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

[Audio Gap] Annual TD Cowen 43rd Conference. It's my pleasure today to co-moderate the orphan neurology Corporate panel with my colleague, Anvita Gupta and joined by esteemed panel of industry titans here. We have one swap out, Gary Romano, CMO of Alector; we also have Essra Ridha, the CMO of AVROBIO; Ryan Watts, CEO of Denali Therapeutics; Bobby Gaspar, CEO of Orchard Therapeutics; William Chou, the CEO of Passage Bio; and Emil Kakkis, the President and CEO of Ultragenyx. So most of you are probably familiar with the general format at this point, but we're going to pitch a few thematic questions on the orphan neurology space, so the panel is kind of split it up between them, and then we'll kind of dive into some company-specific questions and more of round-robin later on. So with that said, let's dive right in.

So obviously, a lot going on orphan neurology space, the breadth of indications has really continued to evolve in terms of what's druggable and the different modalities that are used. So one of the first questions that we want to pose to the panel is really what are some of the most important clinical and regulatory considerations when developing drugs specifically for orphan neurology relative to broader neurological indications. So maybe Emil, let's start with you.

I think the challenge has been that some of the rarest neurological diseases have just not had an opportunity to be treated, and we didn't have the technology, the approach to solve the problem. And so the neurology division, in general, has been more exposed in larger market driving with more traditional drug development programs and that's created a problem where the type of doctors that see these patients and the type of strategy for measuring disease are just very different. So I think it's been one of the largest problems is getting a group of adult neurologists that are looking at Parkinson's studies and depression studies, symptom-driven large market type situation to try to figure out how to deal with something like Angelman syndrome or GLUT1 or some of the other stories that are -- drugs are being developed, and I think there's been a challenge for FDA for a long time. And the recent reorganization did provide an opportunity to have some more rare, specific people, but the FDA has not been able to staff with the right type of people. I'm talking about the rare medical genetics division in CEDAR, which is -- takes on some neurologic indications, but they're not led by a leader that actually has been trained in the field of medicine now. The plan I have here with FDA is that if you're trying to treat one of these kids at a hospital, they request you to be trained and boarded to treat 1 patient, right? But if you're an FDA, you can regulate drugs and treat thousands of patients and not be certified in the medical space. I think that's a serious challenge to what we're doing in regulation, and we have to get past just accepting any MD from any school for any purpose and put them in a position of regulating drugs for disease they've never seen or diseases they understand. So it's one of the biggest challenges, I think, in neurologic space where the complex neurology diseases that people have never seen before and regulated correctly, just won't happen without the right training.

Ryan, how would you answer that question as well?

Yes. Thanks for the invitation to be here. I mean, you're on a panel with some fantastic scientists, physician scientists and CEOs, and they have a lot of opinions about this. And for us, we're kind of in a unique position because we are, as Emil kind of highlighted, we are working on the rare neurodegenerative disease but also on the common degenerative diseases. So we see both ends of the spectrum from Parkinson's, Alzheimer's to FTD and then into the childhood diseases such as Hunter syndrome. And so you asked really 2 parts. One is the clinical aspects and the second is the regulatory aspects, right? And so for us, and I think Emil would agree with this that we need to get to a point where biomarkers are really driving decisions beyond just dose selection. But the biomarkers are linked to clinical benefit and regulators agree that if you see changes in these biomarkers that the likelihood is very high that you're going to see clinical benefit. So let's take both ends of the spectrum. So in Hunter syndrome, in particular, we're working on a biomarker that is a substrate for an enzyme. You have an approved enzyme replacement therapy where there's a correlation between changes in that biomarker and clinical benefit on the peripheral endpoints. And the question is why do regulators not see that on the central endpoints? And depending on what the vision of the FDA you're looking at, they are probably viewing it differently. And I think I agree with Emil that there needs to be a unification around how these biomarkers are correlating with clinical benefit. That being said, you can't develop rare neurological disease medicines the same way you're developing Parkinson's and Alzheimer's medicine that's much more difficult to run a clinical trial that's powered with 600-plus patients in a rare disease. And so you have to believe that biological link between biomarkers and clinical benefit. And I would say that we're in a very unique time with still a fair amount of uncertainty in the regulatory environment because of, frankly, changes in leadership in neuro and in the rare division. But I think directionally -- moving in the right direction, understanding the unmet need in ALS, FTD and even these rare diseases. And at least to our sense is that there's a positive movement at, in particular, the FDA. Now we hope that continues. But when we consider our clinical trials, I think we cannot design the rare clinical trial similar to the way that we're designing trials in common degenerative diseases, yet sometimes regulators believe that's the way you have to go forward. And so that's the dichotomy right now. And I do think it's an exciting time. I do think you're now starting to see approvals across multiple neuro indications. Hopefully, people will realize that there is a huge unmet need. There are a lot of new technologies that are actually advancing therapies in neuro, and it's no longer going to be what was the former graveyard of investment in failures, and that's certainly changed in the last year, not only in the rare disease space even within the last week, but also in common, such as Alzheimer's disease. So it's a very exciting time for neuro drug development, but there are still challenges as Emil highlighted.

And Gary, I know Alector is also kind of straddling this broad and orphan aerospace. So how would you approach this?

Yes. So well, I can think of other examples of what Ryan just spoke of, which is having to look differently at these larger neurological diseases and rare disease. One example for us is FTD granulin, right? This is a genetic variant of FTD. And I think early -- I think FDA has and other health authorities have looked at this through the lens of how they look at Alzheimer's disease in terms of what type of evidence you need for approval. And you have to think back on -- and I think when you just talked about biomarker validation or the acceptance of biomarkers, there, you have to remember that even in Alzheimer's disease, it took many years and long observational studies, the ADME observational studies to show the relationship with biomarkers with disease progression, which is getting halfway there. And the second half is then being able to show that treatment effects on those -- on biomarkers predict treatment effects on clinical outcomes. And we're just starting to see that now in Alzheimer's disease in -- with what can be with out-of-home. So I think it's important to remember that how we got there, and that was -- those recent accelerated approvals are encouraging. I think that the FDA is using its scientific judgment which has latitude to have flexibility using its scientific judgment based on the precedence or the prevalence of the disease, the severity of the disease, whether there are other approved therapies for the disease and so forth to then adjust what their expectations would be. That said, we have to remember that you're still going to need to have substantial evidence of efficacy and sufficient information to show that the drug will [ sail] . But I guess I'm a little bit of an optimist. I see in these recent approvals for Alzheimer's drugs, some flexibility in FDA, and I agree, we'll have to wait to see whether that's going to maintain at their change in leadership, but I'm hopeful that they will maintain.

