Ultragenyx Pharmaceutical Inc. (RARE) Earnings Call Transcript & Summary

So welcome, everyone. I'm Yigal Nochomovitz, one of the biotech analysts at Citi. My pleasure to have with me my colleague, Samantha Semenkow, recently rejoined Citi as a senior analyst. This is the rare neuro panel, and it's my pleasure to have with me two distinguished CEOs in the space. Carole Ben-Maimon, the CEO of Lamar and Emil Kakkis, the CEO of Ultragenyx. So welcome, both of you. Thank you very much for taking the time. And maybe just to start out, if you could just give a very brief 2- or 3-minute overview of some of the rare neurology programs that you're focused on. And then from there, we can move into some more thematic questions related to development of drugs for rare neurology. So Emil, you want to start?

Okay. Sure. Good morning, everyone. So I'm Emil Kakkis, CEO of Ultragenyx. And we've been formed for about 13 years ago and have been building a portfolio of products in the [born] errors, bone, endocrine and neurology. In neurology space, our most important program is the Angelman program and the antisense oligonucleotide arrangement, and we'll probably talk more about that as we get through questions today. The first opportunity to turn on expression of genes in the brain and potentially change the future for disease with developmental delay and a number of other abnormalities related to the Angelman syndrome genetic defects. In addition to that, we are working on several other neurogenetic disorders. We have a gene therapy for CDKL5 deficiency that is heading to the clinic soon. It's basically an enzyme replacement into the brain with an AAV gene therapy. In addition to that in the nonclinical stage, we're working on a prodrug for creating transfer deficiency and a prodrug for gene myopathy, both neuromuscular disorders, and we have a gene therapy for Duchenne Muscular Dystrophy that is a bit further back, but coming. And it gives us a number of possibilities, both in the brain as well as muscle part of neuro genetics. So that's where our big story. We'll probably talk more about Angelman today.

I'm Carole Ben-Maimon, CEO of Lamar Therapeutics. We are a clinical biotechnology company. We have a platform that allows us to deliver cargo across cell membranes. Our lead program is we call it CTI-1601, it's for Friedreich's ataxia, which is a disease that is autosomal recessive and occurs where children are born looking relatively healthy. They get clumsy and their -- around puberty, wheelchairs in their 20s and 30s and they die in their 30s and 40s. They die from heart disease, and it's caused by a missing protein called frataxin. And frataxin is actually active inside the mitrochondria. So the challenge is to bring the protein across the cell membrane and across the mitrochondrial. And that's what our technology allows us to do. And so we have completed our Phase I program. We showed increases in frataxin in buckle cells and skin biopsies in a dose-dependent manner. And we are now conducting a Phase II dose exploration study that is ongoing. We have completed the 25-milligram dose which also showed increases in frataxin and this is actually a very low dose. We were surprised by that. But we did see significant increases in frataxin at day 14 and then at day 28 after going to every other day, we saw a decrease. So we are now initiating a 50-milligram cohort in that study as well as initiating our open-label extension study, which will allow us to dose 25 milligrams daily for an ongoing period, which is really exciting because we'll get to see real-world use of the drug when patients take it home with them. They use it at home, and we'll get long term frataxin data out of that study. So we're very excited where we are in the clinic. We're looking at some other diseases. We have not disclosed those as of yet as we expand out the pipeline.

So let's talk a little bit high level in terms of some of the developments in the rare neuro space. There have been a lot of interesting approvals. Obviously, you mentioned the FA and we saw the approval of SKYCLARYS for Reata. But there have been others [indiscernible], [Casati], DAYBUE, SKYSONA. So there's been quite a few this year. So I just wanted to get a sense from you in terms of what are the implications and learnings from these approvals? And what's your read on FDA's willingness to exercise regulatory flexibility in some of these rare or some not so rare neuro diseases. What are your thoughts there?

Well, I would say my experience is that change in leadership within the neuroscience divisions have had an impact. Billy Dunn is left and also [indiscernible] Eric Bastings, that were both there. Teresa Buracchio is now the head of it, and she has been making a decision that you're talking about. And I think she's done a terrific job at seeing through all the data and buying the appropriate scientific insight to make good decisions. And I think it bodes well for us. I think the neurology area has been difficult in the past because of the way it was regulated. And we've certainly seen an improvement in our relationship over in the Angelman program in this time frame. And I think that I'm encouraged, but it does show you how important one person can be and how the regulation works. And I think that they've made good decisions on those programs in difficult areas and neurology of all the areas needs to respect how difficult it is, change your brain of a kid with a terrible disease, and I'm encouraged for what's going to come forward if they continue the trend that they're showing us now.

