Ionis Pharmaceuticals Inc UBS Virtual CNS Day Transcript

The following is excerpted from the question-and-answer section of the transcript.

Question: Eliana Merle - UBS Investment Bank - Analyst : Maybe just high level, can you provide kind of an overview of some of the programs in the neuro space that you have and the timelines and then we can jump into specific programs.

Question: Eliana Merle - UBS Investment Bank - Analyst : All right. Great. Maybe starting with Alexander's, with the data expected in the second half, can you talk a bit about the biology here and how that translates into the data we should be looking to see?

Question: Eliana Merle - UBS Investment Bank - Analyst : So I guess how should we think about -- I mean, because we haven't seen clinical data yet or at least we haven't, maybe you have.

Question: Eliana Merle - UBS Investment Bank - Analyst : Okay. Like how do we think about what good data looks like here?

Question: Eliana Merle - UBS Investment Bank - Analyst : I guess and then given that this is an ultra-rare disease, maybe if you could speak a little bit to sort of the market sizing here and how much market development do you expect will take in the US for Alexander's?

Question: Eliana Merle - UBS Investment Bank - Analyst : What proportion of this like 300 patients to 700 patients in the US are currently diagnosed if you have a sense?

Question: Eliana Merle - UBS Investment Bank - Analyst : And then I guess, just how like -- I know probably some of the work is still in progress. But like in terms of like the payments that are diagnosed, is the treatment more centralized, let's say, academic centers or sort of centers or excellence? Or is it more spread out, maybe going into kind of the community setting?

Question: Eliana Merle - UBS Investment Bank - Analyst : Great. Well, we're looking forward to seeing that data later this year. Maybe turning to Angelman, maybe can you give us an overview of the biology of the disease, the severity and the unmet need and just how those patients are currently managed?

Question: Eliana Merle - UBS Investment Bank - Analyst : And can you walk us through what was seen in the Phase II data last year. And I guess, the natural history work that's been done to sort of put that data in context?

Question: Eliana Merle - UBS Investment Bank - Analyst : All right. Great. And I guess with the Phase III beginning soon, I guess, can you walk us through the decision to choose Bayley-4 with the expressive communication of the primary endpoint. I guess, was this like sort of the FDA steering you towards this domain versus the others? Or was there some flexibility?

Question: Eliana Merle - UBS Investment Bank - Analyst : And maybe what are some of the other end points of focus? Or maybe just how the sort of KOLs in the space tend to talk about the various endpoints and the relative importance? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 17, 2025 / 6:00PM, IONS.OQ - Ionis Pharmaceuticals Inc UBS Virtual CNS Day

Question: Eliana Merle - UBS Investment Bank - Analyst : Absolutely. And in the context of maybe the competitive landscape with Ultragenyx, maybe what are some of kind of like what you view as differentiating features of your program?

Question: Eliana Merle - UBS Investment Bank - Analyst : And kind of building off of Alexander's disease, like how should we think kind of about both the opportunity in terms of like the number of patients with Angelman that are currently diagnosed. And sort of as an organization, how you would approach the scale-up, especially from Alexander to Angelman from a commercial perspective?

Question: Eliana Merle - UBS Investment Bank - Analyst : How should we think about the diagnosis rate of Angelman today? I mean it's like the symptoms are perhaps pretty clear or at least like from sort of a visit to the doctors. But how should we think about kind of the size of the prevalence pool and the proportion that are diagnosed currently?

Question: Eliana Merle - UBS Investment Bank - Analyst : How should we think about the timelines here, just like how you're thinking about how long it will take to enroll and like basically like when from where we sit, we get next, get an update, whether it's a longer-term data from some of the Phase II study or, say, the Phase III data?

Question: Eliana Merle - UBS Investment Bank - Analyst : All right. So 2027-ish, okay. Well, we're looking forward to seeing that data. MAPT, yes, some interesting yet like early data from the program so far and I get it data coming next year. I guess maybe can you talk about what's seen from your initial first-in-human study and sort of maybe how using an ASO might be different from using an antibody in terms of addressing the tau burden? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 17, 2025 / 6:00PM, IONS.OQ - Ionis Pharmaceuticals Inc UBS Virtual CNS Day

Question: Eliana Merle - UBS Investment Bank - Analyst : Yes. No, it's exciting data. Maybe can you tell us a little bit more about the design of the Phase II? And I guess, what data we should be looking for next year?

Question: Eliana Merle - UBS Investment Bank - Analyst : Exciting. So what's clinically meaningful in terms of like the difference on CDR Sum of Boxes? Or are we still looking at that like 30% or so range? Or yes, how should we be thinking about that?

Question: Eliana Merle - UBS Investment Bank - Analyst : So what would the -- I guess, next steps be, would it be to run a Phase III monotherapy but then also study a combination. I guess have you looked at -- like your plans with sort of combination Phase II (multiple speakers).

Question: Eliana Merle - UBS Investment Bank - Analyst : I guess given the like potential like better safety, I guess what really is the bar from an efficacy perspective? Like I guess that would be the lowest improvement that you could see on, say, CDR Sum of Boxes and still want to move forward and into Phase III given the biology safety?

Question: Eliana Merle - UBS Investment Bank - Analyst : Great. And like how would this work in practice? Is it sort of almost like oncology, where patients would get multiple agents?

Question: Eliana Merle - UBS Investment Bank - Analyst : Turning to maybe the commercial side in polyneuropathy sort of what's the latest in what you're seeing in terms of the uptake of WAINUA and in particular, if there are certain segments where you're seeing more update versus last and how that's going? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 17, 2025 / 6:00PM, IONS.OQ - Ionis Pharmaceuticals Inc UBS Virtual CNS Day

Question: Eliana Merle - UBS Investment Bank - Analyst : You guys have had some interesting commentary on that you're seeing combination use commercially. Any color that you can sort of give there like a proportion or mix that you're seeing with combination use?

Question: Eliana Merle - UBS Investment Bank - Analyst : Absolutely. And last question, just SHTG, a lot of investor focus on this readout later this year. We know that you can lower triglycerides. I guess, how do we think about what's clinically meaningful when it comes to acute pancreatis? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. MARCH 17, 2025 / 6:00PM, IONS.OQ - Ionis Pharmaceuticals Inc UBS Virtual CNS Day

Question: Eliana Merle - UBS Investment Bank - Analyst : Interesting. Well, great. Holly, Wade, thank you so much for making the time and sharing all the insights today, and we look forward to all the data readouts.