Brett Monia: Before handing over to Kyle and Jonathan about the dynamic TTR cardiomyopathy market, combination monotherapy, let we comment on the SHTG. So as a reminder, Jason, we saw remarkable reductions in acute pancreatitis in our FCS BALANCE study for olezarsen. Not only was the reduction substantial, the number of AP events in the placebo group were much more than we anticipated going into that study point. I guess, a very important point that I want to emphasize is that we don’t really know people. It’s not really understood well what the AP event rates are in FCS or SHTG is these trials that we’re conducting that are going to add a lot of light — shed a lot of light on to what the true AP events are for both FCS and SHTG.
Virtually all of the AP events that occurred in the FCS study were in the placebo group. Certainly, in SHTG, we would expect and do expect fewer AP events just based on — compared to FCS based on the fact that the mean triglyceride reductions are lower in SHTG than they are in FCS. But with that said, we have many patients in our SHTG trial that are in the thousands in the FCS range in the study. But the mean reduction — mean TG levels will be less, and therefore, you would expect the rate of AP events to be a bit lower in SHTG. With that said, we are seeing in a blinded manner AP events and they’re accumulating a pretty robust study. If we can replicate anything like what we saw in FCS, the majority of those patients we would expect to be in the placebo group, because the olezarsen is expected to reduce triglycerides even better from a magnitude standpoint in SHTG versus FCS.
So at the BALANCE FCS study certainly gave us more confidence in a positive AP outcome in the study. Reminder, the primary endpoint is triglyceride reductions, AP events in the SHTG study is a key secondary. Jonathan, you want to comment on the changing dynamics in TTR cardiomyopathy and how we’re seeing monotherapy combination play out?
Jonathan Birchall: I think the specific question for me around that willingness to cover the combo. And I guess my first point is very difficult to answer the question, given that we don’t yet have any data and therefore, don’t really understand the profile of the combination. That said, I think there are plenty of other therapy areas, whether it’s Gilead’s work in hep C, where treatments were seven figures, plenty of oncology drugs where there are very expensive combinations that are still covered by payers. And what I can tell you specifically with regards to CARDIO-TTRansform and the combination usages, the market research that we’ve completed has shown that there is a willingness from payers to cover the combination. Obviously, the caveat to that is it will be data dependent.
But so long as with data from what’s effectively the largest study in this area, we’re fairly confident that we — if we’re able to demonstrate the benefit that, that will then ultimately be covered by the payers.
Brett Monia: And we’re very well positioned to demonstrate added benefit in combination based on the design of our trial, the size of our trial and the percentage of patients we have in — on tafamidis versus monotherapy.
Operator: And the next question comes from Yanan Zhu with Wells Fargo.
Yanan Zhu: Maybe to follow up on ATTR cardiomyopathy, just curious, any color on the blinded event rate, any update there? And any thinking about the primary endpoint analysis? And also as the competitor readout their data, what are the key data points and that you will be focused on learning?
Brett Monia: So the blinded event rates in the CARDIO-TTRansform trial are tracking well. They’re on track for what we expected. And that — when I say that, I’m referring to both mortality as well as hospitalizations and the nature of those hospitalizations. We’re looking at it very quickly — very carefully. And there’s no changes to our plans on primary endpoint or timing. As we said in our presentation as early as next year still on track. The study we were to go to its completion, 140 weeks of treatment that would be midyear 2026. And we’re focused almost very much on the blinded event rate to drive the decision with our partner, AstraZeneca, when this reads study out. We’re very much looking forward to the readout of the first silencer in TTR cardiomyopathy from a Phase 3 trial later this year.
And if we learned something from it, it could influence our timing for reading out the study and we’re very much looking forward to it. And I really can’t go say much more about it than that at this point.
Yanan Zhu: If I may ask a follow-up on Angelman syndrome readout. What might be the value? And how do we think about the relative importance of the biomarker EEG versus clinical endpoints like CGI and Bayley-4 when we learn the data?
