Good morning and welcome to Ionis Pharmaceuticals First Quarter 2021 Financial Results Conference Call. All participants will be in a listen-only mode. [Operator Instructions]. As a reminder, this call is being recorded. I would like to turn the conference over to Wade Walke, Vice President, Investor Relations to lead off the call. Please begin.

Thank you, Betsy. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development. And joining us for Q&A will be Onaiza Cadoret, Chief Corporate Development and Commercial Officer; and Eric Swayze, Executive Vice President of Research. I would like to draw your attention to Slide three, which contains our forward-looking language statement. We will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. And with that, I'll turn the call over to Brett.

Thanks, Wade. Good morning. And thank you for joining us on today's call. Last year, we introduced a new strategy to drive growth by developing and commercializing medicines from our wholly-owned pipeline. Since that time, we've taken a number of key steps that have advanced our strategy and moved us closer to successfully commercializing our own products. Most recently, we expanded our Sobi distribution agreement and restructured our TEGSEDI operations. This transaction unlocked significant resources that we are redeploying to advance our wholly-owned pipeline and prepare for commercialization of our highest priority medicines, which include TTR LICA, and APOCIII LICA. We're also using savings from the Sobi transaction to invest even more in our technology to further broaden the reach of our therapeutic capabilities. Turning now to our pipeline. We were particularly pleased with the Phase 2 data from IONIS-PKK-LRx, with hereditary angioedema or HAE. Based on these encouraging results, we're advancing into a Phase 3 study where we hope to further demonstrate the potential of this medicine as a best-in-class product that could change the standard-of-care for patients with this disease. We also recently initiated pivotal studies with two wholly-owned neurological disease medicines. ION363 and ION373 for patients with FUS-ALS, and Alexander disease respectively. Given the severe unmet need of these patients, in the progress we have made with regulators both medicines are on an accelerated path to the market. And we are pleased with the progress we're making across our rich Phase 3 pipeline with medicines for patients with ATTR amyloidosis, FCS, LP little age driven cardiovascular disease and ALS. These Phase 3 programs remain on track with data from the Phase 3 VALOR study of tofersen in patients with SOD1-ALS expected this fall. Positive toferson results would demonstrate for the first time that a disease modifying treatment…

Thank you, Brett. In February, we provided guidance for this year that reflects our new strategy to maximize the value of our wholly-owned medicines focused primarily on commercializing our rare neurological and cardio metabolic disease programs. Our first quarter results of $112 million in revenue, $159 million in non-GAAP operating expenses, and a non-GAAP net loss of $45 million reflected this new strategy and were in line with our expectations. Now turn to our revenues. SPINRAZA generated over $521 million in global sales. We earned $60 million in royalty revenue as a result, and virtually all of that revenue falls to our bottom line as profit. Our first quarter SPINRAZA revenue decreased slightly compared to the prior quarter. Because our royalty rate resets at the beginning of each year. As in prior years, we expect to reach the highest royalty tier by mid-year. The respond into those studies continue to progress well, these studies remain important elements of Biogen's ongoing efforts to enhance estimate patient outcomes and guide treatment decisions. We look forward to additional steps Biogen plans to take to further reinforce SPINRAZAs proven efficacy and safety profile SMA patients of all ages. SPINRAZA remains the SMA market leader and with over 11,000 patients on treatment and over 60,000 SMA patients, in markets where Biogen has a commercial presence. We believe SPINRAZA will continue to be a foundation of care for the treatment with SMA. We also generated combined TEGSEDI and WAYLIVRA revenue of $20 million. As a reminder, our guidance reflects a shift in revenue for TEGSEDI and WAYLIVRA due to the change in [technical difficulty] under our Sobi. We are pleased with the smooth transition of our TEGSEDI and WAYLIVRA operations to Sobi, which are now complete in Europe and well underway for TEGSEDI in North America.…