Yes, I think we see very positive relationships with the agency I've been working with the neuro division since longer than I want to admit, back to Paul Lever, and it has definitely been a transition and a recognition of the need to look at things more in a more novel way. I think Billy Dunn was amongst those who actually felt that way. I think clearly, some of the Reata approval was probably under -- he left the day after or the day before, but he obviously had input. And I think Teresa is continuing [Teresa Buracchio], I totally agree is continuing that flexibility. I think it's -- what's really important is building a data package. I think what they -- we talk about flexibility, but I think what they are actually doing, and I think is really important is looking at the whole data package and not focusing so much on the primary end point of a single study. And I think that's -- if they can maintain that attitude, that mechanism of action plays into this biomarkers play into this patient input and they can really start to look at these -- the data package that's being submitted and developed, I think we'll see good things coming up not only the neuro division but some other divisions at the agency.

You make a good point in taking that into account when you're designing the trials. How do you approach those endpoint selections, both the primary as well as some of those additional endpoints for that data package? And how do biomarkers fit into that package? And how do you convince the FDA that those biomarkers are actually relevant and tie that all up when you're actually designing the trials at the end of the day, you have that data package.

Okay. I need to go first.

Sure.

Sure. So we're in a -- we have the luxury of working in a disease space that we know the cause of the disease. So it's not like some of the other more troubling diseases that we have to deal with in neuro or in other diseases, even muscular dystrophy and some of the others where not necessarily they are hypotheses, but they are not necessarily these very clear direct links. In FA, the cause of this disease is deficiency of frataxin. Now then the question comes, okay, can increase frataxin, but can you increase it in the target tissues? Once you increase it, is it doing anything. And so that's where I think the biomarkers really come into play because if you can show you're increasing it. And now you can show you have an effect on something physiologic. We're looking at gene expression and lipid levels, which are completely off in these patients. The lipid profiles in these patients are very abnormal. So now you say you increase it and you're normalizing something or at least making it more normal, you really start to answer some of those questions. And that's why I say, to me, it's really all about a data package. You're going to have to have a clinical outcome. There's no question you're going to have to see something over a longer term that translates. But building that mechanism of action fixing the problem, then looking at activity, starting to build all that package together, starts to really make it possible to convince not only regulators but scientists that the molecule is likely to be effective. So I think it's a combination of things, Samantha, that include clinical outcomes for sure, but also all these other things that go into a development program.

On the area biomarkers, I think there's still a lot of room for improvement. But the Neurofilament story, which is part of the story with ALS. I think that's been building for a while and Neurofilament is really more of a downstream marker of injury and depreciation that less injury over time should result in less Neurofilament release and the importance of that. I think it's an important step forward for FDA to kind of include that mechanistic piece in the total picture. So I think that's what Samantha is saying. I think that piece is adding to what you see clinically. We need the FDA to do more on biomarkers, particularly in neurologic disorders, and we've had a lot of discussions. Now in Angelman, there are no good biomarkers, but other programs, for example, some of the sorters that have inborn errors related there are a lot of good biomarkers and that's been more resistant. I've been leading a group to try to put more pressure upon them to use a good science and qualify with biomarkers because I think they're very relevant, for example, in disease like Sanfilippo, which I forgot to mention earlier, which is a late-stage program, but obviously, good biomarkers there. And you can do clinical but the clinical takes several years, the biomarkers give the answers in a much shorter period of time. So with a lot less variation in complexity. So I do think that the total picture matters, but the difficulty is in neurology is if most of your treatment is doing is preventing decline and decline takes a couple of years or 3 years to do, doing long randomized studies where the control group is going to have lose their life is a very difficult thing to do, and this is true in some of the [neurogenetic disorders] sort of like Sanfilippo or randomized the control group is basically the opportunity to treat and die. It's just impossible to do a study in that way. natural history control studies have been very difficult to do. So if you have a clinical endpoint, you want to have a natural history control for diseases that take 2, 3, 4, 5 years to show progression. It's been very hard to do. It's all the situation that has worked which is like CLN2 or Pompe disease. In those situations, the decline rate was in a year or 2, right? It goes from nothing to terrible within a year or 2. And that setting, the natural history controls have resulted in approvals. But anything taking 2 to 5 years in time, it's been very hard to get agreement on a natural history control. So we're going to have to figure out this piece how do you design with clinical endpoints that the control group is not being losing their lives over it, Rich, because I just don't think no one believes that that's the right way that we as scientists and drug developers should have a better way of figuring out how a drug works without having some kids get sacrificed in the process. And I don't think all of the agency yet fully appreciate that. It's one of the points of contention. So [natural history] can be part of it. But I do think if you bring the biomarkers with some early clinical data, you should be able to enable more approvals, and I think that's an area for further improvement, particularly in some of the inborn errors where the biomarkers are straight up the material accumulating because of the block. It's not so hard to imagine. When you know exactly what the block is, what the biomarker comes from to predict that this is going to be better if you reduce this accumulating compound. So I think there's a lot of good things that happened, but I do think there's a lot of room for improvement on biomarkers, particularly in the neurology area.

