Hey, good afternoon, everybody, and thank you for joining us once again for the Genetic Medicines and RNA Summit. I'm Yaron Werber from the TD Biotech team. Here, very pleased to moderate the next session with Brett Monia, who's the CEO of Ionis. Brett, always good to see you. Thanks for joining.
Always good to see you, Yaron, and it's a pleasure to be here.
So we have, as normal, lots to talk about. So I think just to give the audience a little bit of a bird's-eye view, we're going to start with Wainua, both for PN and then TTR cardiomyopathy. We'll go to Angelman next, and then to HAE, probably move to Factor B ahead of the GA phase II data that's expected. We're expecting it in Q4. And then olezarsen ahead of the sHTG data next year. And we'll probably ask an LPLLA question as well. And if you have any questions, either email us directly at yaron.werber@tdsecurities.com, that's the new email address. Or you can go ahead and just put that into the website right there, and I can see the questions and take them for you. So let's start with, first, Wainua for TTR PN. How is the launch?
This is still a market that's sort of early in its infancy. Alnylam obviously launched not too far ahead of you. Wainua, obviously, is differentiated in terms of autoinjector monthly, which is pretty easy. What kind of feedback are you hearing so far, both from clinicians and payers as well?
Yeah, thanks, Yaron. So following the approval of Wainua for ATTR polyneuropathy in December, second half of December, we launched in late January. So we have and we reported on the partial quarter revenue of $5 million at our earnings early at our last earnings. The launch is off to a really good start. We are very pleased with the launch. We're pleased with the fact that there's been incredible receptivity from treaters wanting to get to learn more about Wainua, to want to know how to get Wainua, access to Wainua, for their patients, and so on. We're meeting, and in some cases, exceeding all of our key performance metrics that we set out last year to achieve at this stage of the launch. And we're really pleased.
What's been really receptive is, or has been really positively received, is not only the great efficacy and tolerability profile, but the simplicity of patients being able to self-administer using a simple autoinjector. So we're pleased with the launch. It's going great.
Are all patients? Is it exclusively self-administered, or some of them inevitably have to come into the clinic?
Oh, of course. A patient can have the option, if they chose, to have a health care provider do the administration, just like they can a family member. In fact, at home, a lot of these patients choose to have a family member administer using the autoinjector. But a large portion of them just do it themselves. They have that option. It's just not a requirement to have a health care provider administer it.
When you're thinking about the level of diagnosis so far in PN, kind of where is the market in terms of just the maturation of PN as an indication?
Yeah, so we've done a considerable amount of market research over the last couple of years, and leading right up to the final days before launch. It just keeps telling us the same story, that the vast majority of patients today with TTR polyneuropathy are not on treatment, are either not diagnosed, and even if diagnosed, are not on treatment today. That is where we are focused on to expand this market opportunity to really make Wainua the biggest possible success on the market. More than 80% of people today with ATTR polyneuropathy are not on treatment. That's where our focus is. That's where we're seeing the biggest uptake in Wainua in the launch. We've been able to identify and get to the head of the line in many cases for newly diagnosed patients. That was intentional.
We're also seeing switches, Yaron, from all available treatments in the U.S. that are approved today. That's, of course, welcome. But our focus has been and will continue to be newly diagnosed patients.
OK, let's shift over to TTR cardiomyopathy. Alnylam is expected to release the HELIOS-B data, scuttlebutt on Wall Street, which is obviously scuttlebutt as early as next week. And if it's not June, then it's certainly they said July. When there's a lot of questions as to whether that's going to hit in the overall ITT, whether it's going to hit more on the mono side, just given the previous Onpattro data, the APOLLO study, which is obviously a shorter study, showed more efficacy on the combo side. When you're thinking, and there's a lot of discussion these days about whether cardiomyopathy TTR is more wild-type driven, and it's really whether it's a question of sort of homeostasis and maybe ubiquitin-related protein degradation within the cells of modifiables to fibrils, and whether it's really mutant that's driving the cardiomyopathy, or it's really wild-type enhanced immunosilencer or stabilizer.
