Brett Monia: Thanks, Kostas. Not a lot of thoughts on gene editing efforts in the TTR space. I mean, the progress that they’re making is steady. Percent reductions in TTR are absolutely important for efficacy. I don’t think there’s a — I think we’ve known for a long time that there’s not a threshold effect if that’s your question that there’s a specific threshold by which if you lower TTR is that you’ll achieve benefit on neuropathy or cardiomyopathy or whatever. But then it’s actually individualized per patient and percent reductions is very important and we’re very pleased with the mid-80% mean reductions that we’ve achieved in the neuro transform study for eplontersen in polyneuropathy patients, mid-85% range. And as you know we’ve — actually a substantial number of patients actually improve.
And about the eplontersen [ph] and quality of life. So I don’t know what to say about those other programs except that they have a long way to go. Cardiomyopathy indications are going to require an outcome trial in our view to not just be approvable but to actually compete. And it’s going to take a long time to get there. And it’s a new platform that you never know what will come up. So I don’t know much else to say about it other than that Kostas, but we love our program and we’re very much ahead.
Kostas Biliouris: Thank you very much.
Operator: The next question will come from Joseph Stringer with Needle & Company. Please go ahead.
Joseph Stringer: Hi. Thanks for taking the question. Just a quick one on Phase 2 GOLDEN trial and geographic atrophy. When can we expect top line data? And given some of the competitor data that’s out there, can you handicap expectations on what successful Phase 2 outcome looks like. And if the results are sufficiently positive what would be the next steps in the program collaboration with Roche?
Brett Monia: You want to take that Richard?
Richard Geary: Yeah. I’ll take a stab at it. I think, of course, we want a positive trial on geographic atrophy and comparable if not better results than have been presented by other competitors. So that’s the goal. We have no insight into what that is today, but the data will be out next year second half.
Brett Monia: Yes. So second half as Richard said in the second half of next year, what I can add to that Joe is that we also had an interim look in this Phase 2 study that allowed us to select the doses to complete the study. We started with a number of those and then whittle goes down to two doses to complete the GOLDEN Phase 2 study bring it to the finish line. We’re seeing excellent tolerability, we’re seeing profound reductions in Factor B and in downstream effects like split products exactly where we expect to be. So we’re getting great target engagement, we’re not seeing any risk associated with that target engagement by blocking the alternative complement pathway, it’s going great. And what we expect to see is — what we hope to see is slowing down of lesion, formation and improvement in visual acuity.
I mean these are the outcomes that we’re expecting to support a decision whether to go to Phase 3 or not. As far as competitive landscape this is a subcu once-per-month drug using — which could use an autoinjector once it got to the market if it gets there. Simple at home auto-injector like apontersen whereas the drugs that are under review or recently been approved or intravitreal and they have side effects as you well know. So I think this — although there’s been progress made in GA, I think patients are desperately waiting for a joint that’s not so invasive and simple and convenient like a subcu at-home administration.
Joseph Stringer: Great. Thank you for taking our questions.
Operator: The next question will come from Myles Minter with William Blair. Please go ahead.
Myles Minter: I just had a question on ION904. I think you’ve got an upcoming presentation at American Heart Association. Just wondering whether we should be thinking about similar AGT knockdown to the previous like a molecule and just more infrequent dosing or is that potential to get more than that sort of 75% that we’re seeing with that molecule? Thanks very much.
Brett Monia: You got it, Myles. So our presentation on our AGT program at AHA will really focus on the dose-dependent reductions in AGT that we sought to achieve in our — in the Phase II study. This is a molecule that is being dosed monthly. Our earlier generation molecule that you mentioned was weekly and we expect to see greater reductions in our earlier generation molecule because it’s a more advanced chemistry. So that’s what we’re expecting.
Myles Minter: Great. Thanks for the question.
Operator: The last question will come from David Lebowitz with Citi. Please go ahead.
David Lebowitz: Thank you very much for taking my question. With respect to Olezarsen given the recent pivotal data, as you look forward to severe hypertriglyceridemia, how — I know that you achieved benefits with respect to pancreatitis, you received the reductions. But given the dynamics and differences in that population. How easy do you think it’s going to be to show a pancreatitis benefit?
Brett Monia: That’s a great question, David. And it’s a question that our answer today is a lot different than it would have been earlier this year. The SCS data, we in our wildest dreams we hope to see the AP reductions that we saw in FCS. And those are while the streams turned into reality. So — and as we mentioned in our remarks earlier, we have been more pleased and this is the first time anyone has demonstrated that lowering of lipid like triglycerides can actually result in other outcome in AP. My point is that our confidence has grown because the efficacy was so remarkable on reduction in AP events. And that lends confidence to the SHTG population, which although it’s not a genetic form of severely elevated triglycerides, at least no known genetic causes.
It’s not a monogenic disease like SCS. These patients still suffer from a highly elevated triglycerides much like FCS patients. Sure, some of those patients could be in the above 500 range to 1,000 range, but many, many of these patients are in the multiple thousands or at least above 1,000 which are which puts them at very high risk for AP. So I think we’re going to get AP events and in the Phase III SHTG study. And based on the effect size or the effect that we saw with Olezarsen and FCS, our confidence is growing, but we have to see that. And despite the fact that the number of AP events per patient may be less in SHTG versus FCS, it’s such a bigger study. It’s a much bigger study. So we’re going to have much more data that we’re going to collect.
And as Yuji said, we have the ability to combine two Phase III studies CORE and CORE2 to really look at overall the impact of Olezarsen on AP events in SHTG.
David Lebowitz: Thanks so much for taking my question.
Brett Monia: Thank you, David. And thanks everybody for joining us today and everyone who’s participated in our call. We really are proud of all the progress we’ve made this year and we believe that the future has never been brighter here at Ionis. And we plan to continue our momentum by delivering on additional key commercial updates pipeline updates technology updates objectives as we go forward. And we very much look forward to it. But until then thank you again and everybody have a great day.