Thank you, Beth. We continue to execute on our pipeline goals this quarter. Achieving a number of successes and advancing towards significant value driving catalysts. We're particularly pleased with the positive Phase 2 results from IONIS LRx, once monthly subcutaneously administered medicine for the prophylactic treatment of hereditary angioedema, or HAE. Ionis PKK-LRx demonstrated a mean reduction of up to 97% in HAE attacks, together with favorable safety and tolerability. We look forward to reporting these Phase 2 results in greater detail later this year. We are now advancing IONIS-PKK-LRx into a Phase 3 study hope to further demonstrate its potential to be the best-in class prophylactic treatment for patients with HAE. We look forward to sharing our Phase 3 plans with you later this year. We also continue to be pleased with the progress of our Phase 3 pipeline, including our partnered programs Pelacarsen and togersen as well as our wholly-owned programs. IONIS-TTR-LRx remains on track in our studies in patients with TTR, polyneuropathy and TTR cardiomyopathy, and APOCIII-LRx also remains on track in the Phase 3 study in patients with FCS. We expect to begin a second Phase 3 study of APOCIII-LRx later this year. This second Phase 3 study will be in patients with severe Hypertriglyceridemia has a prevalence of over 3 million patients in the US. We also expanded our late stage pipeline with the initiation of pivotal studies for ION363 and patients with FUS-ALS and of ION373 in patients with [technical difficulty] because of the strong efforts of our development teams both of these medicines for rare fatal diseases are on accelerated paths to patients. From our mid stage pipeline, just this week positive data from the Phase 2 study of Ionis AGT-LR x in patients with resistant hypertension, were published in the Journal of…

Thank you, Richard. In the first quarter, we took important steps to maximize the value of our wholly-owned pipeline. We continue to advance and expand our Phase 3 pipeline with IONISTTR-LRx and APOCIII-LRx advancing as planned. And through the initiation to pivotal [technical difficulty] ALS and Alexander disease. We also delivered positive results for IONIS-PKK-LRX and HAE and are planning to advance this medicine into the Phase 3 study. We've taken important steps to strengthen and streamline through our acquisition of Akcea and the restructuring of TEGSEDI and WAYLIVRA operations. We have accelerated our commercial strategy, retain key commercial expertise and unlocked significant resources that we are reinvesting in our wholly-owned pipeline technology in the build out of our commercial capabilities. Importantly, we are financially strong and on track to achieve our 2021 financial guidance. We're using our strong balance sheet to invest in our strategic priorities and execute on all of our goals. I'm proud of the progress we've already made in these areas. And we look forward to sharing more this year as we advance our medicines and move closer to our goal of 12 or more marketed medicines in 2026. With that, we will now open it up for questions.

[Operator Instructions] First question comes from Luca Issi with RBC. Please go ahead.

Thanks so much for taking my questions. Maybe to hear one, maybe on Huntington disease here for either Eric or Richard. I think we started full data last week from Roche. And it looks to me that at least the high dose may have unfortunately accelerated disease given a bit higher dose actually increase ventricle volume over time or some of the low dose and placebo, wondering if you share the same view here. And what are such data substantiate the hypothesis that fair and a wild type may matter here. So again, any thought there will be helpful. And then second on HAE, congrats on advance to the program into Phase 3. So again, wondering if you could give us some color on how you're thinking about the Phase 3 study design? Will it be placebo control, will you need to run a head-to-head trial versus Exciro [ph]? Are you exploring monthly dosing or bi-monthly dosing? Again any thoughts there will be great. Thanks so much.

Hi, its Eric, I guess I'll take the Huntington question and kick it over Richard for a much more entertaining PKK and so I hope. Huntington the data was presented at CHDI and basically reinforced what the IDMC had. And it was the same data set and said the drug wasn't working and providing a benefit. It's true if you look at the absolute numbers that the more frequent dosing was descending a little faster than placebo. But all of those curves were within the bounds of natural history. As to what it means I think it's premature to tell both has some hypothesis that they discussed, and all of which are valid and makes sense to investigate. But I think we really need to unpack the data and their analysis and see what we can learn from the study. We really don't know at this point.

