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

And with our next company presenter at the BofA Annual Healthcare Conference, joined by Ionis Pharmaceuticals and Brett Monia as Chief Executive Officer. My name is Jason Gerberry. I'm one of the Smid Cap Biotech Analyst here at BofA. And Ionis has a lot going on from a pipeline perspective, Brett, maybe I don't know if you want to tee it up at all with some of the near-term updates that you guys plan on having that you're most excited about, and then we'll jump into more specific program-related questions.

Happy to. Jason, thank you, and it's a great pleasure to be here this morning. We're off to a great start in 2024. With the late December approval of WAINUA for TTR polyneuropathy, we launched at the end of January for that indication and the launch is off to a really solid start. We also presented a fulsome data set or overview of our Phase III results for olezarsen and FCS at ACC last month, and we've now submitted the NDA for olezarsen and FCS. And if we receive priority review, we're looking forward to another drug approval in December of this year. We also reported very positive Phase III data in January for our prophylactic treatment for hereditary angioedema, donidalorsen. And we're looking to submit that NDA in the second half of this year as well. And we have one of the richest pipeline -- late-stage pipelines in the industry with 9 medicines in Phase III development for 11 disease indications, and I'm pleased to report that we -- all 9 of those programs are moving forward are on track. We're looking forward to their -- a steady cadence of Phase III readouts for many years to come, including next year, when we are expecting at least 3 new Phase III readouts. So we're preparing to have our first independent commercial launches. The first will be olezarsen for FCS and then soon to follow with hereditary angioedema. So all is going well. And as far as readouts looking forward, we're looking forward to new approvals this year in additional ex-U.S., outside the U.S. markets. The potential, as I mentioned, approval of olezarsen in FCS later this year. And then we have several mid-stage pipeline readouts, including our Angelman's program, which is in a first inpatient study as well as our geographic atrophy study in the second half of this year. So a lot of success already this year in 2024, and we're set up to build on that momentum with a lot of news, a lot of events coming out.

Okay. Great. Maybe we'll start with HAE since it's the most seemingly imminent of the programs where there's an update. And I guess, to me, if there's debates or controversy, it's really around the commercial opportunity. I used to cover Shire. So I remember the conversion of CINRYZE was -- from TAKHZYRO to CINRYZE and a step change improvement used to be IV, used to be androgen. Just thinking about this marketplace, what proportion of it is served by TAKHZYRO versus a androgen, or is it all about driving a switch off of TAKHZYRO into the key U.S. market and then sort of key unmet needs as you see it, the pipeline innovators like yourself can address.

Yes. We're very excited about our HAE prophylactic treatment, donidalorsen. As you indicated, today, the prophylactic market in the United States is served largely by TAKHZYRO, a once-every-2-week subcu injectable with a syringe and vial that has the potential to go every 4 weeks, but there's a lot of loss of control of HAE attacks. So the vast majority of patients are every 2 weeks. And indeed, in the U.S., because most patients are on TAKHZYRO, it is a switch market. Outside the U.S., it's really a market that needs to be developed, that needs to be built for the prophylactic treatment. Right now, HAE outside the U.S. is largely addressed with on-demand treatment, which means your attacks start and then you inject yourself subcutaneously with a bradykinin receptor inhibitor to try to quell the attack. It's clearly prophylactic treatment is coming outside the U.S. But in the U.S., it's a switch market. What we've learned from our market research is consistently that this is a market prophylactic treatment in the U.S. that is -- that there's a need for patients to have better treatment options. Patients are looking for better efficacy. Patients are still getting attacks with HAE. Secondly, patients want better tolerability and in the treatments that they take. And thirdly, they want to have more convenience, less frequent dosing with the advantage that we offer of a simple auto injectors that a patient could administer once every month or once every 2 months is what we're expecting. So we really have the potential to shift the dose frequency algorithm for HAE prophylaxis with donidalorsen. We're looking forward to sharing a full comprehensive data set from our Phase III program at the European Allergy and Immunology conference in Spain on May 31 this year, which will include our Phase -- a comprehensive review of our Phase III data, which we think the reduction in HAE attacks are going to be proved to be very competitive. Secondly, the durability of the protection that we're achieving, we showed really durable protection in our Phase II open-label extension for up to 3 years now. We're also going to share Phase III open-label extension, which I think is going to really, really demonstrate excellent durability. And then thirdly, most importantly, for the U.S. market is a comprehensive review of our Phase III switch data at the meeting. This is the first -- the study we're doing, the switch study we've done and are continuing to do is the first time ever a switch study from an existing prophylactic treatment in HAE, which patients were converted over to a new treatment was actually conducted in a clinical setting. What we're going to be looking for in that study are how well are we protecting patients in the study. How long do patients stay on treatment, do they continue treatment, long beyond the study such that they roll into an extension of the study and what are patient's preference is? Do patients prefer our treatment versus another treatment and why? We're looking forward to that presentation because it's a litmus test, honestly, of the U.S. market, which is, as I mentioned, is a switch market. And we think those results are going to be really eye opening.