So if you can do a faster study like you mentioned, I think you said Pompe, where the decay on the natural history is fast enough to make it tractable. That's great. But what about other types of studies where you have -- you need to do a placebo for a rare neuro indication? How do you think about that? Is that something -- I know it may be relevant potentially for your GTX-102 program, not necessarily just for Angelman's, but in general, I mean, how do you think about a placebo-controlled trial in these types of rare settings?

I think the fundamental ethical question is, is the control group and they'll lose the opportunity to ever be treated permanently damaged by being in a trial. That's a fundamental question. And the Angelman syndrome is not a progressive disease, they're not losing function. They're not going to be damaged by being in a trial for a 6-month or a year period, which would be looking at our data long enough to see the global effect. Now the thing in Angelman, that's very important is we're seeing improvement. We're not seeing just lack of decline. We are actual improvement, which gives you more ability to see a change. So in Angelman syndrome, we have said we're supportive of doing a randomized controlled trial because we can, and we can do it without harming kids, and we had that discussion with the FDA. They were pleased they were thinking maybe we were going to try to go noncontrolled, but I think in this situation, you should do a controlled trial because we can -- that means some patients are getting placebo intrathecal injections, but I don't think -- I think that's the level of sacrifice we need to do as the benefit to those patients is they will cross over on the drug, which means they'll get access to potential treatment way ahead of anyone else. So that's what they give up and what the gain as well. In other disorders like Sanfilippo is not -- is unconscionable to put kids and have the control group is currently apparently proposed to have a kick out of the placebo group if they -- if an individual reach of 15% brain damage apparently is the 15% to 20% average. Then they can exit what you don't realize, by the time they have that much damage, they've lost their window to actually save them. That means the brain is already on the decline stage and treating them late will not save them. So what's really happened is there -- and the other truth about that program is you're trying to stabilize. So in order for the trial to win, control group has to decline. That's the only way the trial works. It's not like if they decline, they must decline in order for the treatment to be approved. So what you're really doing is saying this control group is all condemned to death. And that's just not okay. So that's fundamental with this. We're very much -- we have done many randomized placebo trials where the control group is not going to be harmed by doing this. They may be delayed. They may have certain inconvenience, but they're not going to be harmed. And I think we as a society have to come up with better ways that test science than doing an experiment that harms people.

Yes. We have a little bit of a different situation. First of all, SKYCLARYS omaveloxolone has been approved. And as a new drug that actually changes the progression rate, you take a slowly progressive disease and now slow it down even more. And now you're going to have to do an even longer trial to show whether or not you have an impact on top of it. And the question, if you exclude patients from taking [indiscernible] is that ethical, right? Because there's some one drug out there. There's nothing else for these people. With FA also, it is a slowly progressive disease. And if you can measure something in 2 or 3 years, it isn't reversible, but you could still potentially intervene and prevent further decline. Also, many of these patients are adults and not children. Although the earlier you treat, the more likely you are to have an effect. But we haven't really had the conversations yet with FDA as to what will constitute an endpoint or a development program because we're still so early. But I totally agree with you. There's got to be -- there's some ethics that play into this that we just can't ignore. And it's not -- it's in a lot of diseases. Most of these diseases are not reversible. So whatever decline the placebo group has, they're going to have to live with for the rest of their lives. And that has to be taken into account. And I think the FDA is much more open to hearing those arguments. I also think the patient community has become much more sophisticated at how to lobby FDA not only as individual diseases, which I think has been the problem in the past, but sort of banding together in groups. I think just DMD alone has had a huge effect on other communities and their openness to hearing things. But I think patient advocacy groups also play a huge role. And we've talked a lot about U.S. But the problem is just as big in Europe as it is in the U.S. and needs to be really taken into account as well because in Europe, biomarkers are really even more challenging than they are in the U.S. And these populations obviously exist in places not only in the U.S. but around the world.