So on the HAE question, just a quick up front that we have some regulatory meetings over the next couple of months. And we will be bringing details of the Phase 3 program that later this year. At this point where we're moving forward with those regulatory and then into a Phase 3 program.

Let me just add to that a little bit, I think will be very helpful for our Onaiza to provide some of her thoughts too, on why we are so excited about the market opportunity for this drug, this we really do you think it's a has the potential to be the very best in class. It will certainly be a placebo-controlled study. I mean, that's what is expected in Phase 3 trial designs and there's precedent for that with Exciro and other drugs as well. And certainly, monthly dosing is what we're planning to do right now in the Phase 3 study, which offers a significant advantage, we believe over therapies which is [technical difficulty].

Yes, we'd be happy to add some color over here. I think going back to your question, Luca, is it going to be placebo controlled, or head-to-head, certainly a question for us as we went into the marketplace to kind of test out the profile of our PKK product, and we looked at it versus current treatment options, including [indiscernible] and we really, got the feedback based on the profile that we have, that this is, has the potential to be a best-in class profile. And really a placebo control study will be more than sufficient to really demonstrate that if you take a look at kind of the trifecta of efficacy data that we are able to deliver on this, prevention of attacks, the fast onset of Max clinical efficacy, and the reduction in kind of acute treatments. That's a trifecta of efficacy that's very pleasing and attractive for the HCP in the marketplace. So that along with the more convenient administration is just a very highly valuable and competitive profile. So we're feeling very great about what this is going to bring to the unmet need for hereditary angioedema patients in prophylactic treatment.

Thanks, Onaiza and as Richard said, we'll provide more details on the Phase 3 design later this year.

Got it fantastic. Thanks so much, super helpful. Thank you.

Thank you.

Our next question comes from Yaron Werber with Cowen, please go ahead.

Great. Thanks for taking my question. I have a question specifically to start with on acromegaly. It sounds like if you recall correctly, the study was fully enrolled in December. It's a 12-week study, but plus it's an open label extension. And it looks like you're planning on releasing the data in the second half, and it says plus the OLE. Any medical meetings that we should be aware of where this can be targeted, or is this going to be in a press release? And then any thoughts about what's the next steps with this program, given what you know from the Phase 1 data already? Thank you.

So, we are wrapping up the study now. And we'll be going through the data and it's going to - the analysis of that data will take us into the second half of the year as mentioned in his statements earlier. And then we're going to share the data as soon as we can, we'll probably will not wait for a medical meeting to share the results of that study because we don't have one targeted right now. Although we'll look for such a place that we can share the data in detail. But we'll figure out a way to summer to get the data out along with the open label extension data which has accumulated more and more data which is a rich data set that we didn't want to lose sight up that review. Remember that we also have a second study in progress for our GHR LICA medicine, acromegaly, which is in frontline monotherapy Phase 2, which is getting off the ground now and getting started. I think we're going to want to look at all the data before we can make a decision on the next steps for either the patient population in this Metastatin treated patients that are poorly controlled, versus monotherapy and then make decisions on what the next steps for the program would be.

Great. And then also any update on the potential Phase 1 or IND filing for Angelman syndrome? Thanks so much.

Yes, we're hoping to get the clinical study started this year.

You've definitely selected a construct and you're planning on filing and IND I mean, if you made a decision definitely to go forward.

Yes. You got it. Thank you, Yaron.

The next question comes from Yanan Zhu, with Wells Fargo, please go ahead.

Hi, thanks for taking my question. I just have a first question on the update from the ENAC program? Wanted to under - if you could share a little more about the findings from the toxicology studies, long-term tox study, and whether the tox is specific for the pulmonary route of administration. And whether it's related to the target or generally speaking the ASO presence in the lung? Thanks.

