And we've experienced that in Angelman's and for ALS and so on. So Angelman has been no different than what I highlighted earlier, very cooperative partnership. And we're up and running in the study.

All right. That's great. So Jeremy, if I can maybe get over to you for a little bit. Just for a few more pipeline-specific questions here. Obviously, your lead compound of 350, KCC 2 activator for epilepsy. So getting into kind of the biology of driving the program, can you really speak to how maybe the mechanism you think might confer clinical benefit if there are certain epilepsies that you think are more likely to respond to this kind of mechanism?

So we have a lot of experience in epilepsy. We pioneered first of all, a lot of work around Dravet and LGS with our [ CDKL5 ] Dup15q with soticlestat, a novel mechanism. So number one, I think epilepsy is about to break open in a way that is very, very encouraging to all of us, because of the interesting and new mechanisms that are coming out. So we sought to build a fundamental franchise focused on different mechanisms in epilepsy, recognizing that the vast majority of epilepsy is not going to be cured by a gene therapy or even another genetic therapeutic in the near term. It's likely to have a big impact, but in the near term. So our approach to this is to assemble a war chest of the most powerful first-in-class, best-in-class type of mechanisms. And we've chosen a number in the case of soticlestat, it's inhibiting an enzyme cholesterol hydroxylase in the brain, causing diminution of some very significant [ pro-epileptogenic-type ] products in the brain. In the case of our lead early, which is going into the clinic 329. 329 is we needed to really tackle a known target that is the GABA aminotransferase inhibitor. And as we did that, just as we did in soticlestat, we went through multiple models looking at the -- looking at what were the best epilepsies that we -- models that we could do. And it's a very thoughtful process, but we've done it before. So now what we look down there in 325, it is a gab aminotransferase inhibitor designed to increase GABA levels in the brain. It's got a -- it has a real chance of being a best-in-class therapeutic. It does renown all the preclinical models. It is a significant reduction in hyperexcitability -- and then in addition to that, what we know about it is that it's about -- it has a progenitor thought process. Effectively, there was a compound originally that targeted similarly, but not the same the GABA aminotransferase and that was vigabatrin, grew to be a $1 billion drug. Here, we have some -- we learned from everything that went on there, and we targeted this particular compound. It's about 1,000x more potent than vigabatrin, for example. And as none of the side effects. So as we thought about the targets, tuberous sclerosis and infantile spasms were the ones that were most likely affect it. But if the safety profile pans out and is looking as good as it is, it has a chance just like soticlestat of going from an early stage targeted epilepsy to potentially dealing with the entire spectrum of epilepsy. We need to work on that. But we start with tuberous sclerosis in [indiscernible] on that. In the case of 329, this is another novel mechanism, but we have good proof of concept that it actually works both on genetic models of humans. This is the KCC 2 activator for resistant epilepsies. Here, we're a little early for telling you exactly where we're going. But we already know from preclinical models that it is able to tackle some of the most resistant epilepsies they are. And so it's a rinse, wash, repeat approach here. Just like soticlestat, we picked something, we've got a great Phase II, and we're looking forward to the Phase III results in the first half of next year. And hopefully, as Takeda says a launch in 2024 -- so 2, 3, we've done exactly the same approach in 329 and the same in 350. So we'll be talking about the indications for 350 a little later in the year. In the meantime, we'll be filing the IND for 329.

Got it. Got it. Okay. Great. So a lot of exciting things happening there Okay. Ed, I wanted to ask you a couple of quick questions also. While we're talking about a lot of these epilepsy programs, obviously, you all had first Phase I/II data with STK001 for Dravet syndrome late last year and updated earlier this year. So we saw some pretty promising early trends in seizure reduction. I guess, first, I want to ask you what other endpoints are you measuring in that study that obviously are going to be key complementary measures given your approach to Dravet syndrome? And then also, really, within future reduction, where you kind of see the bar, given a few of the other drugs that are available and have kind of advanced in recent years.

