I'm Sumant Kulkarni, one of the biotech analysts here at Citi, and it's my pleasure to be hosting our neuromuscular disorder panel. I'm joined by my colleague, Yigal Nochomovitz, and we have a very diverse range of companies up here, so it should be a good discussion. I'd like to introduce Richard Daly from Catalyst Pharma, CEO. Then we have from Wave Life Sciences, Paul Bolno in the center there, and then we have Bo Cumbo from Solid Bio. Thank you all for being here today.
Yeah, thank you.
Thanks for having us.
Thank you.
All right, so as I mentioned, you have a pretty diverse panel here, both the modalities, stage of the company, and there's a little bit of overlap on some indications, though, which we'll get into. But maybe we could just kick it off with sharing a little bit about your business model, the types of drugs that you're developing in the neuromuscular space, and what we can look forward to in the future in terms of some exciting catalysts upcoming. Rich, would you like to start?
Sure. So we're a commercial-stage company. We're a buy-and-build organization. We don't have development or research programs, unlike our colleagues here. So we are focused in CNS and muscle space. We have drugs for Lambert-Eaton myasthenic syndrome, Firdapse. We've been on the market since 2019, and the product's growing very, very nicely, really focused on the orphan space. And we also have a product we just launched for Duchenne muscular dystrophy. It's a corticosteroid, a very interesting product. They're doing very well in the marketplace. We launched it in March and it's having a very nice uptake in the market. And then we also have a drug for epilepsy, which is obviously not in the rare space, but we continue to be interested in epilepsy for rare disorders as well.
Great. So Paul Bolno from Wave Life Sciences. We're a development-stage biotechnology RNA medicines company. And I say RNA medicines in the broadest sense possible in that for the last now over a decade, we've been investing in building a proprietary novel chemistry engine for building what we believe to be best-in-class guide strands. And where we're deploying that across the RNA medicine space is across silencing in the case of what we've done with Huntington's, so the first allele-specific silencing therapy for HD. That data read out earlier this year with a 46% knockdown of mutant Huntington, preservation of wild types, so again, the first allele-specific therapy. And we'll talk later, hopefully, about the progress that we made on the regulatory environment with a potential pathway to accelerated registration using caudate.
While we're on this panel, we did deliver our data in DMD on exon skipping and muscle delivery. There we see a strong distribution to muscle, 9% dystrophin production. We saw that consistent across patients, reduction in CKs, improvement in muscle health and stem cell distribution, and we'll have our 48-week muscle biopsy data in the first quarter, and there we'll really be looking to not just see dystrophin and what happens in terms of the continued production of it, but importantly, being able to look at clinical endpoints like 95% stride velocity and time to rise, so looking at other clinical endpoints. We also had the first RNA editing data.
So really taking the platform forward in terms of driving a whole new way of thinking about RNA medicines, which is correction and upregulation, alpha-1 antitrypsin data recently where we showed the production of 11 micromolar of protein, 60% of that being M protein. And that was at a single dose in the lowest dose cohort, so more multi-dose data coming into next year. And the last part on the RNA medicine front is our obesity program in INHBE, the first novel genetic target using our siRNA format. And that'll be filing at CTA this quarter and in the clinic first quarter of next year.
Yeah, thanks, Paul. Bo Cumbo, Solid Biosciences. And we're a precision genetic medicine company that's focusing mainly on cardiac and neuromuscular targets. Our lead program, similar to Paul, is in Duchenne muscular dystrophy. And we're already in the clinic. We've dosed three patients very safely, thank goodness, and we're going to continue to dose going forward. We'll have a data readout on the first three patients in Q1 of next year. We also have a real exciting program, our first cardiac program. We have multiple cardiac programs. Actually, we even announced this morning that we signed a deal with Mayo Clinic on six additional targets with their suppression-replacement gene therapy replacement program. And we're real excited about that collaboration, but we have our first cardiac program going to file for IND in the first half of 2025 for CPVT, catecholaminergic polymorphic ventricular tachycardia. It's a mouthful.
But we're very excited about that program. We're leading the way. We're the only company that I know of that's in the space doing what we're trying to accomplish. And then we have TNNT2, FA, BAG3, other programs following behind that. We also build our own capsids. We think everything in gene therapy revolves around delivery. And so we focus on not only our CMC aspects of making sure we have a pure product, but then we focus on capsids that target specific muscles. And the capsid that we're using, for example, for our Duchenne program is a novel capsid never been in humans before. It's called SLB-101. It's a peptide conjugated AAV9 to where we can target transferrin receptors on skeletal muscle.
We’re very excited about that capsid in general, which is another reason we were happy to see that our first three children did very well in Duchenne to date.
That's great. So thank you for that. And you all mentioned that you have a DMD program. So maybe let's just focus a little bit there. And again, all very different ways of helping to treat these DMD children. So where do each of your drugs fit into the landscape? I mean, I think that they can all kind of be used. And is it an age difference? We can layer all of these on depending on a combination sort of therapy. I'd love to just hear your thoughts and maybe you guys can have a quick discussion on where each of these fit.
