Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Great. Thanks very much, everybody, for those who continue to dial into the fireside chat this afternoon. I am happy to be moderating a discussion here with executives from Ionis Pharmaceuticals. With me, we have CEO, Brett Monia; and CFO, Beth Hougen, who I'm sure folks style they know quite well. Maybe we can start and just have Brett give a 3 to 5-minute overview, set the stage for Ionis' key pipeline events coming off recent progress, and then we can get into Q&A. How does that sound?

Sounds great, Paul. It's a pleasure to be here. So yes, we're very excited about Ionis and where we're headed in the future. Obviously, a lot of news this year and a lot of pipeline events. I mean, recently, we announced several Phase IIb starts of our Factor XI program, our HBV program. And then most recently, vupanorsen with Pfizer on angiopoietin-like 3 last -- just last week, we had a very nice update with our partner, AstraZeneca, on our PCSK9 program, and we feel happy to talk about that more, if you wish. Very exciting program in which we have developed a subQ formulation as well as an oral formulation as well. And then we're looking forward to several additional pipeline updates even later this year, well into next year. This year, we're planning to talk about our [ AGT-L ] contingent program for control of hypertension. And then quite a lot of new clinical trial starts as we look towards next year, as well. I mean, the pipeline is just exploding with information and exciting news coming out over the next 12 months or so. We're planning to start at the end of this year, another Phase III study. That will be our sixth Phase III study in progress for APOCIII LICA in FCS, and then we're looking to other Phase III studies. At least 1 other 1, potentially starting next year for APOCIII LICA. And then we're looking to start a number of neuro programs. Ionis-owned neuro programs. Start clinical trials next year, Prion disease, Alexander's disease and then a registrational study for a former -- a genetic form of ALS that’s to be taken [ TDP plus ], that will begin next year as well. We also have now several Phase II studies fully enrolled that we're really excited to see the outcome and the unblinding next year. That includes our ENaC program in cystic fibrosis, our prekallikrein program in hereditary angioedema, both fully enrolled and our growth hormone program for acromegaly, also for enroll -- and we're looking to the -- results of those Phase II studies, which set us up nicely for potential Phase III studies in the future. And then on the neuro side, additional clinical readouts there as well. We have the C9ORF ALS program -- Phase II program due to read out next year. We have an update on the Huntington program, the open-label extension with Roche next year. And then, of course, very, very excitingly, we have the Phase III results from our SOD1-ALS program throughout next year, which, again, is one of several ALS drugs that are now in clinical development, and it's most advanced, and it's one that we're feeling very good about how the results are shaping up based on really strong Phase II data. So a lot of pipeline news coming, and next year is setting up for a really exciting year, and we're not finished yet this year.

Awesome. That's great. Cool. Well, we have a lot to try to cover. So let's do it. Maybe let's start with TTR. Can you just walk through the update with -- for polyneuropathy and cardiomyopathy for TTR LICA and how that's going? Obviously, understanding that the pandemic presents some challenges for all studies.

Yes. The Phase III TTR LICA programs are going fine. They -- they're in their enrollment phase. We have 2, as you know, one for the polyneuropathy indication, the same indication as TEGSEDI and its enrollment. And we're opening up more and more sites all the time. And the cardiomyopathy study is enrolling. It's a -- obviously, for the broader and to keep a much broader indication for wild-type and hereditary cardiomyopathy. And it's well on its way enrolling and opening up more and more sight as all the time. We did have a -- like everyone has some delays due to COVID pandemic, but we're also identifying ways to get around it, and we have time to make up based on the fact that these are rather lengthy studies. So those studies -- they're going well.

Yes, yes. How do you think about the future of TTR LICA in the market with multiple stabilizers and potentially [ and I’m ] talking about in every 6-month drug. Do you think a once-monthly subQ drug can be a preferred product and a market share gaining product in that space?

We really are very pleased with the performance of all of our LICA drugs like TTR LICA, 1 of 15 LICA drugs now in clinical development. They've all are performing very similarly from an efficacy and a safety, tolerability standpoint, which is very attractive. We've never had a clinical trial be put on clinical hold or be abandoned due to safety or efficacy for any of our LICAs medicines and our TTR LICA is looking like 1 of the best LICAs, 1 of the most potent ones that we've ever developed. At the end of the day, Paul, I think it's great for patients to have stabilizers and RNA silencers and all, these different choices to treat their disease. Tafamidis is doing well in the market, obviously, as a stabilizer. At the end of the day, I believe, and I think the evidence supports the conclusion that the RNA targeting mechanisms will win the day when it comes to efficacy, and they'll have a very good safety and tolerability profile. When it comes to -- and that's based on even the Neuro data we've generated from the Phase III studies that were highly statistically significant, where has tafamidis missed the mark on neuro. And certainly, the Phase III study for tafamidis left plenty room for improvement in cardiovascular outcomes. We've done quite a bit of work, market research work on the value of a once per month subQ injectable, and it's very attractive. Everywhere we look, everyone we speak to says that that is a huge advantage as a subQ low volume injectable. And then once you go start on less frequent than that, Paul, really, everything we've read and seen and all the research we've done indicates diminishing returns. It's really once you get past the month, it really doesn't matter much. So we like our profile. The study is enrolling, and we're excited about getting to the finish line.