All right. Thanks, Brendan. I think our approach is certainly somewhat different. We're really not trying to develop antiepileptics or antiseizure medications. What we're trying to do is to develop a therapy that goes after the entire syndrome. And in Dravet syndrome, of course, seizures are an important part of the symptoms, but there are many, many other aspects that cognitive, the behavioral, the developmental decline, problems with gates, speech -- so it really is a disorder that affects the entire brain. And for us, what we're trying to do is a very specific genetic therapy for the treatment of Dravet and that's to upregulate the missing protein than 1.1, which is a sodium channel, which is important for seizures, of course, but it's important for a lot of other things. So I think, Brendan, you point out some important aspects. In our MONARCH study in the US, it's primarily looking at seizure reduction and safety and PK. But if we look at -- we have another study, Admiral in the UK., that's really focused also on looking at other aspects, so neurocognitive behavioral aspects, trying to look at what are we doing for all of the symptoms in Dravet. And then the other study that we're looking at that is in our open-label extension, where we're dosing every 4 months, and we continue to increase the dose. We're now at 30 milligrams and based on the safety and tolerability. And in those studies, we're also looking at what's the long-term effects on cognition and behavior and overall outcomes looking at quality of life. So those are the things that we're focusing on. Again, it's really a treatment to address the syndrome of Dravet and are simply just the seizures.

All right. Great. Over to you, Eva.

Thanks, and so Shoshana, on your experience with the FDA and biomarker endpoint. The agency has recently indicated that it would like clinical outcomes data to support servers of an NDA. Can you briefly review the trial design and data and give an update on your recent regulatory interactions?

Sure. So yes, unfortunately, the FDA did let us know at the end of last year that they wanted to see clinical outcomes in galactosemia. And fortunately, our pediatric study was already set up to do that and was ongoing as disappointing as that was that the biomarker alone would not be sufficient for approval. So just a quick review on design. This is a pediatric study in children with galactosemia, it's 47 children each 2 to 17. And the first part of the trial was set up to do dose escalation to identify the optimal dose in children and then to look at biomarker reduction of the toxic metabolite galactitol. We showed a 40% reduction in galactitol, which was highly statistically significant. It was a p-value of less than 0.001 versus placebo. And the children are assessed for clinical outcomes at baseline and every 6 months thereafter. And the clinical outcomes fall into the 4 quadrants of CNS function that are most impacted in galactosemia. So speech, cognition, behavior and motor skills. And the primary clinical outcomes endpoint is the global statistical test across those metrics of CNS function. And the way that the clinical outcomes portion of the trial was designed with the FDA. And despite my disappointment that the biomarker alone was not acceptable for approval. This is a good example of innovative design and when the FDA has been flexible with rare diseases. So the statistical analysis is performed every 6 months by a firewalled DMC. And the study will be unblinded when it reaches statistical significance, but we are assessing those outcomes every 6 months. So the first 6-month outcomes assessment, as we previously disclosed is this quarter. So as we previously said, all children have completed their 6-month outcomes visits. And where we're looking at right now is the actual statistical analysis of those clinical outcomes while discussing with the FDA, whether there's a path forward for a sooner approval or an NDA submission prior to actual statistical significance of the clinical outcomes. So the way that this study was designed, and there's -- as is the case for most rare diseases, there's really limited longitudinal data in patients with galactosemia, but we do have a lot of very good cross-sectional analysis that allow us to look at the progression of these outcomes with age. So that helps us to predict how the children and the placebo group should worsen over time. And also the role that galactitol plays. So there's a very high correlation of galactitol with progression on each of these outcomes. So based on those pieces of data available, our study is designed to show statistical significance at the 18-month clinical outcomes point. So we're 80% powered to show a p-value of less than 0.05 between active and placebo at the 18-month outcomes assessment. So we just completed 6 months. So 18 months will be one year from now, which is a great place to be in if we actually end up needing to demonstrate clinical outcomes for approval. But given the high unmet need in galactosemia, the discussion right now with the FDA is whether there is still a path forward for an accelerated approval with some clinical outcomes data, albeit not statistically significant, but a trend or a totality of data in addition to the biomarker that we've already demonstrated. So I don't yet know what the outcome of that discussion is, it's ongoing. To Brett's point, these dialogues are usually very productive with the FDA. We have been very engaged with them. It's literally happening now, and they do understand the urgency based on the fact that the children have completed their 6-month clinical outcomes. So hopefully, we'll have something to report out soon on the FDA's view on whether we can submit an NDA with a totality of evidence, trend on clinical outcomes plus the biomarker sooner, but we're trying to bookend that with what we do know with certainty, which is that clinical outcomes, with a p-value of less than 0.05 is sufficient, and we should hit that endpoint one year from now. So again, no drugs approved in galactosemia and there is an urgency and we definitely hear that from the families. They have been very vocal with Congress in their interaction separately with the FDA. We understand that a year is a long time for a lot of these families to wait for the study to hit statistical significance. We're hopeful that FDA hears that as well. And so we look forward to updating everyone as soon as we can. We just don't know right now. If anything outside of statistical significance will be acceptable to the FDA, but hopefully, we'll know very soon.

