Ionis Pharmaceuticals, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Thanks, Mike. Good morning, everybody. It's great to be here, Mike. Thanks for the invite. As expected, and not surprising with a pipeline as deep and rich as ours, we were expecting a highly eventful year for Ionis, and that's exactly where we are, with a lot more to come in the remaining months of the year. We're on track this year to push three breakthrough medicines across the finish line through the FDA. Three drug approvals, we already have two. Severe hypertriglyceridemia breakthrough medicine, TRYNGOLZA, was approved a few days early in June, and just last week, we had the approval of our first wholly owned neurology medicine, ZANVASTRO, for Alexander disease, the first disease-modifying treatment ever approved by the FDA.

We're expecting a third FDA approval in October with our partner, GSK, for chronic HBV, a real breakthrough that's actually producing unprecedented functional cures in this patient population. We've also had expanding our Phase III pipeline. We completed enrollment in our Phase III Angelman syndrome trial, which is on track for data in the second half of this year. We're pleased to see new Phase III starts from our partners, salanersen. The first follow-on to SPINRAZA for SMA that is on track to produce a medicine with even deeper efficacy than SPINRAZA based on biomarker data with once-per-year administration. sapablursen started Phase III development with our partner Ono Pharmaceutical this year with a profile that has the potential to be best in class for polycythemia vera. Mid-stage pipeline continues to produce as well.

We are thrilled with the first-ever proof of concept for our tau program with Biogen, diranersen, which showed unprecedented improvements in cognition and other functional benefits as well. Our follow-on to TRYNGOLZA, proof of concept as a once-a-year or twice-a-year administration as a follow-on to TRYNGOLZA, ION775 in severe hypertriglyceridemia, which is in Phase II development. With a pipeline as deep and with so many events happening, there's always disappointments. We were disappointed with the negative outcome of the CARDIO-TTRansform study for eplontersen and TTR cardiomyopathy. Despite the fact that we had remarkable reductions in TTR that were as good as anything that's out there today, approximately 80% reduction with good safety and tolerability, didn't hit the composite primary endpoint.

That was a key focus at ESC a couple of weeks ago, where the conclusions were clear that the reason why we didn't hit the primary endpoint was because there was no added benefit on top of a stabilizer. However, the monotherapy group, that is patients that weren't on stabilizer at baseline, has a ratio that's as good as anything that's out there in TTR cardiomyopathy. It has a ratio of approximately 30% reduction. We're working on potential next steps there. Last week, we were also disappointed with the outcome of the pelacarsen Phase III trial in Lp(a) cardiomyopathy. We're looking forward to our partner, Novartis, presenting the full data set there.

But on top of those disappointments, we have a really, really strong pipeline, and we're really proud of all the successes we've had and the launches that are in progress, which are going quite well.

We're pleased to have delivered the first real breakthrough for severe hypertriglyceridemia with an incredibly strong, positive, clean label. Unprecedented reductions in acute pancreatitis. This is the outcome that patients are most fearful of, that physicians are most fearful of, a potentially fatal acute pancreatitis attack. There has been no meaningful treatments for severe hypertriglyceridemia before TRYNGOLZA emerged and was approved by the FDA. As a reminder to everybody, this is a label expansion. Our first indication was familial chylomicronemia syndrome, FCS, a rare population of about 3,000 people in the U.S. That launch was going exceptionally well right up to the label expansion, right up to the approval for severe hypertriglyceridemia. Then we expanded the label, adjusted the price from a rare disease price to a price that's more suitable for a highly prevalent disease. Prevalence of more than 3 million people in the U.S.

This is positioned to be a blockbuster, and we're on track to achieve our goal of $3 billion plus peak product sales in the U.S. The launch is going well. We're liking what we're seeing on all aspects of the launch to date, the metrics that we're assessing. First of all, we're thrilled with the excitement by the HCP community. I'm sure you've done your research, you've talked to your docs. They're all saying how excited they are about TRYNGOLZA and their enthusiasm to want to treat and write scripts and get their patients on this drug, particularly those patients that are at high risk for acute pancreatitis. The launch is going well. We're excited about the enthusiasm. We're excited about the scripts that are coming in. July and August were very good months.

We're excited about what we're seeing from the payer community, the coverage that we're getting for TRYNGOLZA. Although, of course, at this stage of the launch, most coverage is going through a medical exception process with prior authorizations. But we are getting policies in place, and based on those policies, as well as all the other conversations we're having with payers, we're getting coverage to label, right? Not just the high-risk patient population, but the label. That is anyone that has triglycerides above 500. We expected the patients that were going to be prioritized in this study would be those high-risk patients by physicians, endocrinologists, cardiologists, lipid specialists, and that's what we're seeing. These are the patients that have triglycerides through the roof, above 880 milligrams per deciliter, are at high risk for acute pancreatitis attack, with debilitating effects on the pancreas, of course, long-term.

Those that have had a history of acute pancreatitis. Around 700, 800, 900,000 patients that are at high risk. Those are the ones that we're seeing the scripts written for first, not surprisingly. I could also tell you, though, we are seeing some scripts coming in that are in the non-high-risk category. Patients that are in the 500-800 range without a history of acute pancreatitis. So, that's getting out there too, but the priority for us and the priority with HCPs is the high-risk patient population. I could also say that we're excited or we're really pleased how well the dosing is resonating with the HCP community. We are the only medicine that offers dosing flexibility of 50 milligrams or 80 milligrams per month. So if administered using a simple auto-injector.

That dosing flexibility, as I said, has resonated really well. We're seeing scripts come in with the 50-milligram dose, and physicians are looking at the response to 50 milligrams and seeing if their patients are at goal, that is below 500 milligrams per deciliter, they're fine. We're also seeing scripts coming at 80 milligrams right out of the gate. Remember, the 80-milligram dose is what's approved in FCS. We have a lot of docs that are managing FCS patients and are really pleased with the performance of TRYNGOLZA in FCS, and they're saying, "Why start at 50 in my SHTG patients? Just roll it right through, and get those patients to the max dose." We're also pleased how the response by the community, the physicians, and the patients because we require no monitoring in this study. It's a simple administration. Really no significant step edits.

Your patients will need to be on a triglyceride drug, like a Fibrate or a fish oil or something like that, before going on to TRYNGOLZA. All these high-risk patients are already on these drugs, right? They're still not at goal. It's not really a step edit, it's just getting those patients identified and bringing them onto TRYNGOLZA. This is a new category. We're developing a new category. We're going to build this market. It's going to take a little bit of time, but we're pleased with the way the enthusiasm for the drug, and we're pleased with everything we're seeing with the launch today. We're looking forward to providing a more detailed update at our Q3 earnings in a few weeks.