I think in Europe, it's really been evolving too. The MHRA was a very strong and rational voice within EMA and now they're not part of EMA. And so I think you're seeing a little more of replication of U.S. views in the rest of EMA and that's a loss. In the SEBI program, for example, we got EMA signed advice that allowed a biomarker primary endpoint just because of the rare disease. And FDA had rejected that. But I think that's changed now that might not have happened these days. So EMA as an organization has changed a lot. MHRA was really the premier organization that had a highly experienced crew people that were very knowledgeable. And I think DME has changed because of the loss of the MHRA is part of that group.

Yes. And I think also the -- we see differences even between different countries, even within EMA. Obviously, the scientific base is consensus. But we -- if you really talk directly to the individual regulatory authorities, there are differences. And I think I've seen for over the decades, as I'm sure you have, a lot of times it waxes and wanes. So what FDA is doing when they're progressive, Europe becomes less progressive and vice versa. It's really kind of a seesaw of the FX.

How do you think about patient identification for your studies? Like Carole, I feel like you're in a maybe more fortunate situation with Radix ataxia, a very strong patient community, strong patient advocacy. So how do you think about it from that perspective in the context of Omav recently being approved, all the way down with really rare neuro diseases where patient identification is more challenging? And how do you design your trials and find the patients across that spectrum.

I think FA is a different animal than a lot of rare diseases for a whole host of reasons. The advocacy group is clearly one of them, but the disease is very easily diagnosed. I mean it takes a couple of years sometimes because people think they're just weird kids. But eventually, when they get to the neurologists, their pathognomonic physical signs and it gets diagnosed. And then there's a blood test, which is also easy, and it's a -- we know the cause. I think in other rare diseases, it is a much bigger challenge, especially under-diagnosed. And the other -- the problem we have in FA is it's very territorial. There are populations in the United States, in Europe and in Australia. It does not exist in Asia and most of South America, a little bit in Brazil, but only a few patients. And then there's a smattering, there's a population in Canada. So when omav got approved, we're really limited at where else. It's not like you can just go to another territory and do a study that's powered. There just aren't enough patients. which is the other thing that we're sort of thinking about and wrestling with. But I think you probably have a lot more experience with some of these other diseases than I do.

Well, there's a lot of variation between types of disease. I mean, Angelman has a very strong patient advocacy activity and have some distinctive neurologic feature that it can take a while for some of them to get diagnosed. But I don't think patient ID has been a problem for us in that program. I think the bigger problem comes in things like sanfilippo syndrome, for example, where the first couple of years of the critical period, you really need to treat before 2 years but the diagnosis may not come until they're between 2 and 6. And so a lot of the kids will be diagnosed after. And so early diagnosis becomes really critical and other disorders like we've worked on the past like Glut1, for example, a seizure developmental delay, it looks like so many other things if doctors are doing panels or genetic typing, then it's not happening. And we found that a lot of insurance weren't supporting genetic panels for kids with seizure development. And really, you can't distinguish. I've been as a clinician, you can't tell precisely in all these diseases, which one it is. It could be a variation of a common one or it could be an ultrarare one. You don't know. What we've been doing is supporting free diagnostic testing as part of our patient diagnosis program, which we run out of medical affairs. And we just as we're looking for patients and trying to help doctors get diagnosed, we provide access to free testing to help them find their patients. And we don't just support for our diagnoses, we support just a panel that allows them to cover the differential diagnosis. That cost some money, but in the end, it helps us find patients earlier. And I think that eventually, we should be -- insurance should be covering a neurogenic panel. If you have a kid who's one has [developmental] delay and some other neurologeneic findings, they should be getting script gene [screening] for the problem and because it could be very distinct and important things, the time frame may be short, taking action. And with the MPS disorders, there is a big push now for more newborn screening MPS 1 is on the rest now and there are methods for doing that. So we -- I think the lysosomal diseases should be closer now to getting panel screening, newborn screening. I think it's the thing that will have to happen because if you're not really symptomatic before age 2 or you don't have distinctive symptoms, you may not come to saying, I need a diagnosis, right? I mean, I'd be distinctly evident yet. And therefore, you'll miss the window. I think in the situation newborn screening is going to be essential for the ultimate best outcome for those kids with some movement in newborn screening for some MPS, it's really possible to do essentially all of them. And so we hope that, that's going to happen. Every life nation has been working on getting RUS alignment legislation across the country so that every state aligns with the rest. If we get every state doing the minimal screening based on the rest panel, which is the Secretary's Committee for a [newborn screening]. If every state aligns with the Federal government and all we need to change with the federal government committee says that all the states will align instead of doing what we're right now, every state is a different plan, which is crazy as it is. So the [indiscernible] plan was to get all the states to align with the rest and then make the rest a single national focus on newer screening at least for the minimum so that everyone agrees the screening of a certain set of diseases, particularly ones where treatment early is critical and where diagnosis is often delayed past that critical window.