Yes. Yes. Okay. Very good. Maybe just briefly on the cardiomyopathy trial. When -- what are the different timings in which we can get a readout from that study? I believe you talked about these are long-term outcomes trials, but also an opportunity for a potential interim analysis. How should we think about that?

The -- It's a cardiovascular outcome trial, cardiovascular mortality and hospitalizations, and it's projected to be about 30 months in duration. And it's going to be -- we're targeting 750 or so patients in the stuff, wild type and, of course, mostly wild-type and hereditary cardiomyopathy. There's the potential for interim analysis. We have not laid out the details on that yet. And we're actually -- honestly, we're still working on it on how that -- what that might look like and when we would want to trigger that, because you don't -- you got to be careful of taking statistical penalties. When you do that sort of thing, is the risk worth a reward, et cetera, et cetera. So there's a potential for an interim. We're working through the details, and once we know exactly what our plans are, we'll definitely put it out there.

Yes, yes. Okay. Okay. Great. Let's switch gears to APOCIII LICA. And I guess you recently acquired the full rights of that medicine from -- in the acquisition of Akcea. I guess you've talked about FCS. What other indications are you planning on this, given that its safety profile is a big improvement over WAYLIVRA?

Yes, yes, study, as I mentioned, we'll start Phase III -- we're targeting to start Phase III at the end of the year. And we're looking at several other indications for this drug as well. One of the ones that is quite attractive, and it's been talked about by our competitors, and we've talked about it is the severe hypertriglyceridemia patient population, the sHTG, greater than 500, TGs. It's estimated to be, no more than 3 million people. At risk for pancreatitis and have metabolic problems to the high triglyceride and also average for cardiovascular disease when they have trigs that high. And that's certainly something we have our eye on. Then there's also the cardiovascular outcome indication, if you will, patients that are at high risk for events due to high triglycerides, too, which we've been doing quite a bit of work on and talking to advisers on, and that's also another opportunity. So FCS, sHTG and then the -- with the rollout of cardiovascular outcome indication, I would say, are the principal ones that have our attention.

Yes. Okay. And are these both assets that you take forward all the way and wholly own for all indications?

You mean TTR and HTT?

Yes. Yes. Maybe you could talk about your plans there in the context of kind of how your strategy and commercialization has evolved.

Yes. As I've been saying since the beginning of the year, and our leadership team has been saying, Beth and everyone else, we're building our commercial capabilities, and we're building our strategy and our plans. We're going to talk about that in a couple of weeks at Investor Day on how that's shaping up to look. We have lots of levers to pull. We have a rich pipeline of Ionis-owned drugs. We also have a rich pipeline of partner drugs. And we're picking and choosing, which ones make the most sense. We are committed to bringing TTR LICA and APOCIII LICA through Phase III and to launch, and we think it's one of our most valuable assets in the Ionis owned pipeline. And it's hard not to factor that in. It really has enormous commercial upside in those 2 assets. In addition, like I said, we have a lot of other assets that we can prioritize per Ionis commercialization strategy. I think one area that's very exciting is our wholly owned neuro pipeline, which is growing rapidly. We already have about 5 or 6 different drugs in our neuro pipeline. And that's going to grow. And it's expected to grow as we continue to bring drugs forward and work with our partner, Biogen, on which one fits best with Biogen, which one fits best with Ionis. And that pipeline is going to grow. And of course, there, you have sort of a common disease area, theme, efficiencies -- with all the efficiencies that that brings. And that is certainly going to be an area that we prioritize as well. So we have a lot of choices. And certainly, TTR LICA and APOCIII LICA are one of the nearer-term attractive choices that we have in front of us.

Yes. Okay. Great. So maybe we can talk about some of the updates on programs, we'll get at your R&D Day, like in acromegaly, I think you may talk about the HAE program, AGT. Again, within this whole theme of taking drugs forward independently through approval and launch, is this a scenario where you're ultimately going to pick and choose 1 or 2 of these to take forward and then another 1 to partner and what's kind of the thought process that may go into that? I guess, asked another way, one of the questions I get from investors is really, what are the different scenarios for Ionis exiting this year, both clinically and strategically?