Great. So let's talk more about the regulatory side of things. In your experience, how cooperative has the FDA been in designing your clinical programs? And how open is the agency in helping you develop novel endpoints where necessary? Let's start with Essra from AVRO first because you have 2 late-stage trials coming up. I'm sure you've had a lot of regulatory interactions there.

Thank you very much, Anvita, and thank you very much for the invitation as the panel. Yes, I have to say that I found that really approaching the regulators with essentially a very well thought-out clinical trial. And I think, importantly, we were speaking about some of these -- the correlations between biomarkers and endpoints we might choose and how well those are understood, how well do you understand the underlying pathophysiology of the disease and how well you can link that to the potential for clinical benefit is very, very important. They have been receptive when you are really approaching what is a well-thought-out trial design in a well-thought-out and well-defined patient population, you're able to speak to the natural history of the disease and to really speak to how predictive your measures would be of clinical benefit and how you're really going to be objectively able to measure that treatment effect. And so our experience has been a positive one. We certainly learned from a lot of our sort of colleagues in the industry as well as feedback from regulators globally around how they view novel measures. And one of our novel measures for the time being for our Gaucher disease type 3 program is a multi-domain endpoint, and that endpoint really allowed us to consider an ultra-rare disease patient population and enable us to homogenize what is an extremely heterogeneous patient population, so that the trial really does mimic reality in terms of that disease. And so we've had positive experiences. I agree and echo what the other panelists are saying that they -- there is understanding receptivity to the fact that these diseases have a great unmet medical need, and we need to think about treatment options for them.

Bobby, any comments here?

Yes. Well, maybe I'll just add to what's already been said on panel members. But first of all, thank you very much for the invitations. It's a pleasure to be here to and talk to you all. So we've had a lot of experience recently with the FDA. So we're within -- because of the nature of our HSC gene therapy within [indiscernible] and in the [indiscernible] division. So it's not kind of based on a specific disease entity. So I think to Emil's first point, you've got somebody as a clinical reviewer who have -- may have experience in a certain area of medicine, but not necessarily on your own. And I think there has been a lot of turnover with the FDA as well. And so I think the very first thing is really just about education [indiscernible] and that I think is absolutely critical because these are rare conditions. The person [indiscernible] they never come across this condition in their practice previously. And to understand the devastating effect of that disease, how it comes about the pathophysiology and also what options are available. And there are some kind of misperceptions of what might be the standard of care in that particular disease. And we've come across that as well. So I think that educational piece is paramount right at the beginning. And I think one of the things that I think certainly has helped us is not just what we've been saying, but what patient community and the KOL community have been saying to the FDA. And I think that has been incredibly important in informing them about the nature of the disease and the unmet need. So I feel that some of the kind of the progress that we've been able to make is because they have understood the disease and now are able to -- and we can engage with them in a much more kind of informative manner. So I would definitely echo what you're saying, Emil, about having people who understand the disease to be able to then start thinking about how we actually move forward in constructing a [ proven ] clinical trials. So I think having said that, then it comes down to what is available for that particular disease. And we've got 2 examples that we've currently worked on, what is MLB, where there is no standard of care, it's only supportive and palliative treatment and being -- and sort of they are absolutely clear that, that is actually the case. And we can't charge against another intervention of some sort. And it has to be natural history. And that is something they really, really don't want to do, but in certain diseases. Unfortunately, that is what's out there. And that is an appropriate constructive [indiscernible] comparator set has to be the way that we move forward. Where there is something available, and Essra experienced this and we have experienced with MPS I, it's absolutely clear. It has to be randomized. And I think that's the world we're going to have to move in even some -- in a very rare disease. If there's something already out there, it's going to be a randomized controlled truck. And then it's going to be about what are the endpoints that you use and how quickly we can get to those endpoints. And I would say that as far as that is concerned, we had very constructive discussions with them last week -- last year in terms of the MPS I program moving to an IMB clearance and talking about the length of the study, the endpoints and we, again, talk about composite endpoint that involves both safety and efficacy. So I think that business of trying to get engagement understanding at the beginning is the most important. And then you can have -- because I do feel within the constraints that they have been able to approve Doug, there is -- once they see the need, they do want to work with you to try and find what is the best way to move forward.

[indiscernible]

Sure. So I think we've had a great collaboration with the FDA, and I will start out with some evidence from our preclinical program. So we've heard about a desire for the FDA to shorten preclinical timing. And what we've experienced ourselves is the ability to use data from one preclinical program as evidenced for another preclinical program. And that that saved us a lot of time and expense. So that is one case where the FDA did put their money where their mouth is. I'd also say in terms of collaborating for rare disease endpoints, we've had a great dialogue with them. And when you look at GM1 gangliosidosis, and the difference between early infantile patients and late-infantile patients, they've shown a great flexibility to learn about the natural history of the disease and also tailor endpoints that are going to be objective, meaningful and reproducible for each of those diseases.

All right. Great. So I'd love to do a little bit around Robin now kind of diving into company pipelines. Maybe, Emil, we can start with you. I know if you have anything to add to the last topic, I know you have a lot of experience in developing novel endpoints with the FDA. But I also wanted to dive a little bit to the Angelman program. Obviously, a lot of interest here, huge unmet need, really sizable patient population, pretty devastating indication, as I'm sure all of our panels are familiar with. So earlier this year, you confirmed that there's one older patient, one 17-year old patient in the Phase I/II study that showed reduced ambulation, although given at baseline, the patient already had severe scoliosis and was essentially wheel chip-down if I remember correctly. So I guess one thing I would love to get your thoughts on is how extrapolatable to other Angelman patients broadly and even within the study, do you think that signal is? And then can you tell us whether or not the patient has reinitiated dosing yet?