Great. Just a quick follow-up on what are your plans for disclosure around the 6-month interim analysis and also for subsequent interims?

So it is reviewed by a firewall DMZ. So we may not be able to share everything that comes out of that, but we have to see what the data is, right? So if the data is statistically significant, then we'll know and we'll read out that data right away. If it's not, we'll still let the market know that it did not hit statistical significance, but given the conversations that we're having with the FDA, we hope to provide something additional there, so that we can actually discuss whatever the data is at 6 months in the context of what's meaningful and acceptable to the FDA. So again, as soon as we know, we'll let everyone else now. But those are active conversations right now. And the fact that the statistical analysis happens in a firewall format is really what allows us to look at it every 6 months in an ongoing format, which is really helpful in a rare disease that hasn't been studied before and when there is some uncertainty on point in time, you do get the benefit of looking at earlier time points in case they do hit statistical significance, and you're also protected on the back end in case there's less progression than what you had anticipated. But we know that there have been cases in the past where the FDA has been able to look at data in a firewalled format, and we're hopeful that they'll do that for us as well and helps to make a more global decision on whether they're accepting the NDA with anything less than statistical significance.

All right. Thank you. I'll turn it over back to you, Brendan.

All right. Great. So there's actually a lot of great points in there, Shoshana. Also kind of made me think of one other thing I wanted to ask you, Ed, so the Dravet program, I guess as you're really thinking and moving through the Phase I, II, obviously, there's a lot of different endpoints that we need to read out and take a look at. But as much as you can, thinking ahead to a potential Phase III, how -- I guess, within the data that will come from the Phase I/II, how should we think about the potential design of the Phase III in terms of which endpoints you really think are going to be maybe not just most important for approval because obviously, the -- in the precedent there, but seizure reduction is pretty clear. But in terms of actual clinical utility for physicians, where -- is there like a particular bar or a dimension of success for each of those endpoints that you think are going to be the most important in terms of deciding how to actually target it, the population?

