Ionis Pharmaceuticals Inc at Jefferies London Healthcare Conference Summary

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

Question: Akash Tewari - Jefferies - Analyst : <_ALACRA_META_ABSTRACT>Actually, Brett, I'm going to start with another angle. So I think it's interesting. Obviously, with the RFK announcement, everyone is sitting here worrying about what's happening from a regulatory perspective. When I look at Ionis and I particularly look at rare diseases, like I'm going to be cohosting a panel with Peter Marks tomorrow. We talk about the potential negatives. I don't think enough people are talking about the potential positives about accelerated approvals for rare diseases. And you guys are a leader in that field right now. So I'd love to get your take as you've operated in different administrations, but where is the puck headed in terms of accelerated approvals with rare diseases? And where could there be potential upside with your portfolio?

Question: Akash Tewari - Jefferies - Analyst : Understood. And I feel like that's a good bridge. We initiated on your company earlier this year. And I feel like when we looked at the -- when we were looking at Ionis, obviously, a lot of work on ATTR because that's what everyone was talking about. I think we completely missed the ball on Angelman. And that went from a program that I think a lot of investors weren't paying attention to, to now it's probably one of the most important products in your portfolio. Can you talk about the study design that you recently announced and really the endpoint selection you chose? Because to me, it seemed like the inclusion of expressive communication was not something that the FDA was requiring you to do. It was something that you chose. You made a very conscious decision to make that as a part of your primary endpoint. Can you talk about that?

Question: Akash Tewari - Jefferies - Analyst : Understood. I wanted to dig into that a little more. One part about, I think, expressive communication is really how do you control placebo response. Why is expressive communication maybe a better endpoint when we're thinking about placebo, especially as we get to further time points?

Question: Akash Tewari - Jefferies - Analyst : Understood. Now biologically, I think the question that my team and I are trying to understand is just on EEG assessments, right? We've seen whether it's the Roche data, your program, what I think -- the one question I get from investors is like, Akash, why isn't there more of a durable signal shown on EEG? How does your team think about the durability of EEG signals, why there might not be that right now and why you still feel confident on developing your program? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. NOVEMBER 20, 2024 / 2:00PM, IONS.OQ - Ionis Pharmaceuticals Inc at Jefferies London Healthcare Conference

Question: Akash Tewari - Jefferies - Analyst : Understood. Maybe moving on to your polyneuropathy launch. And I think everyone is so focused on ATTR because you have Alnylam, you have Pfizer. But I feel like your polyneuropathy launch is a really important proof of concept about outpatient administration and really the patient convenience angle playing out. Talk to me about what you've seen from a new patient start perspective. Obviously, you're competing with Alnylam in that population, but you've been coming from behind there and with AstraZeneca has helped. So -- what are the advantages you're seeing in the real-world setting about outpatient administration? And how have new patient starts trended as we get into 2025?

Question: Akash Tewari - Jefferies - Analyst : Understood. Now maybe going into ATTR, and I think a lot of us on the kind of investor side are the HELIOS-B data came out, your team takes -- you and AstraZeneca, you guys take your time, you're processing the data. You've talked about, hey, there will be potential modifications to our current Phase III design. I think there are a couple of points that I think are important. Number one, okay, your current endpoint is out to 33 months. But you've talked about the ability to include open-label extension data at a longer time point as a part of the FDA label. And you've pointed to the fact that Alnylam has done that. When you look at the HELIOS-B data and the extension, right, it certainly seemed important for them to go out to 40 months. Is that a reasonable assumption for us right now that we should expect an open-label extension from 33 to 40 months with the Ionis AstraZeneca program? Yes or no.

Question: Akash Tewari - Jefferies - Analyst : Always worth trying. Maybe the other -- two other points on TTRansform. A, it does seem like all-cause versus cardiac mortality, there might be reasons to think that all-cause might be a better endpoint. I'd love to get your thoughts on that. And then number two, this is something that we've been fiddling around with background SGLT2 use, right? Because SGLT2 use is obviously starting to accelerate. It -- I actually think it's shocking how little it's used just generally in cardiovascular health. But from the Alnylam study to the NOVO study, we're starting to see the rates go from kind of the 20%, 30% to even 40% or more. I think that for your trial, you may also have pretty substantial uses of SGLT2. How does that kind of affect your event rate assumptions given your trial is going to be reading out in 2026?

Question: Akash Tewari - Jefferies - Analyst : Understood. And just on all-cause and cardio.

Question: Akash Tewari - Jefferies - Analyst : Understood. And I actually wanted to hit on that. I feel like a lot of times, we just think, oh, it's Ionis' program versus Alnylam's program. But in reality, there are structural advantages that you have with partnering with AstraZeneca, A, from a commercial side, but B, and you and I have talked about this, the depleter program that they've started to show data on, I thought it was quite interesting. You're seeing a pretty remarkable drop. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. NOVEMBER 20, 2024 / 2:00PM, IONS.OQ - Ionis Pharmaceuticals Inc at Jefferies London Healthcare Conference I mean it's one of the first programs where you're actually removing the plaque, and you're seeing a very quick proBNP signal. I mean, something I don't think I've seen before. I can't help but think if there's any shot to kick tafamidis off standard of care, it would be a combination of a depleter and a silencer program. And I would almost think it would make sense because you would treat patients, you would have that initial depletion and then you get patients on a silencer long term, and that might be the best clinical profile from a safety and efficacy perspective. Talk to me about how you look -- how your team looked at that data? And could we see a potential combination strategy between you and AstraZeneca with a depleter and a silencer?

Question: Akash Tewari - Jefferies - Analyst : Understood. Now maybe just going on to olezarsen. And again, I feel like it's important to talk about structural advantages that you kind of have in the space. You're going to have your FCS approval and then hopefully, SHTG after that. You have competitors in the space that I think have a competitive profile with what you've shown. But I think the question is, what are the structural advantages for being able to come out in -- sorry, FCS first -- and then SHTG a few years after that from a prescriber base perspective and then also from a marketing perspective that maybe investors aren't appreciating right now?