And I think that's a big issue also is because the reach has to be out past the academic centers, right, because these kids are not being followed. So again, FA is sort of has advantages. They don't get diagnosed until 6, 7, 8 years old, unless, of course, they have a sibling. And then they aren't really -- they have -- they are not in wheelchairs, even at the earliest diagnosis until 11 years past that. So there's plenty of time to intervene. I think the real challenge for us as we look at different opportunities and different pipeline opportunities is how do you get to a kid within the first 6 months. Most of these kids are seeing primary care docs and then they get referred and by the -- like you're saying, by the time they get diagnosed, there's not really much you can do. And so these diseases that really move quickly, early in life, are much more challenging, I think, from the standpoint of patient identification.

Maybe we can spend a little more time on specific programs for each of your companies in the last 15 minutes. So Emil, just on Angelman's and GTX-102, if we can just drill down a little bit more there. if you could sort of put the efficacy data in context for what you've shown so far, you've reported data across a wide variety of scales, Bayley, CGI, Vinland, I think also ORCA, where would you like to direct investors attention in terms of which scales are most relevant for determining efficacy? And what would you consider to be clinically meaningful on these different scales?

First of all, Angelman syndrome is a complex multi-domain diseases. It has many different domains of dysfunction. And our view is that efficacy should be looked at across those domains and our preference and the primary endpoint that captures either a multi-domain responder next type endpoint where we're looking across five domains or the version that FDA has accepted so far as a CGI score, which is a little bit of a multi-domain assessment is another approach, which was accepted for the Ovid Angelman trial, but also as part of the Rett approval as one of their co-primary. So the CGI multi-domain would be the best way to capture multiple domains. We're more proponent of the multi-immune responder index. We've written a paper on it. It means you would look at, let's say, five domains and pick a score like Bayley, it could be an age and severity scale, Vineland or special behavior scale, et cetera, there's several scales. And each scale then it's scored based on whether they have an important difference or not. And that approach is very powerful. It allows for heterogeneity in the population, and you can have responses in some patients in these two domains or three domains and some in other domains and allows you to capture the efficacy I think, in a very powerful way. And we think that's the best strategy. But if he hasn't quite accepted it, we've had meetings and even had a big meeting with agency about it. I think they're intrigued by it because it sort of allows all comers into the trial. You don't have to select based on what the primary is. You can just accept everyone, and that's a feature of the moving responder next treat the people the way they are rather than picking the ones that match the endpoint you're picking. So the underpinnings of Angelman assessment, though, is to look at the domains that are important to parents. One of them is communication, both receptive and expressive. These kids often don't under hear their name or understand their and don't learn their own name. They don't understand instructions, right? Everything is done by showing them because they just have no language or alternate communication. That's important, express communication being able to express your wants, not just saying words but saying words or pointing or creating other gestures to communicate. We take that for granted, but these kids can't do that, right? So those are all important. So communication is certainly important domain behavior. A lot of the kids have very apparent behavior that can be very disruptive, some more than others. Some kids scratch and pull hair of other kids. They're not trying to hurt them. They're trying to communicate, they don't know how. And that is their reaction. And so reduction in that is very important for parents because if they're not just scaring other kids, and they can go to someone's house, for example, and not have a problem. So bare behavior is and other type of domain of issue. Beyond that, I think things like sleep are really important. These kids have trouble sleeping. It's probably disrupts their whole day when they haven't slept, but they have trouble some kids have terrible problems sleep, some less so but sleep is an important one. We have the age and severity assessment to develop scale for sleep problems in Angelman syndrome. Fine motor, the kids don't use a pincer graft, they grab with the fist. They can't do fine control. For example, they can't feed themselves with a fork by smearing the food and putting their mouth, right? They just -- they claw it. They don't know how to do it. But we've seen the ability to start using a fork, grabbing with the right grabs and poking the food and eating it feeding yourself. So that's really important type of function. Gross motor for Angelman, they have in ataxia that is very distinctive. This is why they have a very wide-based gate, and they have their arms out wide used to be said they sort of walk as if they're a [indiscernible] that someone is moving the arms and legs, very distinctive walk and they fall down a lot for that reason. If appropriate reception how they put their foot on the ground is not well. So if there's any bumps or unevenness, they'll trip and fall. Walking on something like grass or uneven surface, very difficult for Angelman syndrome. So kids fall down all the time. It means you're helping them up all the time. and they're getting hurt because of it. So being able to run or play in the grass, for example, not fall down constantly. Those are all gross motor type improvements. I think would be important. So these are all these different things. And some kids have more of one problem than the other. And we're talking about kids who have the same deletion genetic type, right? So the fundamental genetic defect is the same, near the same. But how it manifests, depends on all the other genetics of the brain. The brain express is 10x more genes than anywhere else in the body, right? That's how much more complicated the brain is. So there's so many other genetic [indiscernible] that will affect expression that all genetic diseases have that much heterogeneity, and we have to be able to sign endpoints that manage the heterogeneity and allow you to capture efficacy heterogeneity in manifestations that had a change in progression, heterogeneity in responsiveness and reversibility. So that's what makes it challenging. But Fortunately, for Angelman, we see kids getting better. And in neurology, if you could see things getting better, it's a whole different game than just preventing decline.