Brett Monia: Yes. Eugene will comment on the clinical endpoints, biomarker EEG and other Bayley-4, et cetera. We don’t — we haven’t settled on how and when exactly we will report out the next step for the Angelman program. As you know, Yanan, Biogen has an option to license this program. And as we’ve said before, when we do announce the next step for the program, when the data reads out, we will be also planning to comment on what Biogen’s plans are for the next steps if they option in for the program. As far as forum, we have not settled on that either. There is an Angelman conference in August of this year, which we regularly attend each year. That could be a forum, but we haven’t made any firm decisions. And of course, if Biogen licensed this is the program, they will be in the driver’s seat to make those calls ultimately. Eugene, talk a little bit about the endpoints that we’re looking at in Angelman?
Eugene Schneider: Yes, sure. Thanks for your question, Yanan. Yes. So of course, we’re — this is a truly a learning study for us. And as such, we’re really exploring a range of different outcomes, including, of course, EEG, which has built quite a bit of data both through natural history as well as some of the early data that was shared with the community. But importantly, of course, the clinical assessments that include standard scale that you mentioned Bayley-4, of course, Vineland is another very common scale used in neurodevelopmental disorders. But we’re also looking at other aspects of this disease, essentially covering a very broad range of presentation and symptoms for Angelman, and that includes things like sleep and behavior and other things. So we’re truly trying to learn as much as possible about the impact that our drug may have on all of those features of this pretty complex disorder.
Operator: And the next question comes from Luca Issi with RBC.
Luca Issi: Maybe one on TTR cardiomyopathy, Eugene, if I may, — what was your reaction to AstraZeneca powering their Phase III trial for the monoclonal antibody at 1,000 patients? Basically, we now have Alnylam HELIOS-B has 665 patients. Your trial is 1,400 patients and AstraZeneca’s monoclonal antibody in 1,000 patients. Does this mean that Alnylam is under-powered, you are overpowered and monoclonal antibody in the purpose of power. Any thoughts there, most appreciated. And then maybe on AGT, what’s the latest thinking on this target. Roche is clearly very excited about it and even willing to run a cardiovascular trial, while it feels that — your target is not getting the same amount of airtime that it once did. Am I off here?
And if so, what’s the next sort of this program? And then finally, on HAE. I think on Page 17, you’re citing that these assets obvious includes near elimination of attacks. Wondering if you can comment on whether that applies to both Q4W and Q8W or only Q4W?
Brett Monia: A lot to unpack there [Multiple Speakers] comment on the trial design. So we’re not that close to AstraZeneca’s antibody depleter for TTR cardiomyopathy, Luca. And so the size of their study, the powering assumptions that went into that all that, it’s not in our area. We, of course, talk to them pretty regularly about how these two mechanisms could synergize down the road, but certainly, we’re not involved in the design of their trial. I don’t think powering assumptions, anything.
Eugene Schneider: No, just on our trial, as you know, we spoke about it a lot — and certainly, we feel pretty confident in our assumptions that are based on emerging data. So that’s what I feel comfortable speaking about. I can’t speculate what others use in their assumptions.
Brett Monia: It’s a different mechanism. We believe in our trial design. We believe that we have the right size of the trial design and the makeup and the demographics in our CARDIO-TTRansform study. With that, I can’t really — I don’t want to comment any more on what others are doing. AGT, no change. We are continuing to progress our plans as we’ve stated earlier that we plan to partner this program and we’re still planning to do that and we’re making progress. For HAE, we know we — as we will share with you at EAACI at the end of this month, both every four week and every eight week dose we showed highly statistically significant benefit in reducing HAE attack rates, but every four week dosing had a greater reduction in HAE attacks. So when we refer to near-elimination, certainly every four week data comes closer to that than every eight week dosing.
Operator: And the next question comes from Salveen Richter with Goldman Sachs.
Unidentified Analyst: This is Tomi on for Salveen. So just to follow up on the previous commentary about the Medicare Part D design. Do you think that — how are you thinking about the possibility that there could be a higher level of scrutiny, especially in cardiomyopathy given the entrance of another stabilizers potentially this year?