Yes. Thanks, Brendan. I think it's an interesting question. And obviously, the precedent has been set with previous antiepileptic therapies for Dravet. It has been really the reduction in seizure activity. So that is certainly a critical aspect, especially for regulatory approval. I think what we're looking at also is what's going to happen as far as for use of this particular therapy once it's out in the community and what's important to patients. One of the interesting challenges with this particular disease and people have asked like, well, are you going to try to enroll naive patients? Well, there really aren't any naive patients in Dravet. It's a very serious disease, and most of the patients that we've had in our trials are on 4 or 5 different antiepileptics. And 90% are treated. They continue to have seizures. So if we look at our Phase I/IIa data, half of the patients were already -- been on Fintepla, which has been kind of the standard of care most of the pediatric epileptologists are going through. And they're still breaking through and having seizures, and we're seeing an ability to reduce seizures and that. I think what we've heard from -- certainly from the patients and certainly from the physicians, if you can improve at least one other aspect of the disease, especially some of the cognitive declines that are occurring, that would be enough of an impetus to get us to use that therapy because right now, there's really nothing that changes the other symptoms, especially the cognitive decline. And one of the things that I was taught going through my residency is that all antiepileptics are basically neurotoxic agents. And what I mean by that is, they're reducing the seize threshold, you're suppressing the brain activity. So if you have a therapy that's not dampening down the activity of the brain, you have the potential that you could improve some of the cognition. So that alone -- that approach is different. And I think for us is, we're going to be very interested is, can we -- can the quality of life can be slowed down some of that cognitive decline? Can we have an improvement in the behavior or even things like sleep, which is incredibly disruptive for the families. Anything else in addition to seizure control that can improve the lives of these patients, I think, would be a big step forward. And I think would be a real change for their quality of life for these individuals and would allow use of this particular therapeutic approach.

Got it. Great. Okay. So I guess just to put a pin in the kind of broader epilepsy conversations here and epileptic-type conditions, Jeremy, I just also did want to make sure that we touched a little bit on OV882. I know you talked about a few other pipeline programs earlier. But obviously, Angelman, as we alluded to earlier with Brett kind of gotten more and more players and is in the fire in the past couple of years here. So specifically for the shRNA mechanism of A2 here, how do you kind of see that playing out versus other potential approaches? And I guess, specifically, as it maybe relates to some of the different endpoints, maybe that Ed was alluding to, obviously, Angelman's a very multifactorial disorder, right? So is there anything particular about that mechanism that you think could kind of differentiated from some other approaches?

It's a really important question. First of all, let's all express the delight that this area is breaking open, okay. Number one, a lot of different therapeutic approaches to it. Now we understand it because from a different perspective, we've got this enormous data advantage. We've had over 100 patients, and we have baseline data to understand them in the NEPTUNE, ELARA stars, we went through Phase III. So we have perhaps the largest collection in the world and certainly, actually, I think that's the case of repository baseline data. So number one, as we design clinical trials for any of our products in Angelman's and 882, we know where we're starting from. Number 2, the -- one of the more interesting aspects of any of these neurodevelopmental disorders is to understand just exactly what that endpoint would be. So if you don't have that database, you then have to consider either biomarkers, which may or may not be relevant or importantly, do you have -- and this is a really tough one, do you have a placebo-controlled trial? Because in neurodevelopmental disorders, when the patients know that they're going to get it, when the families know they're going to get it, when the physicians know they're going to give it, then you have the real need to be stringent in controlling for what occurs. Now that baseline data becomes critical. So #1 baseline data. Number two, with regard to the very good approaches on the ASOs, I think the -- this is a really exciting and good approach. However, as we thought about this and studied what was going on, our approach was the concept that shRNA approach would reverse the silencing of the paternal genome, but differently from the ASOs, okay? The way you do this is, the real differentiation is we are concerned that the ASOs will have an impact, which is fabulous. This is great. But over time, we believe this will degrade. And so what will require repeat dosing to achieve long -- some types of long-term effects. Well, if you take the shRNA, if it's successful, introduce into the cell, it won't degrade or it will degrade much slower. This potentially means that treatment could be delivered in a single dose. You don't have to take these kids in and it's very tough. It's -- you can't underestimate how difficult it is and how disturbing it is to take these kids in for a therapy to a center. Nevertheless, we're encouraged to watch the ASOs as they develop, study those trials and when we are comfortable with what people are doing and understand it, we believe the biology of the shRNA approach will be in the longer term, much better and offer a real alternative to what is being developed. So 2 points there really the data on baseline for placebo control is absolutely critical. And 2, think about how this is going to take place over time, taking these kids back into a hospital or a clinical setting for intrathecal injection multiple times a year, certainly feasible happens, particularly in SPINRAZA, where you have a disorder which people are dying from, but these are long-term treatments for kids who are not dying and they need to -- we need to understand how we can avoid that. So that's the approach. Does that give you a good feel for it?