Thanks. So our engine program in ASO or provide intrathecally change from patients originally had 5 patients treated with very profound clinical effect but also a significant lower extremity weakness due to inflammation of the nerve roots. And that's a major safety pick we had to manage. We've treated a lot more patients now at a variety of doses have not had the problem. And then we had one kid now at 17 that had at the fourth dose had a mild weakness, it was a patient who didn't walk well, and that's the 17-year-old. He recovered relatively quickly. The effect was relatively mild. He had some elevation of protein. So the ASO will cause information to some patients. It's just ASOs have done that, by the way, if you look at a lot of the programs, you'll see 1/3 or more of the patients have protein elevation related to an inflammatory effect so it's something we have to manage. I don't think it's something we're seeing routinely a lot of patients now that the dosing we're doing. We're seeing it except that one patient we've had, not others. But we're still working on exploring the dosing and achieving an optimal dose that will get us the efficacy we see. We're currently expanding dosing into these 2 expansion cohorts of younger and older patients we'll seek to enroll 40 patients, 20 at each level. That allows us to look at how broadly the safety profile replicates and whether there's any frequency to that event or not. And we'll be able to see a little more quantitatively what the efficacy looks like. But everything we've seen so far says that this ASO can activate the UV 3a gene in these patients and generate enough activity to change some very fundamental biology that you've never seen change before. I would say to you, I've been in this a long time, not seeing any developmental function of a child get better with the treatment, usually trying to prevent declines. So to see significant [indiscernible] of improvements in receptor communication, improvements in sleep, that have been dramatic improvements in behavior in addition, some improvement in fine motor gross motor. I do think it's very, very special to be able to see developmental improvement in a kid. And Angelman syndrome without anything I think it's important to recognize the benefit/risk equation. If some patients have this problem, we'll have to manage that and deal with it, but it's a reversible problem. It's something we're going to have to keep our eye on, but I'm encouraged with where we are at the moment. And I don't think that, that problem is going to be a routine problem for many patients.

All right. So I mean you mentioned this ongoing dose expansion. I mean, you guys have done a ton of work trying to optimize that just the dose level, but the actual cadence of administration. So can you give us a sense of where you're at now, what kind of regimens you're exploring in the current dose expansion?

Yes. The expansion ex U.S. is still giving 4 doses at 1 month intervals and then go into every 3-month dosing. All though the original cohort 4 and fiber are lower doses were in middle range dosing to load, and then they'll be able to titrate up during the maintenance phase. We're still working on opening the U.S. fully to the protocol where we are treating some patients in the U.S. who are opening it fully. We may try a slightly different regime with 3 doses and then a different spacing to try to optimize the sort of accumulation of drug effect as well as safety. But that's the approach we're taking right now. I think all these choices on regimen or try to make them based on science, but to some extent, you -- the excise of animals doesn't necessarily explain people. And so you need to look empirically what's going on in your patients that make the best decisions. The animals just give you ideas they don't really find solutions.

Right. So I mean I think this is getting at kind of a pivotal question here that's in some ways probably applicable to all of you in one way or another. A lot of these more Orphan Neuro indications often have a complete lack of disease-modifying therapies if any therapies at all, right? So with that said, I mean, we're -- I mean, we can focus on Angelman here, and we can kind of move through this topic as we go throughout the discussion. But where do you realistically think the bar is for efficacy in your Phase I/II? And kind of how are you thinking about that relative to what the patients need and even in your interactions with the FDA, I mean, how receptive are they to just the reality of that kind of situation?

Well, I think we're already above the bar of what patients would accept because we have people getting intrathecal injection now 1.5 years, 2 years repeatedly coming back for it. Other people wanted to get in. So I think when you can say that your kids might be able to follow instructions and hear you respond to their name, be more alert and cognitively aware that they're not pulling hair or scratching other kids, they're calmer and they're sleeping through the night that you're sleeping through the night. If you started managing those all in one kid going on, and you -- any of you have had kids that don't sleep. This is transformative that amount of data. So I think we're at a level of efficacy that patients would definitely want. We still our obligation to the company is to try to make sure we're getting the most we can from what we're doing. So our time here is really spent trying to see how to optimize. But I would say that the level of efficacy we're seeing is something that is unique, special and valuable to patients and I think we're already there for what they want.

Right. And I think one other thing I wanted to ask you about Angelman and I think as we kind of alluded to this earlier, when kind of talking about regulatory interactions, but endpoint specifically, I mean, Angelman is such a multifaceted disorder. I mean, these patients, their symptoms can range across the board, even sometimes from day to day, frankly. But when you're looking at like a Phase I/II study and trying to plan ahead for a pivotal study in something like Angelman. I mean, which endpoints specifically, I guess, maybe whether it's the CGI or daily sleep evaluations, whatever have it are you seeing at this point that you think are potentially most indicative of the drug's efficacy, but also straddling that line of being able to support [indiscernible].

Well, we've been focusing -- we think there's 5 domains that are probably the most valid but one is an important and Receptor express communication is one which I think patient and family rate on that patient, but family rated the highest being the most important frustration is difficult to communicating with their child. I think abnormal or adverse behaviors or another thing, sleep is important and fine motor being able to feed yourself use a fork, spoon as well as gross motor, which is more about falling down instability in walking. All 5 of those are important. Some patients have one thing or another. Some don't sleep well, some sleep okay. Communication seems to be the most common one that is certainly across all. So if I had to pick one, we would look at communication. Within the types of endpoints, it's really always better to work with quantitative endpoints as opposed to relative endpoints. That means daily expressive communication or receptor score versus CGI score for communication. The reason for that is you can quantify the magnitude effect based on an independent observational measurement as opposed to just the pending of the investigator, what they think they're seeing. We're not seeing -- it's just the kind of thing that usually allows you to measure clinical meaningfulness in a more quantitative way. CGIs are sensitive and that's why people use them. They're more sensitive to change and could be used. But I think in general, they're not the best primary endpoint. So quantitative scores are better. I prefer single domain score rather than mix domain score. In order to mix domain, we view what we call the multi-immune responder index is the best approach where you determine a response for each endpoint individually and add a response rather than using a total score where you're adding up to an important distinction because what happens with these big scores where you're adding up too much, is that if you have 2 things that respond really well, the 3 or 4 things that don't, the noise from the 3 or 4 will destroy your ability to see the 1 or 2 that do. And so when you break up the analysis of each patient to this domain by itself, it allows you to capture efficacy, and we've shown in analyzing other types of data that this approach is tenfold more powerful to detect real change than other approach and we've written a paper on the topic. So we're hoping to get that accepted. I think in Angelman it's a large enough disease where we can do random trial. And if you're doing these kind of endpoints, you're really happy to rent a controlled animate trial for this type of cognitive or response endpoints, there are no [indiscernible]. So the expectation you'd want to a randomized placebo-controlled trial, including a multi-immune responder Nick with 5 domains. And that, to me, would give you the best assessment of overarching treatment effect in the Angelman syndrome.