Sure Yanan. So I want to just emphasize that the clinical data for our ENAC in Phase 1 2a gave us very encouraging results. It has nothing to do with clinical data. We demonstrated target engagement in phase one and good safety in cystic fibrosis patients as well as in patients with COPD. And the cystic fibrosis data will be presented at ETS later this month. The preclinical finding was part of the long-term talks as Richard stated in his statements. Which kind of take us time to figure out what that's about and due to the delays, that are just associated with that those types of investigations. We took a look at our emerging pipeline in pulmonary diseases, and we think we have better targets to invest in that will have they'll bring greater value to the company and to the patients going forward. And we do not believe that this is read through to our platform for pulmonary disease at all. This is something that happens in preclinical tox studies sometimes and we're going to work through it.

Got it. That's very helpful. And then a question on the TTR LICA program. Alnylam recently reported with tisserand, phase three study in TTR, polyneuropathy. Just wondering your take on their data, and every three months, frequency of administration, and how you see that product profile and whether there's an opportunity for the TTR LICA to petition against that profile? Thanks.

Sure I completely respect the question. But Yanan, but it's not our position to comment on other people's data. What I can say that we'll have a very much we like our drug a lot. And the Phase 3 study in polyneuropathy, is enrolling very well. And we're looking forward to the results of that study next year in the cardiomyopathy study for TTR enrolling very well. In addition, Onaiza, we've done quite a bit of market research on frequency of administration and the value that brings to the marketplace and I would love to have Onaiza maybe comment on that?

Yes, should be happy to, I think your question was monthly versus quarterly. In general, I would say, most kind of market conditions, particularly from a patient perspective, as well as HCP clinician perspective, there are definitely some improvements in profile, when you go from daily to a weekly and weekly to a monthly. But after that I call it, there's just law of diminishing returns on more extended frequency particularly for a [technical difficulty]. And we've found that here for TTR, as well, we've done some extensive market research to understand that dynamic a little bit more, because it's a really one of our key products that we're bringing forward to commercialization. And we're not seeing really a big difference between the monthly and the quarterly at all, I think rightly so physicians are more, excited about the profile of the product, as well as the large clinical trial that we have ongoing in myopathy and really looking forward to seeing our data, with and without standard of care. I think that's going to be the place of big differentiation here.

Got it? Thank you. That's very helpful.

The next question comes from Yale Jen, with Laidlaw and Co. Please go ahead.

Good morning, and thanks for taking the question. We understood the failure of the Huntington disease in those trial. And I believe you guys have a very great confidence on the tofersen in the AIS. So would you mind just maybe compare or contrast a little bit between these two and besides the different diseases and where your confidence seems to stem from for the better trials?

So I'll open up and then it's very good question Yale, maybe Eric can expand. So we're confident in our neurological disease platform, we think it's leading in the industry in many ways SPINRAZA and then tofersen coming in behind that and plus ALS and a whole host of other drugs. All of the drugs, and there quite a number now, not all had been presented yet. All of the drugs that we've took into clinical trials have shown target engagement in robust target engagement in our trial, so we know we're hitting the root causes of diseases are the top we're going after to test our clinical hypothesis and inside one ALS tofersen is no different than that some very nice reductions to SOD1 and based on the Phase 2 data that was published in the New England Journal Medicine and we've presented and our confidence is high in tofersen, and our confidence is it lends us even greater confidence in for ALS in general because if tofersen is successful and like I said the preliminary not preliminary but the Phase 2 data was very encouraging. It bodes very well for the rest of our ALS franchise, which we have four drugs now in clinical trials two in Phase 3. The other part of your question, I think, had more to do with being able to target different regions of the brain, how is ALS compared to Huntington is compared to other drugs in our pipeline for neurological diseases. And there, I'll ask Eric, to jump into the weeds a little bit deeper.