Yes. Yes, absolutely. Obviously, to your point, it is a very exciting time, so we even are able to have these kinds of conversations about discussing differential approaches here, right? I think obviously, we're going to really be watching the space very closely over the next couple of years to see how some of this data emerges. And somebody who actually knows 2 kids with Angelman syndrome, I know families are enormously excited for a lot of these things to be moving forward. So it is a great time. It's good to hear that. So actually, I think that's a really good segue to get back to you, Brett, I did want to ask you. You mentioned SPINRAZA here. Obviously, you guys are also working on -- you've been really, really active and consistently progressing next-generation ASOs, and that now includes the next-generation SPINRAZA. So I guess I wanted to ask you a couple of things here, just what is it that you are hoping to see with this next-gen version of SPINRAZA relative to, obviously, the huge success that we've seen with the commercially available one. And then I know you guys have a couple of other really big readouts coming this year, too. So I want to also touch on that. Maybe we can just address SPINRAZA first.

Sure. Happy to, Brendan. Thanks. So at Ionis, as I'm sure most people appreciate, we pioneered the field of RNA-targeted therapeutics, which encompasses ASO, SI and so on, and we continue. And we've done that based on the investments we made in the technological platform over decades, really. And we continue to do that. And in fact, we're investing -- the investments we're making now are resulting in unprecedented advancements that basically are enhancing the profile of our medicines in various ways, enhancing potency, opening up new organs, tissues for delivery to tackle new diseases, to increase durability, as Jeremy mentioned, for patient convenience for long-term chronic diseases. And SPINRAZA in SMA is just one example of a recent advancements we made in medicinal chemistry. Our drugs, one aspect of the pioneering work we've done over the years is in CNS. We have, as I mentioned earlier, a pipeline of 13 drugs in development from early person patient studies to Phase III development. ALS, Huntington's disease and so on. And we continue to invest in SMA. The new advancement for the follow-on molecule to SPINRAZA is basically to making more convenient for patients, enhance durability. Our drugs are administered by intrathecal bolus injection infrequently every few months now, but through advancements in chemistry, we're getting to annual dosing, places to go, once a year dosing and that's based on Ionis-discovered chemistry. And based on the preclinical data, we think we can get there, we have to prove it in the clinic. And those clinical studies should be starting soon. In addition, that chemistry is potentially applicable to many other programs in our CNS pipeline and future drugs that are come into CNS. So that's the main goal. That's the nature of the molecule, and that's the objective is to make it more convenient for patients because SMA was once a lethal disease, the #1 mortality cause mortality and infants, a genetic cause of mortality in infants. And it's now become a chronic disease, right? SPINRAZA made it a chronic disease, especially for the type 1s. And so now we have to make it more convenient for the patients. And that, of course, also will further solidify our position in the SMA space with Biogen and to address emerging competition. As far as data readouts and upcoming pipeline advancements from our neuro franchise, which is one of our leading franchises, of course, very much looking forward to news on ALS this year. The Phase II data for a genetic cause of ALS mutations in the gene called C9ORF will read out first half of this year. We're focused on demonstrating substantial reductions in the toxic dipeptides that are produced from the mutant C9 gene in patients to -- and of course, with safety and tolerability, which could -- which could allow us to select the dose for a pivotal trial. And that comes, of course, on the heels of the tofersen Phase III data that came out last year for patients suffering from ALS due to mutations in the gene called SOD1. In that study, we did not hit the primary endpoint to ALS functional rating scale, but there were strong trends in other aspects of the disease, notably in muscle strength and in the statistically-significant reductions in a biomarker neurofilament light chain, which is a marker of neurodegeneration. And that the open-label extension continues. And we're gathering more and more data as we go. We're very much looking forward to news on potential next steps for tofersen in ALS as well this year. So these are 2 of 4 drugs in development for ALS, 3 target genetic causes. 2 of these are in Phase III development and then one drug per sporadic ALS that's in development, too. Also on the neuro front, for this year, we're very much looking forward to -- I mean, we've been focused on CNS, but we have a Phase III drug that will read out for a peripheral neuropathy TTR amyloidosis related to -- that causes polyneuropathy in patients with hereditary TTR amyloidosis and that Phase III data will read out in -- by midyear this year, and if positive, we'll file for an NDA this year. And based on all of the clinical data generated to date for eplontersen, that's name of the drug, we're very much confident that the Phase III data will be strong based on the reductions in TTR that we've seen already as well as the excellent safety tolerability and the convenience of a once a month subcu injection. So a lot of news coming out from the neuro franchise this year as well as other franchises as well.