What do we know about the biology for TTR cardiomyopathy? What's the pathology driven by?
Well, sadly, the biology isn't as well understood as we'd like it to be and should be at this stage with several treatments on the market and more coming. That's largely because there are no preclinical models that really are any good for predicting ATTR polyneuropathy, hereditary, or wild-type cardiomyopathy. That's not due to lack of trying. Over decades, people have tried to replicate amyloidosis, TTR amyloidosis, in animal models that have failed. So it's really been left to the clinic to really make those assessments. The toxicity of TTR amyloidosis, whether mutants or wild-type, is generally regarded as the two components. One is the toxicity of amyloid fibrils that cause neural cell degeneration and cardiomyocyte degeneration. In cardiomyopathy, in addition to that, it's a restrictive cardiomyopathy.
Just a buildup of TTR amyloid in the heart, whether it be hereditary or wild-type, just causes a restrictive cardiomyopathy, making the heart stiff and preventing it from functioning. Under both of those scenarios, where you have toxic myofibrils that are created due to the unfolding of the tetramer, TTR tetramer, or the buildup of amyloid in the heart, a silencing mechanism would be predicted to be very effective. It would be blocking the production of the myofibrils as well as the buildup of amyloid in the heart. Obviously, which one of those mechanisms are playing the biggest role in neuropathy? It's working for silencers very effectively, with the majority of patients actually improving, not just slowing down the disease.
At least for familial hereditary TTR cardiomyopathy, in the silencing phase III studies for neuropathy for the mixed phenotype patients that have cardiac involvement as well, we're seeing very strong evidence that we're benefiting on the patients who are benefiting on cardiac endpoints as well. Obviously, the targeted phase III studies in the cardiomyopathy patient will be the ultimate proof to the silencing test.
What's your view? I know, again, it's probably unfair to ask you this a little bit, but I'm sure you have a view relating to the Onpattro data and why the combo looked better than the mono. Again, short endpoint, much smaller study, obviously. But the stabilizers did show sort of a more rapid effect.
I think, honestly, Yaron, I think there was encouraging data in the APOLLO-B study that spoke to the likelihood of a silencer showing meaningful benefit in cardiomyopathy. But I really think that going beyond that is going too far, because it was too, as you highlighted, it was too small of a study. It was too short of a study. And it was also an endpoint that was, it's a functional endpoint that can be variable in measurements, the 6-minute walk test. So I just think it wasn't the right study designed to prove that. But I actually view the silencer data for the first silencer that actually was tested specifically in the wild-type population that it was encouraging.
When you're looking forward to your data, the primary is a composite. Do you have a view as to whether you can show a survival benefit as well, just given that you moved a lot of the study after over-enrolling sort of early on in the U.S.? You then sort of capped the U.S. sites, and you moved to the U.K. and South America, where patients are going to be sort of newly onset. Is there more of a chance to show a survival benefit? Were those patients newly onset versus advanced, or are they newly onset and kind of earlier stage in their disease?
So we strongly believe that we have the right, the optimal trial design for today's TTR cardiomyopathy patients with more than double the size of any study that's been out there that's out there today, that's ever been conducted in the past, or that is ongoing. The size of our study speaks to your question very directly. Our study is powered for the primary endpoint for today's patients, the shifted demographics, particularly cardiomyopathy, that are now being diagnosed earlier in their disease because of better disease awareness, treatments that are available, and better methods to diagnose. That is why we upsized our study more than two years ago to take advantage of that. Our study is powered for the primary endpoint, which is cardiac hospitalizations and mortality. Our key secondaries are mortality and other secondaries, such as with and without the tafamidis.
But it's not necessarily powered for that. With that said, we're hopeful we'll be able to get a benefit, direct benefit on statistical significance for mortality. Certainly, if anyone's going to be able to do that, our study design is designed to be able to achieve that. But I also believe that strong trends matter in improving survival, because that, coupled with the primary endpoint and other subgroup data and the richness of the data that our study is positioned to deliver, will be extremely valuable, even with strong trends in mortality, because we're going to have more patients in combination with the tafamidis, and any study that's been done before. And we're going to have more patients as monotherapy in our subgroups than versus any studies that have been conducted before. So we're hopeful to have a mortality benefit.