Kyle Jenne: For the Medicare D population, I mean, things are evolving a little bit, right, with the IRA regulations and things that have come into play. And historically, there’s been quite a bit of distinction around the out-of-pocket expenses for patients and the way that those had to be paid in terms of timing and time lines around that. I think where we’re at right now with Medicare Part D is a much more favorable position than we have been historically, and it’s only anticipated to get better in the coming years. So out-of-pocket expenses are going to be limited for those patients, either $3,000 or so this year. It goes down to $2,000 or so next year. And then there’s also the ability to spread those costs over time. So it’s not a one assessment for the patient, which I think is very positive.
So when we’re thinking about WAINUA and other programs that we have that will go through the Medicare Part D channel, I think we’re very encouraged that we’ll be able to work effectively within that system and support patients appropriately. And keep in mind, it’s not just about our treatment for Medicare Part D but it’s a combination of all of the therapies that those patients are on that will hit that ultimate cap of $3,000 or $2,000, respectively. So I think we’re well positioned in a good place to the reimbursement channels to allow patients to have access and appropriate access to our treatments.
Operator: And the next question comes from David Lebowitz with Citi.
David Lebowitz: Would you be able to comment on ION224 and you get to as far as the data that you recently presented, and what you think about that therapy given the burgeoning [MASH] landscape?
Brett Monia: Yes, we couldn’t have been more pleased with the Phase II data we reported earlier this year on DGAT2 in patients with MASH. This is the first time. So our target of DGAT2 — by targeting DGAT2 and blocking the triglyceride synthesis pathway in the liver. We certainly expected robust reductions in liver fat based on this mechanism. We were very pleasantly surprised to see not only that, we also saw reductions in NASH resolution, that is inflammation of the liver by biopsy, as well as a turnaround of fibrosis, positive reduction in fibrosis in these patients. First time ever, a treatment that blocks fat synthesis was shown to actually achieve this. As we mentioned, this program, as exciting as it is, doesn’t fit really well within our focus Ionis on — for our wholly owned pipeline in neurology, cardiovascular and maybe specialty rare opportunities.
So we think this program fits best with a partner. And that’s what we’re doing is we’re moving towards partnering this program to take it to the next stage of development, which could certainly be a Phase 3 program. There’s certainly interest and those conversations are progressing pretty well. It’s early in the discussions but they’re progressing well. And maybe we have time for one last question before wrapping things up.
Operator: And that last one comes from Kostas Biliouris with BMO.
Kostas Biliouris: Can you remind us what is the status of sapablursen in PV and when should we expect updates from this program given the increasing activity in that space and the multiple readouts in 2024 ? Also any thoughts around the commercial opportunity of that program would be helpful.
Brett Monia: Yes, sapablursen program in polycythemia vera Phase 2 continues to progress well. I think we’ve said before, it’s an open label study and we’ve been — we’ve said before that we’re clearly seeing evidence of robust activity, efficacy in this study. What we’re doing in this Phase 2 study, that is reductions in hematocrit red cell accounts, normalizing in many cases, in many patients. And what we’re doing is dose ranging to understand what the right dose and dose regimen will be for a potential advancement into Phase 3 development. So we’re looking forward to sharing that data potentially this year. It continues. As far as the market opportunity to create a question, we’re assessing that now. We don’t have an answer for you.
It’s a very interesting area. And our commercial organization is well on its way in doing all the market research for the opportunity in the United States and outside of the United States. So we have not decided on where this program fits best at Ionis or partner. We’re going to try to provide an update by the end of the year on the program. So thanks for the question, Kostas. And thanks, everybody, for joining us today who participated on our call. We plan to continue all this great momentum throughout the year, and focused on next level value for our shareholders and all stakeholders. We’re also looking forward to providing a comprehensive overview recap of the Phase 3 donidalorsen data we’re presenting at EAACI on May 31st. So stay tuned for that.
And we’re looking forward to the webcast as well on that day. We hope you can join us on the webcast. And until then, thank you, everybody, for joining in, and have a great day.
Operator: The conference has now concluded. Thank you for attending today’s presentation. You may now disconnect.