That's great. So I did have obviously a ton of big data readouts going for you guys in near future. I did want to ask really quickly about the ALS readout just as a follow-up. I do remember that in the Phase II with the SOD1 drug, obviously, you saw this kind of just thinking with the fast progressing population, right? So obviously, there's some excitement there for sure. I kind of wanted to get your thoughts on specifically for the C9ORF population relative to SOD1. Just like pathogenically how -- is there like a distinct difference, I guess, number one, is there something like a clear fast progression population within the C9ORF patients as well? And at the same time, how is just the overall rate of clinical progression for the genotype kind of compared to some of the SOD1 patients?

Let me just start with C9ORF ALS is the most common genetic cause of ALS that's known today. It's about 5x more prevalent than SOD1 ALS. We have 3 drugs for genetic ALS as I mentioned before. The third one is targeting FUS mutations, FUS-ALS. Both FUS and SOD1 ALS are considered some of the most rapidly aggressive progressing forms of ALS that have been identified to date. And that is based on the presence of these fast progressors based on certain types of mutations. They progress extremely quickly following symptom onset in those forms of ALS that typically happens on average within a year or so after symptom onset. C9, there are no known rapidly progressing mutations, despite the fact that there's approximately 50 mutations in the C9 gene that cause ALS, no known rapidly progressive forms of ALS. So it's a somewhat slower progressing disease than FUS or SOD1 ALS. But -- but the genetic -- but the outcome is still the same. Although it progresses somewhat slower, these patients will eventually succumb to muscle failure, respiratory failure gone assisted ventilation and die of their disease, unfortunately, of course. But we've taken that into account in the design of the study that we're going to need more time to assess clinical outcome. And the other thing is, we've learned so much from the tofersen Phase III study on how to design better trials, look for better markers, the value of a neurofilament light chain as a really important biomarker neurodegeneration. The length of time you need to treat and start treating earlier in neurodegenerative diseases is absolutely important as we've seen in -- even in SMA for these neurodegenerative diseases. And all of that is going to be factored into future clinical trials, including if we bring C9 to Phase III, it will be incorporated into the Phase III design for C9ORF as well.

Okay. Thanks so much. Eva, over to you.

Thanks. So AT-007 is in a potentially pivotal trial in a second indication. Shoshana, can you review the design of that trial for SORD deficiency?