Yes, sure. And Brett alluded to great things, person in the data packages that we have real evidence in the New England Journal paper for improvement and disease, we didn't have that in Huntington. And while we hadn't started reduction, and decided to look at it in the Phase 3. As far as target ability, we've talked about this I think before, I think our treasure trove of preclinical data has done a good job of teaching us where we can target in throughout the brain. And we have a high level of confidence that we can target all the regions that are affected in ALS. And we have a high level of comments that we can target much of the brain regions that are affected in Huntington's disease. And Roche has talked about this extensively at medical meetings and presented a lot of the data. It is true that regions like the CART A [ph] are less susceptible, but the case that makes sense to us that we could target that region. So I have a very high level of competence that, especially in programs, like the tofersen program, and our MAPT program and others that are targeting the whole brain and need to target the whole brain that we can engage those regions.

As a reminder, Yale, as mentioned in Richards statements earlier, that MAPT that type of data will be presented in July, I believe, this summer. And, and I think that will end even further conference, because Biogen has said the reductions in tau have been substantial and durable.

Okay, great. That's very helpful. And maybe just one more question here, which is a little bit more looking ones, in terms of the HA, you guys seem to sort of decide to move forward with Phase 3? Let's just assume it is successful. Just curious whether this is a drug, you guys want to potentially launch it by yourself, or potentially, to be a partnered out, at least at this early stage of thinking? And thanks.

It's a great question Yale. And it's one that we're working through right now. We think this is a great drug I really do. And whether or not we will keep this and it's ourselves or not, we will provide an update that will provide an update on the Phase 3 design later this year. We're moving into the Phase 3 study ourselves. So if you can just stay tuned on that it's, right now Onaiza's team is conducting a lot of market research and competitive, better profiling work to make the business case or not. And if you just stay tuned, we'll give you an update in a little while.

Okay, great. Thanks a lot. And again, congrats for the quarter.

Thank you.

The next question comes from Paul Matteis with Stifel. Please go ahead.

Hey, this is Alex on for Paul, thanks for taking our questions. I guess I have two. The first one is a clarification on ENAC. It sounds like the preclinical talks with that, it may be related to knocking down ENAC long-term. Do I have it right, that you're no longer going to pursue any ENAC program, either this program or another follow-on program in ENAC? And then secondarily, just curious if you want to give any thoughts on business development with all the cash you guys have now? Thanks.

So as I mentioned earlier in the question that was posed. We're still working through the data preclinically. We don't have any evidence directly that this is related to ENAC inhibition. Let me make this point, this is a very important point, the observations we may have made preclinically were not related to the same types of toxicities that were observed for small molecules systemically applied ENAC inhibitors, we're not seeing hyperkalemia, we're not seeing effects in the kidney and that sort of thing. So this is separate. And again, I think we'll work through it and we don't believe based on the data, all the data we have, we don't think that this is a read through to our pulmonary, our ability to go after pulmonary diseases. But what it does represent is a delay. And we have a lot of drugs coming with other targets. And although we're not slamming the door close on ENAC, future, those targets will start approaching and catching up to ENAC pretty quickly. And we think that those are significantly better targets for pulmonary diseases. And that was really both that that in totality was really the basis for why we just continued ENAC. We're really trying to focus on the program to bring the greatest value. And obviously with there.

So just to be clear, it's really more of a pause on the ENAC development rather than discontinuation?

Now we just continue to ENAC this program in favor of other programs.

Thank you.

The next question comes from Jason Gerberry, with Bank of America, please go ahead.

Hey, guys, thanks for taking my questions. Just one quick follow-up on PKK and then ETT question. Just on PKK, so it sounds like you view kind of a diminishing return on dose convenience beyond a month, but as it pertains to every two weeks versus a monthly that I guess you would say that's a key point of differentiation, as you think about you characterizing a potential best-in class profile, because it looks like dosing convenience is sort of a main feature that you'll be able to hang your hat on relative to the data [ph] on prophylactic agents. And then ahead of ACC, just wanted to probe a little bit in just in terms of what we're hearing from physicians in terms of what they want to learn about the profile of this drug. And it's has it pertains to consistency and durability of impact on blood pressure. One thing I think we're hearing is a physician just want to make sure there aren't dramatic spikes in blood pressure on a week over week basis. So you're curious if you could set the table, if we'll get any data that might help us understand a little bit about that attribute of your ASO there? Thanks.