How much more work do you have to do to help get the FDA over the hump in terms of the -- accepting the multidomain responder index, what other arguments seem to make? Or is it just a matter of showing them more data? Or...

I think we haven't really debated yet under or with our division. We've been talking to the FDA at a larger -- at a higher level. We have to show them the data we have. We haven't brought them enough data yet. We've -- last year, we spent time in this year, titrating, optimizing. We're now expanding a cohort at what we think is a nominal dose for loading and that's going on right now. We'll certainly have the data we already have from extension patients that we can use to help support our approach. But our point would be to have a larger body of patients, ultimately, 30 to 40 patients who've been treated in a more consistent way that would give us the kind of data set that would allow us to look at the end point of the number of ways and show them why our multi-domain responder is actually giving you an accurate and meaningful analysis of the data. But remember, the multi-domain responder is all the underpinning endpoints are still in the study. So you don't lose them. It's just a way of analyzing them that allows you to capture the totality of data in a mathematically accurate way. But the other end points are there for evaluation, too. So I think we have made progress on understanding multi-domain nature. They know it's complicated. They've asked us to see the clinical outcome group, which we will with here and start that process. But for the first approval of Angelman of this type of treatment, I think we're comfortable with trying to blaze a trail. We've done another rare disease that never had any trial before and it takes developing the data. I think we have a lot of good data, give us, I think, many options actually on the endpoint.

So you mentioned in your intro, the 25-milligram cohort efficacy and safety data that you saw I'm wondering how has that data influence your expectations for the 50-milligram cohort, which I believe you're going to start in the near term? And what do you need to see in that cohort to convince you that, that should be your go-forward dose?