Yes. We're very excited about SORD deficiency. I know that previously, we had planned for galactosemia to come about a year ahead of SORD deficiency indication. And so a lot of eyes are on galactosemia and also because that's under active discussion with the FDA about what's the path forward here. But SORD deficiency is a really exciting opportunity. It's the same size market as galactosemia. So there's about 3,000 patients in the U.S., about 3,500 in Europe, same-sized market. Again, this program is under review at the neurology one division, which I think we all have a little more comfort around the biomarker situation there. So patients with SORD deficiency are missing the sorbitol dehydrogenase enzyme, so they're unable to metabolize sorbitol. And aldose reductase which is the target of AT-007 converts glucose to sorbitol and then these patients are missing sorbitol dehydrogenase, so it has no place to go. So there's a pretty straightforward biology here where sorbitol is a marker of disease activity. There's been decades of work previously into the role of sorbitol elevations causing diabetic peripheral neuropathy. So there's a lot that we know about neurotoxicity of sorbitol and that's why the nature of publication that sort of unveiled SORD deficiency as a disease than the pathogenic mechanisms was still groundbreaking because it was very clear from the start. These patients have 100x normal sorbitol levels. We know sorbitol is neurotoxic. That's why they have a hereditary motor neuron disease and really aggressive peripheral neuropathy. So the Phase III design is -- it's a 2-year study, where we look at sorbitol reduction at 3 months. We're also looking at reduction in neurofilament light chain at 3 months. To Brett's point, NFL is a pretty well-validated biomarker right now in terms of neurological stress neurodegeneration. So -- and we know that NFL is highly elevated in SORD deficiency patients. So at 3 months, we're looking at sorbitol reduction and NFL reduction. The patients then go on to have clinical outcomes assessed at 12 and 24 months. So again, we're pretty hopeful that this time around the biomarker is sufficient for accelerated approval. We've also become a little paranoid and protected ourselves in case it's not. So this trial is already ongoing and set up to provide clinical outcomes with an interim assessment at 12 and 24 months. The primary clinical outcome that we're looking at is the CMT-FOM lower limb domain, which is a 10-meter walk or run, plus time stairs plus timed up and go. So just as a reminder, SORD deficiency patients had been previously symptomatically characterized as Charcot-Marie-Tooth type 2. So the CMT-FOM metric is a pretty good metric for these patients and 100% of them show deteriorations in their lower limb function over a pretty short period of time. So that's why we chose the lower limb domain of the CMT-FOM as the primary endpoint. We're also looking at things like muscle MRI that have been shown to be good tissue biomarkers that sometimes have a lead or fall ahead of some of the clinical outcomes. So we really -- again, it's a rare disease, small population. So we've built one pivotal study, close collaboration with the neurology division to provide biomarker data, which we hope will support an NDA later this year and then followed by clinical outcomes. And the timing of the 3-month biomarker data will hopefully be in the second half of this year. So we're really looking at a lot of catalysts moving out to the second half of this year and into early 2023 with that clinical trial really up and running now and patients coming into the clinic. So we're pretty excited about that program. We're hopeful that people will take a little bit more of a look at that. While we're figuring out what to do with galactosemia with the FDA, it's a pretty exciting program.

Just as a follow-up, can you talk about the progress you've made towards characterizing the natural history of SORD deficiency and what that tells you about the degree of sorbitol reduction as meaningful?

Yes. We -- first of all, we're super thankful to the inherited neuropathy consortium. So as I mentioned previously, even though SORD deficiency has its own cause of disease is relatively new, that nature publication came out in 2020. And it's since then that we've really been able to examine sorbitol levels and aldose reductase inhibition as a strategy for that disease. But these patients were captured and studied well before 2020. So because they were symptomatically diagnosed as CMT2, many of these patients were captured in a CMT natural history study. And that's been run by the Inherited Neuropathy Consortium. It's a group of experts that we're responsible for that nature publication, and they've been so collaborative and really working as our partners to advance AT-007 for SORD deficiencies. So they have data on SORD deficiency patients going back many years. And based on the metrics that are available from that natural history data that we've been able to design our Phase III to focus on the metrics that we know deteriorate over time in these patients. It's also how we're able to know that there's a correlation between sorbitol and severity of disease and also NFL with severity of disease. So here's a place where academia has really advanced the natural history forward in a way that we're really appreciative of now because we're able to extract all the SORD patients from the CMT natural history study and just look at them as a stand-alone and have a really good idea of what we're going into with the Phase III design. So to Jeremy's point, in these rare diseases, having access to natural history data or baseline data across a wide swath of the population is really critical to designing the right Phase III trial. So even though it's a new disease, we actually did have access to that, and that's what gives us the confidence around the clinical outcomes that we built into our pivotal study.