Good questions, the attributes of our PKK LICA, certainly key attribute is the dosing frequency. But it goes beyond that. And again, I'll ask Onaiza to expand.

Yes, I think you're right, I think so the important thing here, and I talk about these is each medicine has in the market that they're entering for has to you have to actually look at dosing and convenience in there. And for the HAE market, as you know, with Tech Zero, it's a high volume injection every two weeks, and most of the market research and the physician said as always, the efficacy is only as good as its compliance. So we do believe that that will be a big play. But we do think that is not the main thing we're going to hang our hat on, as you said, I think it goes back to what's really important for these patients in prophylactic treatment and goes to, again, prevention of attacks, the number of zero attack rates that you get, and the ability of our product profile to deliver on that with the faster onset of reaching max clinical efficacy. And the third prong of kind of an order of efficacy parameters is just the ability to reduce the number of acute medications that they take. So when you think about it, really, it's just all three parts of the efficacy paradigm that we're just winning on, along with the convenience that will again have patients takes us on a regular basis be compliant and deliver on the efficacy of the product.

Yes, that's great. And I think just to add to that, the Phase 2 study, hit the nail on the head on all three of those. And we've got all those patients also rolled over into an open label extension, and looking very carefully at long-term lack of breakthrough, and that's also a very important component.

And then the AGT data, I talk a little bit about what is to be presented at ACC but also the Phase 2b study and what we're hoping to get out of that.

I mean, you'll be able to actually go to the publication right now, and it's available I can't believe it's posted Journal, American college cardiology and then the other piece to that is the presentation that we'll be giving. And there have been no, either hypotension or hypertension on recovery events. And absolutely, that's an extremely important piece to the puzzle. So the data is showing that's a very clean profile. And we've moved into a Phase 2b study that will further elaborate on those issues.

The Phase 2b study is really powered to nail down the magnitude of blood pressure control, we expect to achieve in a Phase 3 study, it's a significantly larger study, it's a longer study, select dose for a Phase 3 study, and to really rule out any of those of the concerns, hopefully, that physicians have raised, you've mentioned spikes in blood pressure, hypotension, and so forth. So that's the intent of the Phase 2b study. But first, certainly the publication in the ACC presentation will support the safety and the efficacy of this mechanism in this drug.

Got it. Thank you.

The next question comes from Jessica Fye with JP Morgan, please go ahead.

Hey, guys, good afternoon. And thanks so much for taking our questions. Not to belabor this, but just following up on the prior questions on ENAC. If the talks you notice is not related to the platform or exposure in the lungs, and it's not related to the target? What's your current thinking about what it might be related to?

Well, we don't know, Jess, that's the thing we have to work through various talks finding sometimes happen long-term studies. And it could be a sequence of related effects of that particular molecule, it could be something like that, but we really have to work through it. The confidence comes from other experience with other drugs.

And I think further, it's the clinical experience, I mean, the clinical experience was absolutely clean. And we were into longer term treatment in the clinic. But timelines can get significantly impacted by a preclinical finding, and this was just one of those. And we want to make sure that we're focused, we're early in development. And we've got so with at most - the riches are beyond what we're looking at, we have so many targets. And some of these targets are really impactful in particularly COPD. And some of these other very interesting and areas that we want to focus on. So we took a step back. And we're looking very carefully at this and focusing what we do in the midterm. At the same time, we've got this incredibly rich Phase 3 program going with all of the products that have now moved into late-stage development, and we've just wanted to make sure that we're not dosing our efforts. And we're focused.