Do you think -- well, I have a sense of if there's a strong preference to Q8 versus Q4 out of the Switch study data? And what is your operating assumption regarding sort of where the market would net out with your Q4 versus Q8?

The Switch study only includes every 4-week dosing. So patients that entered the study is only 4-week dosing, but we will have a considerable amount of data from our Phase III study with every 4-week and every 8-week dosing. The way we see -- we see this, as I mentioned, the ability for patients as a base case to be treated once per month versus once every 2 weeks for the lead prophylactics on the market in the U.S. today as a real game changer by itself. The ability for patients to administer treatment every 8 weeks, every 2 months, it provides dosing flexibility. And patients are going to have the option to be able to dose themselves every month or every 2 months of dosing. If some -- if a patient happens to have an attack every -- with every 2 months dosing, they can always come back to every month at once per month dosing. We expect that there's going to be a sizable portion of patients that are going to be attack free. They're going to do just fine on every 2-month dosing. But what this does is it provides dosing flexibility that's not available for patients today with any HAE prophylactic treatment. So it's -- we think it's another aspect of the differentiating profile for donidalorsen over existing treatments.

Got it. As we think about this as a Switch market, what are the learnings that are out there that give you confidence that patients are willing to switch? And do you look at oral therapies, the launches of oral therapies as a good analog for Switch dynamics?

I think there's a lot of evidence that patients want better treatment options and are willing to switch. First, the ORLADEYO launch is direct evidence that a newly approved medicine, despite the fact that it's HAE protection, it's -- the improvement in HAE rate of attacks that is seen with ORLADEYO was on an average basis was inferior to that of a TAKHZYRO. Patients were still willing to try it. And in fact, that happened quite a bit, and then patients tended to switch back based on our market research because they weren't getting the protection, but they're willing to try it. Secondly, our Switch study has enrolled very quickly. It's a sizable study, more than 60 patients on existing prophylactic treatments, whether it be TAKHZYRO, ORLADEYO or CINRYZE eagerly moved into our study, moved on to donidalorsen, and I'm pleased to say that the vast majority of those patients have stayed on treatment long term. So I think we have real evidence there. In addition, the market research and the advisory boards that we've had over the last couple of years really indicates that patients are looking for new options, and they're willing to try new options.

Okay. Well, maybe shifting gears to Angelman's. I believe you'll have an update for folks midyear, whatever midyear means? And then there's an Angelman's medical meeting in July, I believe. So against that backdrop, if you can maybe just the latest in terms of where you are at with that trial, which is open-label and there's a data package handoff to Biogen at some point, if you can maybe just frame where we are, we go from there.