Yes. So we're very optimistic. And we have data from our MAD study. on the 50 milligrams for 7 days that clearly shows a significant increase in frataxin more dramatic than what we saw in the 25 even for 14 days, but also -- and so I think we're very hopeful about the 50 milligram. Obviously, it's experimentation, so things can happen. But we're very optimistic about the 50 milligram. When it comes to exactly where do we need to go, we've actually done an analysis where we looked at the age of onset for various patients. They are changing far as by year. And it's actually far as non-enforced because it's older data. and then the frataxin levels. And there's a clear correlation and a continuum. Patients who are -- have onset of disease earlier have lower for frataxin levels and a much faster rate of progression. And so I think, quite honestly, any measurable increase in frataxin is worth pursuing because it may not halt the disease but it will slow disease. And it's already a slowly progressive disease, and that gives more time for more innovation and more experimentation and more dose escalation. And so I think at least we don't want to throw the baby out with the bath water. It would be great to get to heterozygous levels of 50%. But getting to 30% or 40%, we'll probably still likely impact the disease progression and shouldn't be dismissed as useless. It could be very useful. And then in combination with some of the other therapies that are now in development and coming out, you may actually really be able to impact the quality of life of these people for the long term. So we're very hopeful. I think we're actually quite honestly, as excited though about the open-label extension because like I said, we're going to have patients who are for the first time taking the drug home with them. We think it signals that the FDA actually saw the frataxin level increase. They would not be allowing us to go into an open-label extension trial and have patients exposed to all the trials and tribulations and problems and risks associated with clinical trials if they didn't think there was a potential for benefit. And so we're actually very excited to see what happens over the long term in that open-label extension. It was a commitment we made to these patients as you were just alluding to that if they were going to participate in our placebo-controlled trials, they would have access to drug, and it's taken us a while to get there. And so we're very excited to be open-label extension as well and give these patients access.

Yes, I agree. I was very excited you announced the open label extension, particularly daily dosing for an extended period of time. So can you talk about the data that we're going to get from the open label extension when we'll see it and how you expect that to inform your potential development?

So we started enrolling in the first quarter of next year. It's an academic center study. So it takes a little longer to get all the bureaucracy done. And our first cut of the date will be the fourth quarter of next year. And it will be frataxin, obviously safety and any other biomarker data that we might have as we start to move through the program with gene expression and lipid data. And then obviously, we'll have some insight into use, compliance and things like that, which are really important with an injectable drug in this population. It's no -- not insignificant that they have limited dexterity. Our patients are pretty progressed, more than 50% of them are in wheelchairs already. And so they do get upper limb dexterity problem. So we want to make sure the caregivers can administer it and if not, patients can administer it themselves. So getting that experience is really critical to long-term success.

And you talked a bit about the potential for background [indiscernible] in the open-label extension. But the question is, is 1601 save with omav. Can you talk about some of your efforts to sort that out? And when will you speak with the FDA?

Yes. I mean given the effect of Omav on a lot of the cytochrome P450 system and drug interactions, we want to be really careful. And so we are doing drug-drug interaction studies of our own. That data should be coming in second half of this year relatively soon. That data gets submitted to FDA. We are having conversations with FDA about how we might think about including patients. It's obviously going to complicate things somewhat, but we want to make sure that we understand our safety profile and we also get over the hump with their safety disabled liver function increases and all that. So we want to make sure that patients are stable and that all has come to sort of a good place, and then we can start drug. So we're thinking about it. We're talking to the FDA. We'll make sure they're on board, but those conversations are just going on.

I'll try to squeeze in one more for Emil on Angelman's. So you have an Analyst Day or R&D Day next month. where I believe you're going to make some comments about Angelman's but sort of broad comments. And then next year, you're going to have more detailed unveiling of the expansion data. So could you just kind of describe that in a little bit more detail. And what are the -- what's kind of the trigger in terms of what you want to see from the totality of the evidence for Angelman's to really have the conviction to move into pivotal?

Yes. So in October, our Analyst Day, we'll focus on the extension patients who have been titrating and been treated for a period of time now as well as the few patients from the first group of patients that have been redosed. We'll focus on data, and then we'll cover some values from the endpoints as well as the clinical influence of what's happening to them. And I think it should be a meaningful update on what's going on in the program. we're going to push out the expansion data patients mainly because we wouldn't have maybe 8 to 10 patients with data through 6 months of treatment by the end of the year. And so our feeling was it was just too small a set. We haven't seen data yet, but it's just not enough in, but because a lot of patients got enrolled in July, we have well more than 20 already enrolled, we should be able to provide them data on 20 early in the year, and that was what we pushed out I think getting 20 or more patients worth of data will give you a kind of a handle on what's happening. And so that's -- we'll push out the expansion then. But the data in October will include a significant amount of data from the current extension patients and the redosing patients and I think provide a meaningful update on how the drug is doing and what we expect from the drug and a little bit about how we expect a trial to be designed and the kind of things we will be measuring.

Perfect. All right. Well, we're out of time. Thank you both very much.

Thanks for having us.

[indiscernible] with the conference.