Got it, makes sense. Working to other questions just on the Alexander disease program, can you talk about some of the efficacy measures you have for ION373, is that gives you the confidence to advance that into a pivotal study, and the size of that opportunity, and just how well you think the product might be able to address the market.

We really haven't disclosed the full protocols or the endpoints for the Phase 3 program. We're very confident that we can engage this disease being the known genetic cause of the disease. It's toxic gain function of the protein called GFAP. And that's what we're lowering in our preclinical work. And this has been published and it's really a remarkable improvements in what I think are pretty good preclinical models of disease. So here I think we have based on the preclinical data and the known pathophysiology of the disease. I think we have a very high level of confidence that we're in the right spot for this. Onaiza, if you can show programs.

Yes, we're looking at about, 400 patients globally, from a prevalence perspective. And again, as Eric said, this would be the first and only therapy for Alexander's disease. And I think the preclinical data and the models that we have suggests that we're going to normalize the production of access to GFAB improve gross motor function, reduction of significant symptoms that these patients are feeling both on the cognitive side and some of the GI side and really prevent disease progression.

Onaiza, it also be helpful if we talk a little bit about Jess, about our rare disease, neurological wholly-owned pipeline, more broadly about how GFAB and FUS and all these synergize together as a franchise that we're planning to bring to the market?

Yes, no, absolutely, really good point. So, when we think about these, let me see a prevalence for an individual disease and condition, we're really looking about how we scale these collectively together, to get the significant commercial synergies that will be really important in the marketplace. And we have them with great products. Alexander's being one of them, but we also have just one for Lafora disease. And later on, we're looking at, I don't know if we've disclosed one other, but we have one more, and they're just servicing kind of the severe pediatric diseases associated with epilepsy in the marketplace, that it really comes together as a whole. And then when we add in FUS and ALS, even though you wouldn't think there may be as many synergies there's actually a pretty high overlap, and the physicians were treating that as well. So it comes together very, very nicely for us as a portfolio in neurology.

Got it. And maybe just a last question, going back to the comment about reaching the peak royalty tier 4 SPINRAZA, around midyear, similar to last year, can you just unpack that a little some of the assumptions underlying that in light of the competition you're seeing in the U.S. from [indiscernible].

So Jess, hi. So I think, as you can see, when you look at the effective royalty rate on a quarterly basis over the past years, we get to our maximum royalty rate, very quickly, the tiers, there are four tiers, and they very quickly, and therefore our sense is that SPINRAZA, will continue to perform as it has recently, and therefore, we would get into the highest tier on a similar path, similar timeframe as we have in the past few years. And that gets us up into that 15% very quickly.

Got it. Thank you.

Thanks, Jess.

Next question comes from Mani Foroohar with SVB Leerink. Please go ahead.

Hey guys, thanks for taking the question. I hate to beat a dead horse, but I'm going to beat the dead horse a little bit. So given that you're where you are on ENAC in some ways in the lead of your closest competitor, competitor in terms of maturity and data, is the is the right interpretation of what you're saying that would have that going back and redesigning and moving forward with a different construct would have been required would have been requisite to feel comfortable and you're getting around this preclinical talks. And is that the right way to interpret what you said? I mean another not getting a different question.

We don't have an answer to that first question, because we're still going through the data. Trying to figure out what the next what's the best path forward is? So that might require a different drug or it might not. But we think we have we think that there are better targets out there that we're working on to bring greater value and the epithelial sodium channel that was our lead drug that was that was that was further along but we have others that we think will be more provide even greater benefit to broader disease in ENAC.

Okay, that makes a lot of sense. And then on HA obviously you have a really exciting dataset, optically superior to what's on the label for any of the approved therapies have obviously cross trial comparisons are fraught by nature. When you think about commercialization, obviously the quality of therapies available hasn't had improved from you know, the time group enough to kind of the lead asset, how do you think about openness and a willingness to switch? And in commercialization would you see this primarily as a switch market versus other existing prophylactic therapies? Do you see newly diagnosed patients as the lowest hanging fruit? Like how do you think about commercialization strategy, presuming you continue to have what appears to be a best-in-class event reduction profile?