All right. Great. I know I want to shift gears a little bit and maybe talk to Ryan about Denali's pipeline here. So I mean you always really pioneering this transport vehicle platform that you guys are using. And it's I think part of what's unique about it is it's nary specific to any one education, right? It really is trying to get at how do we get into the CNS. I mean this has just been a historical issue irrespective of modality across the board for years and years now. So maybe just give us a really high level understanding of how you see -- first of all, really, what it is for those who are maybe a little bit less familiar, but also really how you kind of see it evolving your pipeline over the near term?

Yes. Great. So you're speaking specifically of our transport vehicle technology, which utilizes transparent receptor to get large molecules across the [indiscernible] or some type of receptor for receptor media transcytosis. So this idea was first proposed in the late 1980s. There were a set of papers and it took a long time to go from academic to industrialization of the technology that are now multiple molecules in clinical testing using transparent receptor to cross the blood brain barrier, not just from Denali, but from other companies as well. When we founded Denali, we wanted a platform that was highly modular that allowed us to get -- to unlock certain targets and to enhance other targets. So for example, you have enzyme replacement therapies that can effectively treat the peripheral disease or the [indiscernible] in the body, but not the brain. And the idea is that by getting these enzymes across the blood-brain barrier, you can then treat the neurological indications of Lysosomal storage disease. And in that case, at least in our experience, we couldn't give a high enough dose systemically to treat the central nervous system. Enzymes have a pretty fast half-life. They're cleared pretty rapidly. So truly, this type of technology would unlock that and allow you to treat both the body and the brain. And then when it comes to antibodies, it's really a question of enhancing. Antibodies do cross the blood-brain barrier. There's some people in the blood-brain barrier field that claim that they don't, but they absolutely do. And I think lecanemab, is an example, and aducanumab and these molecules across the blood-brain barrier, but you have to give pretty high doses. And the idea is to essentially enhance the antibody approaches by being able to get a lower dose to get a higher C-Max, right? And then there are other indications, in fact, Emil was just talking about, there's other modalities such as ASOs that have to be given directly to the spinal cord or to the brain that when given systemically, don't cross the blood-brain barrier. Again, they're cleared pretty rapidly. So this would be another sort of modality that we could unlock with the transport vehicle technology. So 8 years ago, when we founded Denali, the idea was to create a platform that would enable enzymes antibodies and antisense oligos to cross the blood-brain barrier. And we started with transparent receptor. We continue to explore all sorts of receptors, but the clinical data that we presented in 2020 in Hunter syndrome was the first validation of the transport vehicle technology and a couple of interesting insights from that data. So one is that at the lowest dose, we saw normalization of the substrate heparan sulfate, which is what either sulfate basically processes. And this was a 90% reduction after just 4 weeks of dosing. We've now seen up to 2 years of this is normalized. And I think we now have a second program getting progranulin across the blood-brain barrier, TREM2 antibody enhancing its uptake and potency. We'll bring a fourth program for Sanfilippo where there isn't a standard of care, there isn't an ERT that has been approved. And then ultimately, we want to bring ASOs across development varies. So you can see is really a platform technology enabling multiple modalities using an iron transporter that's highly expressed to the blood-brain barrier.

Right. So I think -- I mean I'd love to touch a little bit on maybe each of those really quickly. So I mean, first, your MPS II program in DNL310 and your lead enzyme conjugated transport vehicle, you've shown I think it's pretty clear evidence that it's getting into the CNS but like you said, I mean, you're able to normalize HS levels in the CSF, which is just something that you don't really see at all with standard ERTs, right? So -- and then the question then for the Phase II COMPASS study that you all have going on now, which has dual primary endpoints, I believe, that are looking to show reduction in the biomarker, but also establish cognitive response, right? So can you maybe give us a sense in MPS II, first, how well understood is the correlation, which is again kind of getting out of way as referred to earlier in the conversation, how well understood is the correlation between the biomarker response and the cognitive response? And then maybe how long you think you would potentially need to actually observe these patients on treatment to see significant response on cognitive measures.

I think the key here with the Hunter program is that we're trying to blaze the trail for multiple programs and enzyme replacement therapy. And so as I pointed out and as you highlight, first step is to show substrate reduction. Second is to show and so I'll call that like the biochemical rescue. And then the second would be a cellular rescue, which we're looking at lysosomal biomarkers such as GM2 and GM3, which alone when elevated can cause neurological damage. And then you're looking for the rescue of the network. And I think probably some of the most interesting data we presented at World just recently this is 1-year data. We have 2 years of safety and biomarker data, but on a small subset of patients and in a much larger set of patients where we have 1 year data -- we can see biomarker improvement. So heparan sulfate at the biochemical level. We see lysosomal improvement. We see about a 50% reduction, which is essentially normalizing these lysosomal biomarkers. And then we're starting to see network improvement. One example of that is improvement in hearing. And this is done actually in an unbiased way where you look at brainstem electrical activity, and we're seeing improvement over time. So this would be network improvement. And then ultimately, when we look at the VAB, so the Finland, the Bailey and Global Impression of Change, across all scales, we're seeing that the majority of patients are improving and others are stabilizing on these scales. And so for us, we're establishing that correlation now between the biochemical rescue and the cognitive and behavioral benefits. So you also mentioned the co-primary endpoint, which is essentially CSF reduction in heparan sulfate where we see 90% reduction in normalization. And at this point, essentially the VADBs, but I would highlight sort of the totality of the clinical data. And I think Emil, I would just repeat everything he said, but I won't, looking at single domains, improvement on socialization, communication and I think this is critically important. I think if you look at a case -- from a case study, these patients are certainly improving.

All right. So I mean, you also alluded to some of the other programs that you have going on to so you have a program in FCD that you've showed initial data from last year thinking another update retro the middle of this year. But I mean, again, this is a similar conversation, right, so biomarker response versus cognitive response, and I know Alector is also looking at this education as well, so we move it into that then. But give us a sense of the midyear update, what are you really aiming for? What are you hoping to see? And then how is that going to kind of position your thinking about the program moving forward?

Yes. So this is a healthy volunteer data. So what we're looking at is safety and looking at dose relationship and increase in progranulin actually in CSF. And I think that probably just the simplest way to explain our approach is very similar to enzyme replacement therapy. These patients have a loss of one copy of granulin gene, which produces progranulin and the idea is that we're going to restore progranulin by crossing the blood-brain barrier, and we're actually reintroducing progranulin in the system, similar as we've done with either solace for Hunter syndrome. The key now is enrolling actually MTD granulin patients, where you're going to see the biomarkers we published a paper and sell around the biology of granulin, it's role in the lysosome and looking at lysosomal biomarkers. And so that will take time, obviously, to enroll that study and to look at clinical endpoints. But again, the idea here is progranulin replacement therapy.