The study wasn't designed to hit, wasn't powered to achieve that. But we have a very potent drug. And if anyone's going to be able to show that, we certainly have the best prospects to do so.
Just remind us, that study does not cap what percent combo there would be with the tafamidis, right?
Yeah, it was more of a soft cap in the sense that we were able to pull levers to ensure that we had a good balance of monotherapy usage and tafamidis usage in our study. We were shooting for like a 50/50 outcome. We weren't exactly that, but we're close. We're very pleased. We were able to do that by slowing down enrollment in areas, territories where the tafamidis was widely available, and to prioritize territories where the tafamidis was less available or not available at all. We succeeded. We succeeded in achieving our goal to get the demographics we wanted to get and designed our study based on for this study.
OK. And again, for the audience, if you have questions, feel free to either email or put them up as well. And then so it sounds like the patients who are going to be on combo, one would imagine they were on tafamidis, and they're rolling on Wainua on top of it. In that study, is it possible to start with Wainua and then roll onto tafamidis, or at that point, it's too late because you're going to count as a chances are when they're adding that patient in, the patient has progressed because of an event?
Yeah, of course, the patients don't know, and the physicians don't know whether they're on Wainua or not. They could be on placebo. But I think what you're asking is, do they drop? Are there drop-ins? And do they have that flexibility? And they certainly do. They can drop in. They can add to tafamidis based on a physician's discretion. But we're also monitoring that. And I could tell you that the drop-in rate in the study that is a patient that's not on tafamidis at baseline, but then moves onto tafamidis during the course of the study, those numbers are very low. And we believe will end up being very insignificant. Remember, tafamidis also has a very slow onset of action, right?
So even if you were on tafamidis for 6- 12 months, like you dropped in and were on tafamidis for, say, 12 months, using as an example, it probably doesn't matter, because you're not going to be getting much, if any, benefit before the start of tafamidis and the readout of the study. So it's a very small number of drop-ins, and it probably doesn't matter much at all.
Then maybe finally, on that program, BridgeBio is talking a lot about their relative risk reduction and the survival benefit. The tafamidis showed roughly sort of a 30% survival advancement benefit. Is there a bar as mono that you think a silencer needs to hit? Or are the rates very different these days than they were back in the days?
Well, as I mentioned, the rates certainly are different when you look at patients from diagnosis to the rates that they experience for quite some time, because they are being diagnosed in general with more mild disease. They're being diagnosed earlier in their disease process. So it is going to be very difficult to compare anything to ATTR-ACT tafamidis. They're very different patient populations. But the devil will be in all the details, right? How do class I's and class II's and class III's perform on the silencers? Are we getting strong trends or statistical significance in mortality? We also have some great imaging work that's ongoing in our study subgroups looking at imaging of heart function and amyloid burden in the heart alone and in combination in the course of our studies.
And all this data is going to really, really be incredibly important and valuable for prescribers to decide whether or not they want to put a patient that's on tafamidis on a silencer, regardless of statistical significance. But if they're convinced, they're going to advocate for their patients, because the vast majority of patients on tafamidis today are progressing, and some are progressing very significantly. And they're going to advocate if there's data, whether it's imaging, whether it's secondary endpoints, whether it's trends, whether it's statistical significance, to advocate for their patients who are dying of heart failure, regardless of the treatments that they're on today. So I think benchmarking and putting a line in the sand on risk reduction, I think it's risky. It's a dynamic patient population that's changing. You have combination usage. You have monotherapy usage.
I mean, there are standards for relative risk reduction in CVOTs between 15%-25% that are generally regarded as meaningful. But I really believe the devil's going to be in the details for all of this. There's a desperate need for better treatment options for this patient population, whether it be combo or monotherapy.
