Ionis Pharmaceuticals, Inc. Common Stock Wells Fargo 21st Annual Healthcare Conference

Thank you, Yanan. Good morning, everybody. It is great to be here.

Sure. Happy to. I will be brief, though, because I know you have a lot of questions, Yanan, and we want to get to those. But as expected, this has been a highly eventful year for Ionis. We have had several really important positive strategic outcomes this year, and we have also had some disappointments. Not surprising when you are consistently seeking to deliver breakthrough treatments in new therapeutic areas, sometimes you have disappointments. But I really do want to emphasize the incredible success we have had this year already. We have had two FDA approvals, both in areas where there is high unmet need and we are first. TRYNGALZA for severe hypertriglyceridemia, ZANVASTRO for Alexander disease, both wholly owned products. And we are anticipating a third FDA approval by our partner GSK later this year in chronic HBV. Again, another breakthrough producing unprecedented clinical functional cure rates in patients with chronic HBV.

We've had three phase III readouts this year, and we are on track for two more. The pipeline, in addition, continues to deliver and go very well. We initiated a phase II study for ION775 in severe hypertriglyceridemia that supports twice or once a year dosing. As a follow-on to TRYNGALZA, we started a phase II study in Dravet syndrome using a very important new chemistry that we've created that supports potentially twice a year or once a year dosing. I can go on, but maybe we should just open it up for questions. It truly has been a strategically successful year so far.

Yeah. So sad for the Angelman's community. We really feel for them. This is a community that has been in desperate need for a treatment. They've been disappointed many times with unsuccessful clinical readouts. With that said, we see zero read-through to our program. Prior to the readout from the program that you just referred to, we've been signaling to the investor community and to anybody that'll listen to us for well over a year that although we are hopeful that the study would show signs of success, we were not very optimistic that it would be successful for several reasons.

Most notably, Yanan, is the fact that despite the fact that their molecule and our molecule are using similar mechanisms of action, a mechanism of action that we actually pioneered and published on for the first time, and they have similar potencies based on a whole host of data that we've generated, they were dosing substantially lower than us. That's because they ran into toxicity issues in the clinic and pre-clinically that forced their dose to be capped, substantially lower dose, and we were concerned that they were underdosing. We do believe that that was the culprit in their study at the end of the day. Our program, of course, rides the heels of a proven platform in CNS diseases.

Let's not forget that Ionis is the only company that has delivered oligonucleotide successes that have been FDA approvals in the clinic to date, proven platform that has delivered SPINRAZA, ZANVASTRO now, Calci, and proof of concept even in Alzheimer's disease with our tau program. We're dosing at the maximum dose we set out to dose at, and we think that we will max out on efficacy when our study reads out next year. We fully enrolled this year, the study, and we're looking forward to data in the second half of next year.

Yeah. This is another first for an Ionis discovered medicine to test the Lp(a) hypothesis, if you will. That is to address an independent risk factor that's been strongly associated with cardiovascular disease. High levels of Lp(a) are strongly associated with cardiovascular disease. We set out to determine whether or not it could be modifiable with a pharmacological intervention, pelacarsen, by lowering pelacarsen to normal levels. That's what we did in this study. We got substantial lowering of Lp(a) that were similar to what we purported in our phase II study on the order of 75%-80% reductions in Lp(a). We saw good safety in the study. Those reductions in Lp(a) really normalize a lot of patients. Unfortunately, it didn't result in a successful outcome on MACE, a four-point MACE endpoint.

The study did not achieve statistical significance in the primary endpoint. It also didn't demonstrate benefit in the subgroup of patients that were at higher risk in the study. It's unfortunate the drug did what it was supposed to do with respect to lowering Lp(a) with good safety, but it may implicate Lp(a) as an independent risk factor, but one that may be unmodifiable, at least in this patient population that all other risk factors are well controlled. LDL, hypertension are very well controlled. As a secondary prevention, maybe it's just not modifiable. We'll see. We don't see a path forward for pelacarsen. Novartis is going to be presenting the full phase III data at a medical congress as soon as they can, maybe later this year. Stay tuned for that. Unfortunately, we don't see a path forward for pelacarsen.

Yeah. I really want to highlight that we had three presentations related to eplontersen in ATTR cardiomyopathy at ESC last week, all high-quality presentations in large forums at the meeting. The overall study outcome, and then the focus on the subgroup in combination with tafamidis, if you will, or stabilizers. The study did not hit its primary endpoint in the composite of cardiovascular mortality and serious CV events in the overall population. However, in patients that were not on stabilizer at baseline, we call this the monotherapy group, we saw a remarkable efficacy. We saw efficacy that is similar to the only other silencer that is on the market today with respect to a risk reduction of nearly 30% risk reduction. We saw TTR reductions that were as good as anything that has been out there today, around 80% TTR reductions, all with good safety in the phase III study.