Yes. Angelman syndrome is a nerve developmental disease, a rare disease, genetic disease that -- in which there's a very, very significant unmet medical need. This is a reasonably -- a highly prevalent disease within the rare disease category. And there are no treatment options available to date. We think we have a potential best-in-class molecule for Angelman syndrome. We reported encouraging data at the fast patient meeting last year in November, which we reported that several indications of clinical benefit as well as EEG data we're trending in the right direction after only 4 weeks of treatment. And then all those patients, really completed enrollment in the study and then all those patients have now enrolled over into the long-term extension. Some of those patients have gotten now gone beyond a year of treatment. This is a complicated disease, and it's a complicated trial. These patients suffer from a whole host of problems. It's a neurodevelopmental disease. As I said, they suffer from intellectual, cognitive challenges, communication challenges, both receptive and proactive, fine motor, gross motor function problems, seizures, sleep problems, all kinds of issues related to the disease. Our Phase II study is designed to capture as much data of any study ever done in this patient population. We're looking at children. We're looking at adolescents, and we're looking at adults. And we're looking at various measures such as Bayley-4 or CGI or Vineland that are different ways of addressing the different aspects of this disease. It's an open-label study to make the study even more complicated. We don't have a placebo group, but what we have is great natural history data that we're going to be relying on. And what we're looking for are indications that certain aspects of these diseases are improving in a meaningful manner. And what we're hoping to see is that we can see commonalities between Bayley-4, CGI, Vineland and other measures, which will lend greater confidence that what we're seeing is real, even though it's a noncontrolled study. And of course, what we'll be comparing to is the natural history data. Our objective is to gather together enough data and have the confidence that would move us into a pivotal study as the next step of the development of this program.

So we don't need to get into the technicalities here, but target knockdown is difficult to measure and you won't be able to measure it in the foreseeable next 6 months. So as we think about observing other antisense oligonucleotides that have been explored clinically in this space. I mean, this is very much a very directional positive analysis that we're conducting here with these therapeutics, do you feel each ASO is kind of constructed individually and uniquely, or would you expect if one works others should have effect as well? Just maybe what's the read across from competitor updates kind of directionally?

So for those that are new to this, this is a loss of function disease from the maternal UBE3A gene, and what we're doing is on silencing the paternal gene to upregulate a protein called UBE3 to basically replace the protein that's deficient in this disease. There are 2 antisense oligonucleotides programs in development and relatively at the same stage. They're both utilizing the same mechanism of action. Our platform, our chemical platform, we have a great deal of experience with. It's the same chemical platform as SPINRAZA, a blockbuster for SMA, as QALSODY, a breakthrough for SOD1-ALS and the rest of our rich 11 medicines in development from our CNS program. So we have a validated platform, a platform that we have a great deal of safety and efficacy experience with. As for other programs read through to what we will see, we're really focused on our trial. We don't think that there's going to be much read-through. It will be very interesting, however, to be able to determine when our study does read out, whether or not the areas of improvement that we're seeing in our study are similar to what other programs are showing us that would lend even more confidence that what we're seeing is real. Again, both studies are uncontrolled. So there's no placebo group. So anything we can get to garner more and more confidence will be helpful.

Okay. And so I guess to summarize, as you go into this HALO study update, Vineland, Bayley and EEG probably have the richest amount of natural history and those should be maybe the 3 endpoints to focus in on the most. Or I don't know if you would push back and say, it's more nuanced than we need to consider other factors.

I would say Bayley-4 is the most important and the subdomains within Bayley-4. And I would view CGI and Vineland as more supportive because the Bayley-4 is a physician-administered measure of performance. Others are patient-reported or family-member-reported outcomes, and they could be more subjective and more subject to false readings. And the subdomains within Bayley-4, I think, is what's really going to be most important. And also breaking that down to how is the -- how are those subdomains performing in the children, in the adolescents and in the adults. All that, I mean, we purposely cast the widest possible net for our Phase II study so that we can inform on our design of a potential Phase III trial going forward.

We could probably spend the next hour talking about regulatory path. But maybe just at a high level, have you interacted with FDA on Angelman's. And as we think about pathway forward, I don't know, do you feel optimistic that it's a manageable pathway forward from a development standpoint?

Well, with the caveat that we haven't completed a review of the data yet, if we do go forward to a pivotal study, the first -- the next step will be FDA regulatory advice and end of Phase II meeting to set us up for a pivotal study to come. So we have not had formal -- we have not had discussions with the FDA about what a Phase III trial design, it's premature. We don't have the -- we haven't submitted for -- with our data yet or anything like that. We reviewed our data in totality yet, but that would be the next step. And it's a data support. So I'm confident that the FDA will be able to negotiate a reasonable path forward with the FDA. They're -- they've been very supportive of Ionis. They've been very supportive of our platform for neurological diseases, and they understand the unmet need.