OK, terrific. OK, let's move to Angelman, because that program alone, we can speak about it for 20- 30 minutes. We're waiting for the HALOS phase II-A data with ION582. That's going to be the upcoming Angelman meeting in late July in Ohio. It's the Angelman Syndrome Foundation meeting. And I think you've said in your press release that about 60% or 70% of patients had a benefit relative to natural history across several of the parameters, that it was consistent across scale, so to speak, and it was clinically meaningful. And I think you've also made some comments that you'll be moving toward a phase III. You'll talk about it with the regulatory agencies, and you'll most likely pick a Bayley-4 subdomain as one of the primary endpoints. And for the audience, I think Ultragenyx said they're going to take the Bayley-4 cognitive scale.
You didn't say you wouldn't comment cognitive is potentially one of them. There's one other scale potentially as well, which could be hyperactivity. But that one you haven't commented on as well. When you're thinking about the Ultragenyx data, the biggest pushback from investors has been, one is the lower extremity, lower extremity weakness. Let's put that aside. The other one was because there wasn't a placebo, there's always constant questions that we're getting about how clinically meaningful is that data, and how likely is it to predict success in the future phase III that is going to be placebo- adjusted, obviously. I think in some ways, if I remember correctly, you and your team view the Ultragenyx data as also kind of being confirmatory a little bit for an anti-sense oligo approach. And your data will further build on that. So can you comment on all of that?
Yeah, happy to. We're really excited about our Angelman's program. And we're very much looking forward to presenting an in-depth update on the phase II, the phase I/II study that you referred to in July. The unmet need here is enormous. Even though it's a rare disease, it's a highly prevalent rare disease. And these people suffering from this disease generally have normal life spans, which means that caregivers, families have an enormous burden as well in caring for these individuals. This is a really big unmet need. And it's a complex disease. These patients suffer from all kinds of problems, whether it be communication, motor function, cognition, seizures, sleep problems, all these other things. And the trial we ran is a bit complicated as well. As you mentioned, it's an open label study, which adds level of complexity.
We also casted the widest net of any study that's ever been done in these patients, in that we included both patients with mutations as well as deletions in the UBE3A gene. We included much broader age groups in our study, newborns, children, but also adults in our study. We did that because we wanted the largest data sets that could inform most effectively, if warranted, what a phase III design would look like. We got exactly what we wanted there with respect to the richness of the data to help inform on what a phase III study would look like.
It is open label, but we have the benefit of probably one of the strongest data sets in a rare disease from natural history here, published reports as well as proprietary and non-published data in the progression of these endpoints that I just referred to, cognition, motor function, seizures, communication. That gives us a lot of evidence. But it is complex. I understand why some would view, well, you don't have a placebo group. Well, we have great natural history data. But what's also really comforting is the fact that despite the instrument, the assessment instrument, whether it be an objective assessment like Bayley-4 subdomains or more subjective assessments that are either administered by a treater, a health care provider, or from family members, such as SAS CGI or ORCA or Vineland, we're seeing really impressive consistency in the subdomains that we're seeing benefit in one instrument.
We're seeing them in virtually all of the instruments in the same direction. That's extremely comforting. That lends to our confidence that what we're seeing is real, and it could be and also substantially real, which is why we're so excited about presenting the data and bringing it to phase III as quickly as we can. As you mentioned, you touched on it briefly, we're seeing an excellent safety profile as well in our study. Our plans are to get to the FDA soon and have our end of phase II meeting and put the final touches on the primary endpoint.
When you're thinking about the secondary endpoints, I think this is where you diverge maybe potentially a bit from Ultragenyx. I think they've talked about using a multiple domain responder index. They talked about using some of the validated sort of traditional endpoints, but also some of the Angelman Syndrome Assessment, the ASA. The MDRI and the ASA are not yet validated historically. Are those endpoints that might resonate with you? Or would you look at CGI? Would you look to the Vineland and sort of those kinds of other domains of the Bailey, et cetera?
It's too early to comment on that, Yaron. We really want to get regulatory feedback on what our phase II trial design will look like, size, dosing schedules, dosing primary endpoint. I think those are secondary right now. I just don't want to comment before we actually get agreement with regulators on what our design will be.
Would you talk to FDA and EMA? Or usually you talk to FDA first, and sort of EMA follows?
That's the latter, FDA first and EMA, yeah.