Onaiza.

Yes, I'm happy to take that one. Really great question here. I think that when you're on prophylactic treatments, as we think about entering the market over here, it's clearly for new patients. This is the, you know, the best choice, right? So for new patients, we, we've kind of tested this, we have the best-in-class profile, that's where it's going to go. For patients who are already on therapy, I think, you know, they're in will be, how do we get switches in the marketplace? And we're really thinking of this in a variety of different ways. Are there you know, kind of breakthrough attacks happening, there definitely would be a sense of patience, there are patients who are not compliant on the full set of therapists that there are, so there's an opportunity there, and then I do believe that we're looking at particularly a switch design in our Phase 3 as well, although it's not confirmed, we're definitely evaluating whether that will be actually nice added benefit to our design as well.

That makes sense to me. And do we do we have a sense of where what proportion of patients you think, are modern and on the most modern and prophylactic therapy effects are, et cetera? What proportion of them based on your cable conversations, interactions, clinicians clinical trial experience? What portion of those patients see meaningful enough breakthroughs to fall into that that early share switch early adopter population for you guys. Just ballpark, I know we're far from being a commercial asset quite yet.

Yeah, hard to give you percentages over here on that, it's a really good question. I think we're going to do some claims, database analysis and do a retrospective look to get a better sense of that. So it's definitely in our list to help evaluate, but you would give in, again, the most, I think, profound part of the research and insightful for us was that the compliance piece right and given texture is that two weeks and four weeks, there are a lot of patients who were actually are trying to stretch this out over the four weeks, just because it's a very high volume administration. So we do see a lot of people who are not complying, and as a result then have breakthrough attacks. As to quantify that I think it's going to take a little bit more work on our part before I can give you a better sense of where that is.

That makes a lot of sense. Thanks. And I'm going to hop back in the queue. I know, there are lot of people waiting.

Maybe Betsy we'll take one more, and then we'll have to close it out.

The next question comes from Myles Minter, from William Blair. Please go ahead.

Hi, thanks for squeezing me in. Just a question on Biogen sort of pushing for a higher dose for the [indiscernible] program. Just wondering whether that's got any raid through the veil or and whether there's any room to maybe push the dose afterwards kind of in a SPINRAZA like scenario. And for the FUS programs and the Ataxan programs that are earlier stage, it's likely that we'll see a push in the dosing in those early clinical studies?

So the plan which is that the drug is very well tolerated. So and Biogen's is very committed to ALS, and in particular C9 ALS as well SOD1 ALS. And so, before moving into Phase three, you want to make sure you get those right. So there, they wanted to get more data and examine a higher dose. So I don't really think the read through is anything more than that the new era. It's really that the drug is very well tolerated and they want to get more experienced before taking the plunge for Phase 3. And I didn't quite get your FUS ALS question. We have selected those. We have a single dose level for Phase 3 that we're evaluating the program. So we're not planning to look at multiple doses in FUS ALS, we think we have the right dose and we're plowing ahead, we don't plan to escalate dose or deescalate.

Okay. I guess that was that was my question. Just like why the sane on off programs specifically? They're testing a higher doses. I know they're not involved in the FUS program, but even the Atax program like why wouldn't you just go with a higher dose here? Is there a risk of overshooting the knockdown of this protein?

No risk of on target that toxicity over overdosing or anything like that each drug is different. So Myles for C9 we do have an illegal selective drug and only because of the nuances of the way the transcripts are processed, our drug only lowers the pathogenic, expanded C&I or 72. So we don't look for the nonpathogenic C&I.

Okay, cool. Thanks for the questions.

Thanks, Myles and, and with that, I'd like to thank everybody who joined us on our call today. It's been a highly eventful start to the year and we look forward to more throughout the remainder of the year and sharing those results with you. So with that, thank you and have a great day.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.