So we have as I mentioned, a number of -- quite a large number of opportunities that we can bring to the finish line and commercialize ourselves. And what we're focused on our near-term value drivers. And I mentioned TTR LICA and APOCIII LICA as prime examples of that. And also areas where we can build like sort of a level of -- or a center of excellence in a common therapeutic area or more than one, like, as I mentioned, in neurological diseases. I would not preclude us from getting the commercialization to a broad indications. Right now, we're focused on rare indications. But obviously, TTR LICA is quasi rare, quasi broad, and we're in it. And we think that there's opportunities to get it to broad indications. In addition, like you mentioned angiotensinogen for hypertension. Now I wouldn't rule out the possibility that we would participate in the commercialization of that drug to reach the market. So we have a lot of options in front of us, and we have the financial strength, which is very important to be able to pick and choose which ones we want to go forward. And we're going to layout that strategy in a little bit more detail at Investor Day this year and then we'll really hammer it on next year as these programs really start coming to the finish line.

Yes. Okay, great. So which programs will we get new data for at the Investor Day?

Certainly, we're going to focus on angiotensinogen, and how that's profile -- what the profile of that drug looks like and why we're so excited about it for treatment and control of refractory hypertension. I think we want to expand a little bit on our PCSK9 program. It being a remote meeting at the AHA, it was limited on how much people can really talk about why we're so excited about it. And why AstraZeneca is so excited about it, I think we're going to do that. And we'll certainly provide updates, brief updates, but updates on our HAE program, our acromegaly program and our ENaC program for CF as well. But since those Phase II studies are now coming to the finish line, the real Phase II data for those programs will come out next year.

Yes. Okay. Okay. Got it. So maybe let's talk about AGT briefly then. Obviously, it's a great target. I think just the amounts of proof-of-concept data, it would seem like AGT knockdown is going to have a pretty substantial hypertension benefit it, but and I don't see why you wouldn't show something similar. I think the one kind of comment I've gotten from KOLs in this space, and I'd be curious how you think about this, is really what do you think the AGT compound will look like when given on top of other standard of care antihypertensives? Because I heard from some docs, there's a mixed history of dual RAS blockade and that the profile can look very different from sort of a monotherapy mild population into a combo therapy severe population . I think you have a trial going on that may offer some insight into this? So maybe you could set the stage for people on the panel and talk through that?

Yes, that's great, great questions. We're very excited about our AGT program. It's the most advanced program of any of the new mechanisms that are targeting AJT, RNA silencers and what have you. And we're the only ones that I'm aware of with real patient data. Data in patients that are poorly controlled on ACEs and ARBs, in which we've then brought on ARB drug in and have evaluated safety as well as efficacy in the trial. And we've actually now completed that -- 2 Phase II trials, one in patients that were well controlled on antihypertensive -- antihypertensives, in which they were weaned off the drugs and put on our AGT. And then the question there was, can we safely control their blood pressure, and we'll talk about that. The more relevant study, if you will, is the patients who are uncontrolled, have uncontrolled hypertension on 3 or so antihypertensive agents, and they're still uncontrolled. And then us adding our angiotensinogen drug on top of those patients and then asking the question, can we get those patients under control? Can you get their blood pressure down? And that is where -- and that is what we're going to talk about at Investor Day. So we're going to show the data, and we're going to show the results. And it's not just efficacy, it's also safety. Because I think you alluded to this is concerns over combination with ACEs and ARBs. The concern with ACEs and ARBs is principally renal failure. We know that the RAS system, the RAS AGT system is active in the kidney. And when you inhibited that system in the kidney, you can cure a significant reductions in GFR, leading to renal failure. And these are patients who already have -- often have compromised renal function patients with refractory hypertension. And that's the risk, is not only are the ACEs and ARBs causing sometimes reductions in GFR and renal failure, putting them on the fence to go into renal failure. You don't want to add another drug on top that puts them over the fence and closing that. Our strategy, of course, is one in which we're only targeting AGT in the half side with our LICA strategy. So our hypothesis was that we won't cause added issues in the kidney. We'll just principally get the benefit of an anti-hypertension -- hypertensive activity by knocking an H2 production from the liver. And that's what we're seeing. So it's a very exciting novel strategy for controlling refractory hypertension. And of course, the unmet need there, the commercial upside is enormous. So we're looking forward to sharing our thoughts and data at Investor Day on that program.