Thank you, Shoshana. I'll turn it over back to you, Brendan.

All right. Great. I know we're coming up on the last minute or 2 here. So one question, obviously, we like to end a lot of these panels with that I'll just post to each of you kind of just high-level take on what you think the biggest surprise in the development of orphan neurotherapy will be over the next 10 years. Ed, what do you think about that?

I think it's going to be really -- we've had the promise of genetic therapies certainly for the last, I would say, 30 years. And I think what we're going to see in the next 10 years that there really is going to be a breakthrough both in RNA splicing. I think it's going to be -- certainly in gene therapy, I think we'll finally get there. And I think we'll be able to really appreciate the value of genetically-based therapies trying to address the underlying cause of the disease.

All right. Jeremy, what do you think?

Well, I'm super excited. And so I think the biggest surprise will be the stuff that we're not looking or talking about, platforms to follow on from its common platforms that solve for the inherent barriers of AAV that they carry large genetic payloads, genes that really matter; two, that we can actually dose intravenously and successfully enter the brain -- across the blood brain barrier and not intrathecally; three, that what you inject doesn't provide an immunogenic response; four, that it can target the cell and really have tropism so you know where you're going; and five, you can manufacture it at a cost, which is really effective. And I think this will be -- we will definitely see this. You'll hear more about this and certainly from us in the years ahead.

All right. Brett, how would you answer that question?

The genetic revolution has identified the root causes of so many neurodegenerative neurological diseases, diseases like Huntington's and ALS and your severe causes of severe seizures and Angelman's and so. And now with the advancements of so many new platforms, whether they're DNA-based platform, small molecules, antibodies or so on, I believe that diseases that have been a death sentence in the packs like ALS and Huntington's disease, and Angelman's and the other diseases as well as well as your chronic diseases like Alzheimer's, but these rare genetic life lethal diseases are going to turn into chronic diseases. They're going to have treatments for the first time. Drug development is not for the faint of heart. And for those who are pessimistic based on a few disappointments over the last 5, 7 years or so, you need to see the long run. You need to see the long picture. Neurodegenerative diseases is where cardiovascular diseases were 30 years ago. We're just learning how to treat these diseases now. We have the armament to do this today. We just need a little bit of time. We need to figure out how best to prove their value in patients. And I think that's coming. And as Jeremy said, the future is very exciting.

All right. Shoshana, what do you think?

No. I mean what Brett just said really resonates with me. People might not know this, but one of the first diseases I worked on coming out of grad school was SMA. And at the time, the drugs that are now approved were just ideas on a lot of these companies. And so seeing what was definitively a life sentence, I mean we were talking to parents who knew their children are going to die. At that point in time, has now really changed the playing field in such a different way. There are so many diseases where we now have treatments 10 years ago, we didn't. And with the number of rare disease clinical trials that are ongoing right now and drugs that are in development, we particularly don't work on gene therapies, but I think that across small molecules and genetic approaches, there's a huge opportunity to advance treatments for diseases that had nothing available before. And so I'm pretty hopeful that in the next 10 years, we see a lot more first therapies available and treatment options that take a lot of these diseases that were either previously death sentences or really horrible outcomes into a place where there's a much more favorable future. And I think that's really possible, probable. And to Brett's point, it's not for the faint of heart, right? Like this is not easy, but the reward that's available at the end of it for families, for patients is really what drives this forward. So I think there's a lot coming in a lot of rare diseases, and it's a lot to look forward to.

All right. Great. Well, I want to thank the 4 of you for joining us. It's been a great discussion. The rest of today and the next couple of days we have a lot of other really great ones lined up. So thank you guys for getting us kicked off in a really exciting way. And we look forward to talking to you again soon. Take care, everyone.

Thank you for having us.

Thank you. Have a great day everybody.