And I think I would probably be remiss if I didn't ask even that we are neuro panel about your markets programs, right? So I mean, again, you recently initiated on you're looking at LRRK2 ton of floods in the market is community has for a number of years here. And I think you have ongoing study in LRRK2 positive patients and then also in idiopathic Parkinson's patients. So I guess give us -- I know these are just getting underway here, but do you have a sense of how the trajectory could go in terms of timing, but also really what it would indicate presumably, if you get LRRK2 positive data, does it have read-through to the broader market sense population? And what kind of information are we realistically looking to see from even maybe biomarker perspective ahead of potential cognitive...

Yes. So switching gears a little bit. Just a reminder that we've talked about the transport vehicle program, which are large molecules, enzymes, antibodies, ASOs. Now we're switching to the small molecule programs. And we have a Parkinson's program, which is a LRRK2 inhibitor. And the background is that there are mutations in LRRK2 that increased kinase activity, so these are kinase inhibitors. And this was discovered in 2004, we started working on it in 2006. And then when we founded Denali, we licensed the work that we had done previously and then invented a set of our own molecules. And now after as many years from discovery to now looking for efficacy, we have 2 ongoing late-stage studies. The LUMA study, which is focused on idiopathic Parkinson's and the LIGHTHOUSE study, which is on LRRK2 carriers. But the simple way to explain it is that inhibiting LRRK2 improves lysosomal function. Actually, hyper-activating LRRK2 has been shown because of lysosomal dysfunction. So again, in the sort of category of lysosomal stores diseases, I often look at Parkinson's disease as like a very mild form of lysosomal stores disease or links to GBA, obviously, LARK2, GALC, many of the genetic, about 50% of the genes are linked to the endolysosomal pathway. So these studies are now kicking off and they're based -- they're focused on clinical benefit. So UPDRS as endpoints in both idiopathic and LARK2 carriers. Now obviously, the rationale is the strongest is a large carrier, but there's substantial evidence in broader life in Parkinson's disease that there is lysosomal dysfunction and hence, the focus there. So it's all about enrolling and operationalizing those larger studies back to the very original question, which is the mindset of regulators, these are big 640 patient studies for idiopathic, 400 patients for LARK2 carrier studies.

All right. Moving on to AVROBIO. Essra, let's talk about AVRO [indiscernible] programs first. You announced very positive interim data update late last year from the 4 GD1 patients in the Phase I study and 1 exploratory G3 patient treated with your AVR-RD-02, lentiviral gene therapy. So in your view, what are the endpoints that are clinically meaningful in GD1 and GD3? What is needed for regulatory approval? And then additionally, is there a data point in that preliminary data set that makes you particularly confident about success in the planned registrational trial in GD3 that you plan to start later this year?

Thank you for the question. So really to speak about Gaucher disease. We really consider this disease as essentially a spectrum of severity and continuum, if you will. It is one disease and all Gaucher patients essentially have mutations in what is the GBA gene. The result is an enzymatic deficiency in glucocerebrosidase and the result of that is an accumulation of the storage material glucocerebrosidase, which essentially likes to accumulate within the macrophages of the patient, forming these in large or engorged macrophages, which we term Gaucher cells. Now these Gaucher cells will essentially accumulate throughout the body in all tissues and organ systems. In TDI, we see that predominantly in the liver, the spleen, the bone marrow and the bone itself. But as we move into Gaucher disease Type 3, that is more systemic and we see that in the central nervous system. We see them in the lungs, we see them in the lymph nodes. And these areas are particularly refractory to standard of care therapy where the enzyme just cannot really penetrate these tissues. And so the important thing that we see from the GD1 trial, which we see as an important group of concept really is that we're seeing this -- the totality of evidence, the story that we're seeing, which is that we infuse our genetically modified stem cells. They nicely engraft. They will differentiate on the various nematodes [indiscernible] lineages, importantly, the myeloid lineage and really replace those disease macrophages with healthy corrected macrophages in the periphery and microbial within the central nervous system. And what we're seeing in the GD1 trial is that there's healthy macrophages that have been genetically modified and derived in the HFCs, they are able to process all of that storage material. And the result is a dumbing down of the inflammatory responses, a reduction in organ volume, which is very important to really give us a sense of how well we control the disease and our ability to remove that storage rate that really triggers so much inflammatory damage and end organ damage down the road. And so GD1 gives us that important insight from the liver, the spleen, the bone marrow, the bone itself. But as we move into Gaucher disease type 3, we really are looking beyond these organ systems and tissues. And looking at the brain in particular, looking at measures of ataxia looking at that biochemical correction as well in the CSF, where we're looking for enzymatic enzymatically constitution and substrate reduction importantly, but that will also translate to how the patient is feeling really with the gross impairment that they have in terms of their [indiscernible] and walking abilities from a gross motor function perspective, and we're assessing that through the [indiscernible] cell.

Got it. So I guess let's go into the details about the Phase II/III trial design and the powering over that you have for GD3. What's the magnitude of benefit on that primary endpoint are you hoping to achieve compared to the control arm? What is the control arms activity that you have factored into your borrowing?

So thank you for the question. And really, just to give an overview, the Phase II/III clinical trial for Gaucher disease Type 3 is an open-label, randomized controlled trial and probably the 2 earlier. We are really going to be randomizing patients one-to-one to receive the gene therapy or remain on the standard of care, which is an enzyme replacement therapy and assessing and evaluating these patients over the course of 1 year. Now typically, and what we'd expect in that control arm is once you've established these patients on the standard of care therapy, which is a minimum sort of 6 months before they're enrolled into the trial, we expect the control arm to remain stable. They've hit the maximum. That's some ceiling of the treatment effect on ERT or even worse on some parameters of the disease. And that's because we know that the enzyme replacement therapy cannot penetrate the blood-brain barrier has no activity within the central nervous system or any discernible degree of activity within the CNS. And it cannot penetrate certain histories around the body such as the lung, for example, in particular, nor the liver and spleen to maximum benefit as it were. And so in the control arm, we expect stability or even deterioration in these patients over the course of 1 year with the gene therapy invest on the data that we have approved to date, we do expect improvement across the parameters of our multi-domain endpoint, which includes ataxia. So the measure of neurological treatment effect, diffusing lung capacity for the pulmonary aspects of the disease, which can very well be life limiting, but also the liver and the spleen volume. And so we're really looking at superiority against the standard of care in a minimum of 2 or more domains of disease over the period of 1 year.

