Ionis Pharmaceuticals Inc at TD Cowen Healthcare Conference Summary

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

Question: Yaron Werber - TD Cowen - Analyst : Great. So usually, we start with WAINUA and we sort of go chronologically. Actually, I'm going to maybe reverse engineer it in the order of questions. And I want to talk about two assets that are going to have data this year. You mentioned one of them, Zilganersen for Alexander's disease, the data has got to be expected in the second half of the year. And the mechanism is that GFAP. Can you talk about maybe what is the biology? What's the primary endpoint in the study and this potentially is a registrational study, right? Talk a little bit about Alexander?

Question: Yaron Werber - TD Cowen - Analyst : And so the -- can you just remind us the trial design? How many patients are in the study and what the design is on the primary endpoint?

Question: Yaron Werber - TD Cowen - Analyst : And is it against Placebo? Or is it against baseline?

Question: Yaron Werber - TD Cowen - Analyst : The -- when you talk with the FDA, can you get -- I mean, you're looking at seizures as well. This is a neurofilamental disorder, similar tangent when they probably face a -- some motor deficits, but probably not as severe. They are ambulatory, they do have seizures, do you need to hit the primary? Or can you do trends in the primary and also hit with biomarkers and NfL?

Question: Yaron Werber - TD Cowen - Analyst : And based on just your understanding of the prevalence as of now, how many patients are in the US and what's their longevity?

Question: Yaron Werber - TD Cowen - Analyst : Okay. The other data we're going to get this here that I think it's in many ways overlooked is the Sapablursen, the impression polycythemia Vera study. This is a 50-patient that's a Phase 2a, the injection's monthly. The primary endpoint is change in phlebotomy in the last 20 weeks of 37 week treatment period versus baseline. Can you talk about -- this is the TMPRS -- TMPRSS6, yeah, TMPR6. Can you talk about maybe this how that genetic manifestation impacts PV?

Question: Yaron Werber - TD Cowen - Analyst : Can you remind us in the Phase 1 in how -- admittedly in healthy volunteers, what was the level of hepcidin increased that you are able to see? 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 04, 2025 / 3:30PM, IONS.OQ - Ionis Pharmaceuticals Inc at TD Cowen Healthcare Conference

Question: Yaron Werber - TD Cowen - Analyst : And what do you think is clinically meaningful in terms of the primary endpoint and the reduction of phlebotomy? Is it sort of 25%, 30% or is it higher?

Question: Yaron Werber - TD Cowen - Analyst : Okay. By the way, for the audience, if you have any questions, feel free to just raise your hand. Okay. So let's move to the next question. And again, I kind of what I'm trying to focus on things that are maybe not typically discussed. I want to talk about pelacarsen, which is obviously as discussed. A couple of things. Number one, with the HORIZON study, which is a secondary prevention study has gotten pushed out a little bit to the first half of '26 from the second half of '25. Obviously, because of the event rates are may be accruing a little slower than expected. Can you just remind us how the study is powered by Novartis? And what percent benefit on [MACE] do you think is clinically meaningful?

Question: Yaron Werber - TD Cowen - Analyst : And in terms of LDL -- LDL control, confusing with Lp(a). The LDL control, what level are they targeting? The secondary prevention since patients with risk, there's obviously going to be different risk parameters. Are they targeting less than 70 and make sure everybody is controlled. There's less than 100? Or is it lower?

Question: Yaron Werber - TD Cowen - Analyst : Okay. Has Novartis talked about plans to commence a primary prevention. I think Amgen is talking about starting it this year. Lilly has now commenced their primary prevention engines, obviously about 1.5 years behind, so we'll be behind them?

Question: Yaron Werber - TD Cowen - Analyst : I want to move to TRYNGOLZA and specifically the sHTG data coming up. So you're running three different study CORE 1 and CORE 2 with the actual Phase 3. The ESSENCE study is the sort of the Phase 2b, which is in a slightly different population with lower triglycerides at baseline with slightly higher cardiovascular disease. It's also a safety study. 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 04, 2025 / 3:30PM, IONS.OQ - Ionis Pharmaceuticals Inc at TD Cowen Healthcare Conference Data from ESSENCE, you might have that midyear and then CORE 1 and CORE 2, our second half. Is the thinking to have all three data sets out at the same time? Or would you put out ESSENCE first and then CORE 1 and 2 together?

Question: Yaron Werber - TD Cowen - Analyst : In the FCS study, can you just remind us what was the reduction, obviously, different population, but what was the triglyceride reduction. And in that study, if I remember correctly, there were seven cases of acute pancreatitis and placebo versus maybe one only. And on TRYNGOLZA, was there a correlation to a certain threshold in triglycerides, just to see that?

Question: Yaron Werber - TD Cowen - Analyst : In that population, do you remember what -- was there a correlation between triglycerides levels?

Question: Yaron Werber - TD Cowen - Analyst : Yeah. Okay. I'm going to shift to Angelman. And by the way, we're doing a panel today, 3:50 with KOLs. It's going to be about a half hour in epilepsy and about 20 minutes or so on Angelman. The [review] study is going to start enrollment, I believe, first half of this year, randomized 2:1. This is the Phase 3 of ION582. You're targeting essentially all mutations, your competitor's targeting the UBE3A, the lesions, and you're going to be targeting both adolescent peds and adults. But is the primary endpoint of expressive communication going to be in all patients? Or is it going to be really in the adults and peds while you're actually including adults for safety, et cetera, and obviously, efficacy?

Question: Yaron Werber - TD Cowen - Analyst : And in the adult cohort against placebo, I assume that's randomized against placebo, I think you said that. Is that 100 patients in that cohort? Or is the next 100 are spread between the adults and the zero to two year olds?

Question: Yaron Werber - TD Cowen - Analyst : Okay. Is the adult cohort powered for efficacy? Or is that going to be mostly supportive?

Question: Yaron Werber - TD Cowen - Analyst : And the zero to two year olds, I mean that there -- is there a placebo controlled in that study? Or is that -- that's very hard to do a placebo-controlled in that age group.

Question: Yaron Werber - TD Cowen - Analyst : And that's a separate cohort, and that's purely supported based on safety mostly?

Question: Yaron Werber - TD Cowen - Analyst : Okay. No placebo. Okay. Any questions from the audience? Last. Unidentified Participant So let me say, catalysts on at HORIZON, which ones would you point investors to specifically over the next 12, 24 months? One or Two? The most significant either at derisking or value creating impact in terms of driving company --?

Question: Yaron Werber - TD Cowen - Analyst : Great. I think we're exactly at time. So Brett, thanks so much for coming. We appreciate it. Good to see you.