OK. Do you normally start the study before you get EMA alignment? Or how does that work?
Sometimes. It really, that's more a logistical issue than it is like a standard process. But sometimes we do. We hope to get alignment with all the key regulators before we start in their territories, of course, we have to get in their territories, but we want to get to open up sites in all the territories we're targeting. So you've got to get alignment as fast as possible.
OK. Let's move next. And I'm thinking on things that are the way we're kind of progressing based on things that I think are going to be important for the stock and where things are there's a little debate. So I'm going to move next to Factor B LRx, which is now the phase II geographic atrophy study that's ongoing. I think we're expecting the data. And it's a big 330-patient global study. There's a part A that was 30 patients with three doses respectively designed. And two doses were then chosen for the protocol, moved into the randomized part B, and that's 300 patients, so two doses against placebo. And again, the data we're expecting in Q4, I think the company said second half in geographic atrophy. And the primary endpoint is. It is a 12-month and different vision-based endpoints as well, obviously safety.
I think in prior data you've shown about a 75%, maybe even 80% reduction in Factor B systemic sub-Q, I believe Q4 weeks. The first question we always get is Factor D. So Roche had a Factor D antibody, which was intravitreal, and that failed in phase III. Again, that's an antibody intravitreal injection. People are still unsettled as to whether Factor B is a good target for geographic atrophy. Can you talk about that and some of the genetic data that you have?
Sure. So our Factor B targeting treatment drug, as a quick reminder, is in phase III development for IgA nephropathy, which is going well. Phase II data was really strong. And then in phase II for geographic atrophy. There is pretty compelling genetic evidence that the alternative complement pathway, and Factor B specifically in that pathway, is linked to dry AMD, geographic atrophy. Overproduction is associated with higher risk, and the opposite is true for less production. That's genetic data. It's association. The Factor D, D as in David, targeting antibody that Roche previously developed is upstream of Factor B and failed, as you said. And that was an intravitreally administered drug. The vast majority, 99%+ of Factor B comes from the liver.
We believe the evidence is pretty compelling that that production of factor B accumulates within the blood-retinal barrier, activates complement factor B, and then causes destruction of the macula. That's a hypothesis. The genetics support and the magnitude of production of factor B from the liver supports this. With that said, we have to prove it. It's not without risk. It's a significantly risky program. On the other hand, the upside is enormous, right, since this drug would not have to be intravitreally administered. It would be injected using a simple autoinjector once per month by the patient themselves. It could be a real breakthrough, game changer for this indication. It does not come without risk. Meanwhile, the IgA nephropathy study, which is ahead, is going very well.
We're looking forward to providing an update on the phase II data in the second half of this year on the open label extension phase II data, and then the phase III to follow.
And just maybe final question. Just remind us, at the time that you did the deal with Roche, the IgA nephropathy so Roche ultimately licensed the program. Ionis, were you already running the phase II GA study? And that's an Ionis conducted study. And then Roche, when they licensed the program, they went into phase II IgA again, and then they moved to phase III. Just remind us chronologically how things happened.
No, we were not running the GA study. They came to us. We've been publishing on Factor B. We hadn't settled on an indication to take it forward for Ionis only at the time. They came to us and pushed for a GA study to be conducted, which is the one that we just talked about. And during the course of us conducting that study, both sides agreed that we should take a shot at IgA nephropathy based on the compelling evidence that Factor B, the alternative pathway, is playing a big role in IgA nephropathy. So we did a pilot study. The pilot study showed remarkable reductions in proteinuria, great safety, steady GFR, no reductions in GFR. So we doubled the size of the study. And we showed durable and consistent reductions in proteinuria.
So we advanced it to phase III development, which Roche is now conducting, and the study is enrolling.
All right, terrific, Brett. As always, I think we're just a little bit over. Great to see you. Thanks so much for the time. We'll continue to stay in close touch.
Absolutely. Thanks, Euron. I enjoyed it. Take care.
Thanks, everybody, for joining us. I think it's the last session for today. Then we have a full day tomorrow as well, starting at 9:00 A.M. with a Biosecure panel. Thanks so much.
Thanks.