Got it. Okay. And then so you're still enrolling the GD1 patient in the Phase I/II. How does that factor in into your clinical trial development? Like are you hoping for a broad GD label for this therapy or are you going to pursue a different trial for GD1 administration.

We consider that the disease itself is very much the one disease with essentially the same underlying pathophysiology of the disease. And so as we -- and we look at our gene therapy, AVR-RD-02, which is the 1 gene therapy that is effectively replacing the mutated gene if you will, with the correct copy of that gene. And so across the board from G3 all the way through to GD1, we're looking to accrue that data and really sort of demonstrate the consistent safety, tolerability, efficacy and the durability of the treatment effect, which we view is very important across the Gaucher program. And of course, we're pioneering this very much integration with these spaces, but it really is on a body of evidence across the HSC gene therapies that we believe that consistent [indiscernible] seen.

Got it. You also have a Phase I/II program in Hunter's syndrome that just got into the clinic, you're dosing our first patient in the first half this year. How do we think about the endpoints here? When do -- when should we expect some data in this? And what would be good data from this initial dataset?

So we're enrolling patients with the severe neuronopathic form of [ Hunter syndrome ] into the clinical trial, we will enroll them at a young age of to 12 months of age and really aim to treat with an HSC gene therapy approach. The -- what we would like to be seeing and what we anticipate is complete biochemical correction once we've seen the engraftment of our genetically modified cells. Importantly, this resident microglia that will enable the cause correction of the CNS tissues is key here. And so we expect to biochemical correction. But beyond that, some of the measures that Ryan mentioned earlier as well, where we're looking to see that we can stabilize patients who we've enrolled who have minimal to no cognitive deficit, but also see these children develop in line with healthy children at a similar chronological age of the 2-year period.

Got it. I think the final question would be on cystinosis. You've shown really promising data from the Phase I patients in the UCSD trial. Now given that our focus of this panel is neurology. So how important and prevalent are the neurological impairments in cystinosis patients. Are you collecting any cognitive data as part of that study? And what are you seeing there?

Yes. Thank you. So the cystinosis patients have a very distinct visual special motor coordination and visual motor integration deficit with relatively preserved problems or function on full scale like us verbal language scales as it were. And so what we're looking at is specifically the visual motor integration elements, visual spatial and motor coordination dysfunction in our current clinical trials. And we're certainly seeing that preliminarily that these patients are showing improvement over time in some of these aspects and some of these deficits over the course of a 2-year period. And so for our future trials, we're certainly looking at a pediatric population and looking earlier in time to be held and how they about [indiscernible].

All right. Great. I want to pivot over to Gary and I'll let to a really quickly here. So obviously, we touched on some of the indications that you all are pursuing, but maybe we can start with FTD, right? So this lead indication for AL001 or latozinemab. Updated Phase II data with AL001 in FTD-GRN patients showed about 48% slowing of clinical progression of disease relative to a curated natural history cohort. So this, again, kind of gets a little bit of what Bobby was referring to earlier in terms of what is FDA looking for when it comes to actual comparators here. So can you give us a sense, first of all, how are the patients in the natural history cohort selected for the inclusion in the analysis? And then at this point, how close are they do you think to the target patient population for the ongoing pivotal study?

Yes. Thanks, great question. So just a little background here. This is a Phase II study in FTD branded on these genetic variants. It's an open-label study. These patients have really rapid decline in behavior and popular function. And so that study -- in that study, we had a pretty robust biomarker evidence of treatment effect. So this is being treated with the anti-sortilin antibody, which is latozinemab, which basically blocks sortilin reuptake of progranulin and therefore, increases the half-life progranulin in the CSF and raises progranulin levels in the CSF by about 2 to threefold. And we saw -- as a result of that, we saw strong effects on normalization of lysosomal biomarkers. We saw normalization of GFAP, which is [indiscernible] protein, which is a marker of vascular cytosis that goes up dramatically and rapidly in these 5 granular patients came back to normal. We even saw effects on some inflammatory markers, other inflammatory markers and on region of interest volumetric MRI, even in a very small sample, there's a lot of directional effects that were pretty impressive. So the question we had was, is this providing any clinical benefit, and it was an open-label study, for the reasons I explained. So what they did -- what they did was they did what they call propensity matching to try to find matched control of individuals from an observational cohort or the Gen cohort. This is a European ram-European observational cohort of genetic FTD. And this was a blinded approach. And it took -- they went to 4 steps. So first, they took all they went to the GMP database and said how many patients who GMP database have granular mutations and had a baseline and at least one more data point on the CDR is called the CDR NAC FTLD scale, which is a -- basically a CDR scale it's adaptive for TV. And they identified this 100 patients. And then they went -- the second step was to go through and look for baseline matching on the disease severity. So that's again on the CDR NAC FTLD [indiscernible] came to that, it was about 25 patients. And then the third step was to adjudicate on secondary covariants like age, gender, NFL levels and the time duration of disease. And with that, they came to 10 patients that MAC were 10 patients match to 12 patients in the interventional trial. So that's the process that whole process was blinded to progression rate, so we didn't know who we were getting in terms of what their progresses. And that's where we can compound about 48% treatment, right? And slowing of disease is 48% slowing of disease progression in the interventional line. And I think the question we ask is, well, how does that -- you said how does that compare to -- how does that sample in the interventional study compared to our Phase III study. It's the same criteria. They're very overlapping. So they're very close. We had a range of -- where we are in our enrollment there tells it indicates to us that this is going to be a very -- very close to the overlapping improvement, sorry.

Why because I was just going to follow up on that to say when do you expect to complete enrollment in the ongoing pivotal study. And I think you recently gave an answer to what we might actually see data for that.

This is the last quarter.

Sorry. I'm sorry. Just give us an update maybe on enrollment timing and when do you think we might actually see pivotal data from this study?

Yes. From the Phase II study or...

The Phase III...

Phase III study. Yes. So the Phase III study is ongoing. It's been ongoing for a couple of years now. It's a -- this is a randomized double blind study of [indiscernible] patients. It's a global study. And as I said, it's been enrolling steadily for some time. We've not disclosed exactly where we are in enrollment, but what I can tell you is that we've been following closely with the data emerging from these observational studies. And with more and more data, there's been increasing precision and granularity about progression rates and variability of progression rates and cloud markers and clinical outcomes. And recently, there was a paper published about late last year by the Gene and all FTE cohorts who took their data, actually saw the -- looked at these progressors, saw they were very overlapping and were able to do a variety of analyses and modeling of that data. And they predicted that from this data that you should be able to conduct studies in FTD that were considerably smaller and shorter in duration in the study that we planned. And so we took a look at that data, we did some internal analysis and came to the conclusion that, in fact, are some of our assumptions undergoing that original design, the need for that many patient iteration. We're really overly conservative. And with greater precision around the variance of the data, we feel very confident now that we're going to be able to close that study sooner with less -- fewer patients than we targeted and for a shorter probably definitely a shorter duration. And so that's where we are. We are -- we have planned an FDA meeting soon to talk about our statistical analysis plan for this, which we had always planned to discuss around this time with FDA. So will keep you posted...

Great. Okay. So Bobby, I think it's been a clear part of what you said earlier about regulatory interactions has continued to come full circle and you've had no shortage of these recently. So regarding the regulatory filing with Libmeldy, I think you just said yesterday that you completed your Type B meeting and you've been confirmed for a pre-BLA meeting with FDA, I think sometime coming up. And I guess, give us a sense, first of all, if you can confirm the timing of the pre-BLA meeting and then what are the different possible outcomes of that meeting? And then how you're kind of able to extrapolate your experience with MLD to maybe some of your other programs as well in terms of regulatory interactions.

Yes, sure. Thank you. So we announced that yesterday that we had a productive Type B clinical meeting and that we have a confirmation now of a date for the pre-BLA meeting. So that's been -- I think that's -- we feel that is very encouraging. About 6 months ago, we had interactions with the FDA where they didn't feel that we were ready for a pre-BLA meeting. And they guided us to have a Type B clinical meeting to address the clinical issues and also they wanted to review the CMC packaging as well. So I think from where we were 6 months ago to now having been granted a pre-BLA meeting, that's a big step forward. So I think we feel very encouraged about that. So on the Type B clinical meeting, there were some specific issues, and I talked about them previously, but just to kind of recap. They wanted to understand that given that we're treating some patients pre-symptomatically, how can you predict what the clinical deterioration will be when will they deteriorate because they're pre-symptomatic. And also, I wanted to talk about the comparator and again, I mentioned this previously. There is nothing else out there. Is this a robust natural history comparator. And so those were the real main sticky points as far as the Type B clinical meeting is concerned. And I think those are very important discussions that we had leading up to that meeting and within the meeting itself. And that was the evidence that demonstrates that the genetics and the biochemistry can accurately predict the clinical course. And there's a lot of literature out there to support that. But probably even more importantly, all the patients that we treated pre-symptomatic and all the siblings, it was too late to be treated, and we know exactly when those individuals when those patients unfortunately deteriorated. And there's a lot of evidence, again, to show concordance between sibling pair. So if the older sibling deteriorates at 2 years, it's very, very likely that the youngest something will deteriorate at 2 years, it will take a couple of months. So I think that body of literature evidence and also support from patient bodies and KOLs gave us -- gave the FDA a very clear guidance on that particular point. In addition -- as far as the natural history comparator arm is concerned, again, it's one of the largest that has been assembled in this disease. It's operated by other registry data, which supports what we've seen in our natural history comparison data. And also we had an independent review committee that the FDA guided us to putting together who looked at all of the data in the natural history as coward. And again, there was a lot of consensus between what they -- how they adjudicated on that and what our investigators at adjudicate that. So I think all of that cleared the concerns that the FDA may have as far as the clinical package is concerned, that's why we were able to proceed then to request a free delays. We're still in -- we've had a lot of interactions with them on the CMC package as well. And it's really about the CMC comparability given that this program has evolved over the last 10 years or so. And so that is something that we're actively in discussion with, and we're getting questions which we're responding to, and we'll have an opportunity to discuss that out of a pre-BLA meeting or even during the review period. So I think as I say, we have to get through the next step, obviously, but I think we feel that we're in a good place to be able to do that. Depending on what comes out of there and whether there is further work that needs to be done, I think we're currently anticipating a submission in mid-2023, having had the minutes back and then going forward to put forward to for. So if that is the case, then if we submit in -- we have a file acceptance in mid-2023, then we would be looking. And I think we unlikely to get priority review given the nature of this disease, and that would be a first half approved. So again, it depends on what comes out of pre-BLA meeting is the work that we would need to have to do before we do so. But we're kind of -- I say, I would kind of put forward a guideline to that.

Right. Okay. So this is MLD now. So you also have a program on us getting into a pivotal study in MPS I and then a slightly earlier stage in MPS IIIA. So I mean, given a lot of these interactions you've been having with the FDA, maybe not even on the nitpicky things, but really maybe bigger picture study design, getting again to the same understanding of clinical endpoints versus biomarkers. I mean what can you tell us about how you're thinking about designing the pivotal study for MPS I? I know a few of you are in these MPS indications here. And then if you think based on that, and you're thinking for the MPS 1 pivotal study, if there is some kind of carryover to MPS IIIA or other potential...

Yes, sure. So for MDS 1, it is different because there is a standard of care, which is an allogeneic transplant. And the allogeneic transplant outcomes show survival, but there are important parameters that are not well addressed by an allotransplant. So there is cognitive decline. And importantly, there's very -- we see very severe skeletal, musculoskeletal abnormalities as well. So these kids have joint movement problems, they have for growth, their skeletal dysplasias, et cetera. And what we've seen in the proof-of-concept stud, 8 patients treated follow-up now ranging from 2 years to 4 years in these patients. So quite significant follow-ups that there is stabilization of cognitive function, but also the [ musculoskeletal ] are significantly improved. So all these patients are on the normal growth parameters, there's improvement in joint function, et cetera. So there's a lot of excitement about what this can offer over and above what a transplant can be. So we -- as I think we've talked about that, that needs to be a randomized study, it will be 1:1 40 patients randomized to either a transplant or to autologous gene therapy. And then the dialogue that we had with the FDA was really about constructing the endpoint. And that brings into play both the safety features, which would be death, drop versus host disease, return to enzyme [indiscernible] failure of therapy. And also importantly, efficacy outcomes as well, such as cognitive fine and grid. So that gives us an opportunity to address both the limitations, both the safety limitations and also the clinical limitations and it's successful, again, adds to the commercial value. So I think in terms of read-through from MLD to MPS I, I think it is slightly different. I think the main reason has really been kind of understanding of the disease and the limitations of what's currently available. I think there probably is a greater read-through from MPS I through to MPS IIIA because for MPS III, there is no standard of care. But like MLD, there's no enzyme replacement therapy or transplant. So I think what -- and given where we currently stand, a pivotal study in MPS IIIA would need an appropriate natural history comparator on. And I think some of the learnings that we've had with the FDA on MRD could then translate to how we do that for MPS IIIA. I think your other point, which is -- which was mentioned previously as well, is the ability to use biomarkers that could reasonably predict clinical outcome, and there is guidance from the FDA with respect to that. And I think it's understanding what the literature and the evidence suggests about a correlation between a biomarker and clinical outcome. And I think for MPS IIIA, there has not been very well established so far as to how the improvements in biomarkers and substrates, does it result in improvements in [indiscernible] consensus. I think there's still work to be done there to establish a body of evidence that could accurately or more accurately speak to being able to use that as a -- to use a biomarker as a sole [indiscernible]. I think there's an opportunity in MPS I to do that. I mean we have an endpoint construct that's already been agreed by the FDA, but we wanted to think more about using a biomarker as well, that's another opportunity. And so that's how the said will...

Right. So I think that's actually a great segue to will. I want to talk about looking at really trying to understand, again, biomarker correlation to cognitive improvement, specifically in GM1. So I know you guys released some really encouraging biomarker responses and early signs of cognitive improvement in your GM1 treated patients. Again, this is an AAV gene therapy that's administered ICM. I did want to ask specifically for GM1 patients and I think we see this in your study so far, but I think this is clear for the GM1 patient overall. Some pretty wide symptomatic variability. So with that in mind, I mean, when you're looking at things like [indiscernible], do you see one scale as potentially more useful than the other, whether that's trying to draw this correlation with biomarkers or you've been just trying to understand how that deal will react to the data?

Sure. So based on our discussion with the FDA, so clearly, the daily scale is what they are most interested in seeing. So something objective that is done by a clinician. Looking at our own data, we haven't seen one particular functional area jump out because there's such a heterogenous group of patients who are coming in. I will say based on our discussions with them, when you look at finding a single objective, replicatable measure something, say, for instance, like the achievement of Citi. So it's going to be different for early infantile than it is for late infantile. Early infantile patients generally never achieve sitting, whereas late infantile do achieve sitting. So if you have a great metric like that, it could be a great potential single binary endpoint for early infantile patients. But for late infantile patients, you won't be using it in the same way. You could potentially use it as part of the inclusion or exclusion criteria. Now you also asked about biomarkers and correlation. So what we've seen in GM1 preclinically is a very clear correlation between dose escalating dose, improvement in biomarkers, so a decrease in GM1 gangliosides and improvement in clinical response. So that's in our preclinical models. What we've seen so far, as you alluded to in our Phase I/II study is a nice correlation between dose and GM1 ganglioside decrease and also increase in beta-gal activity. What we are -- what we've also noticed in our first 6 treated patients is that those patients who have less developmental delay at time of treatment seem to do better with our treatment. And so what we're looking forward to in the next phase of our trial is going -- is 2 things. One, we're going to a 1/3 even higher dose because we've seen such a nice dose response and because the toxicity profile has been so favorable. And we're also going to be narrowing our inclusion criteria to target patients with less developmental delay at the time of entry.

Right. Okay. So I mean this is GM1 program. And I did also want to ask since I'm now realizing about half of you on the panel are in FTD-GRN in one form or another. Can you give us a sense of how it's been where you are in terms of launching sites for FTD-GRN and maybe any potential challenges you've found now that what was a very rare disease, what is a very rare disease, but really had very few options just a few years ago is an increasingly crowded space. So kind of what's the cadence of when we could potentially see initial data from a...

Sure. So we have 3 open sites right now, and we'll be opening 2 more sites in the upcoming months. We've seen great momentum in patient interest. So we have multiple GRN positive patients at our active sites who are interested in joining the trial. I think one thing to say about being a gene therapy in this space is particularly for patients with frontotemporal dementia, going to the doctor, or going to the hospital multiple times they have a behavioral aspect of the dementia where going to the doctor is not something that they want to do. So the attractiveness now for recruiting and also in the future of being a onetime therapy, we do think it's differentiating and it certainly has helped our recent recruiting so we're really looking forward to second half of this year, sharing data from cohort 1 of our FPD trial.

Great. So in the last minute here, I'd love just maybe one sentence answer from each of you going down the line here. What do you think the biggest surprise in the development of therapies for orphan neurology, maybe over the next 10 years would be, Gary, maybe we can start with you.

Okay. Well, I work for like some a little biased, but I think we're going to see that modulation of the brain immune system is going to be able to provide benefits to a whole host of diseases from genetic and sporadic rare diseases. And that's on the basis of the fact that the immune system of the microbial sells primarily provide for neuronal and brain health in pleiotropic ways. So I think these will be helpful inhibition as add-on or as a stand-alone therapies to help protect the brain against various pathogens, threats and diseases.

Essra, what do you think the biggest surprise will be?

So potentially an increased focus on gene regulation and really considering the expression of the gene, whether it's at the epigenetic level, transcription or transitional level, apo neurological diseases.

All right, Ryan.

Yes. So early diagnosis, biomarker-driven approvals. And obviously, with some bias the ability now to access the brain will help us transform therapies.

Bobby?

Well, I'll go from one sentence to one word, and that's a cure.

Well...

So I'll say 2 things. First, the combining of 2 mechanisms into a single delivery vehicle for both monogenic or non-monogenic diseases. And then to the idea of cure, I think we're going to go from these diseases being a fatal diagnosis to more of a chronic management...

And Emil.

Yes. I think the most important thing would be to see a breakthrough to FDA and understanding how the underlying science of a biomarker that's a source of disease is not just a random associate chemical, but it actually is the disease. And if you measure them, we will make good decisions and that the biomarkers that are the primary disease activity type biomarkers are ones that will change the future. And if they -- that they will break through on this topic. They will start accepting those type biomarkers for diseases that treat underlying cause, and we'll see this enormous number of new therapies come out first ever for a live diseases. We're filling to promise that really all of these precision medicines have given us. And I think in the FDA, we'll put out exciting press release of how proud they are of all these things they've accomplished. And I'm happy to have them on the back at that time after that breakthrough. We all do.

All right. Thank you very much, everybody, for joining us. Thank you to our team analysts. I appreciate it.