I mean, I think our approach from the beginning has been really focused on production of Becker-like dystrophin protein using exon skipping. I think we've looked at the field. We look at Becker patients, and we realize for this community that generating that functional protein ultimately can change the outcome and lives for those boys. So stepping back and thinking about how we approach DMD and why N531, starting at exon 53, was really reflecting, as you said, on the space and what the needs for in the space. And I think all of us can attest to discussions with the community that there is an enormous amount of unmet need in the community based on the current available therapies. So for us, it was really about addressing a couple of key features. One, truly producing dystrophin. Can we see splicing?
Can we get muscle concentrations, skipping protein, and ultimately see that translate to clinical functional benefits? Where we started was the ability to get to muscle. We see 30 times the delivery to muscle than the transferrin conjugates. So a lot of exposure into the muscle, but without having to put an exogenous conjugate on. So our PN modifications on chemistry are getting accessibility, retention without having to use peptides or transferrin and the liabilities that come with that, as we've all seen. So that gets us exposure. We then saw that that could translate to high degrees of skipping, so 57% skipped transcript, and ultimately that translated to 9% dystrophin. So again, protein exposure, protein skipping.
And so as we think about that going forward with durability, the last piece we were seeing beyond the consistency that we saw that expression across the boys in the study was now the potential for monthly dosing and a safety profile that looks similar to standard of care, so the PMOs. So as we think about kind of the current context, it's to start with exon 53. We've got that profile. We'll deliver the 48-week data. That should tell us about what's happening with protein over time. Do we continue to see that protein increase?
But we already feel like we're at a threshold where we should begin to see separation. While not powered for clinical differentiation, we should start to see, given that time horizon of a year on therapy at those levels of dystrophin, starting to see separation on 95% stride velocity, time to rise, and other clinical measurements. If we think about building out from there, the goal is really to walk across the various exons. So we have data preclinically on other exons that have as good, if not better, skipping across 51, 52, 44, 45. And so the goal is to continue to build out across the exon skipping landscape with the production of functional dystrophin protein.
Yeah, I agree with everything that Paul said regarding what his company and what his drug is doing. I'll take a little bit of a different take on where the future is going to go. And I spent 15 years in HIV. I started in HIV in 1995, and I think I finished in right around 2010. And over that period of time, we went from patients literally dying to getting to a point where it was a chronic disease and manageable. And some of the lessons I learned there, I think, apply to Duchenne. And it's how all these combination therapies are going to play a role until we find a true cure. And I see a world in the future where with Rich and his drug working on inflammation and Paul's producing full-length dystrophin, and I'm producing a microdystrophin, and they're all coming together in combination therapy.
This is after our clinical trials and after we get on the market. But I do see a world where all these drugs play a major role in the future of these kids because you are going to meet these children at different age points and different parts of the disease, different exons to Paul's point. And there's a wide variability in Duchenne. And I think it's just going to take a whole host of drugs. And I believe that the future is going to be bright for these kids because there's a whole great group of companies that are working on very exciting next-generation technology. I also see a world that redosing is going to play a role in many of these therapies.
Paul doesn't have to worry about that from an AAV standpoint, but if you're going to be an AAV, you have to think about the future of potential redosing. So then you have to think about how you lower these antibodies and get down to a threshold and dose, transduce, and express in a very specific time. And you have to have technology that can do that, can transduce and express in a very narrow period of time, 10 days or less. And that's why we work on capsids with high binding capacity that can transduce and express in a very quick period of time. So I think that the world is going to be a much better place in the future for these children because of the work that Wave and Catalyst and we're doing. And eventually, these drugs will come together and hopefully transform the kids.
So I agree. I think this is a really exciting time to be. As challenging as it is to be in Duchenne and to be a caregiver or a patient, this is an incredibly exciting time to be in this space. Steroids are the foundation of therapy. And when we look at the work that's being done by Wave and by Solid and by everybody else, it's just so exciting. When we deconstruct the market, we take a step back and we look at the 11,000-13,000 boys and young men that have this condition. And we think about what's going on with these young men. The challenge is from a steroid point of view, 95% of them have been on a steroid and only 70% are currently on a steroid. And why is that? And we classify it as the problem of the twos.
They start too late, they're on too low a dose, and they stop too soon. So the current therapies are not adequate. And so if this is a foundation and it prevents inflammation and it helps in the current therapy compendium to help prevent any type of inflammatory reaction, what are we going to do? Can we offer a better alternative from a steroid that would help them start earlier, stay on the right dose, and stay on longer so that they can stay ambulatory and even after they lose ambulation, maintain dexterity? These are the critical things that matter to these young men. And so when we look at the opportunity, we think that all of these advancements are incredibly exciting. And all of them, I think, have an opportunity to work together. And we're just really excited.
This is what we think we offer when we think about the drugs that we bring forward, so we're really excited to be here, and we think all of it fits together and fits together really, really nicely. We get asked all the time, "What do you think about all these other therapies?" and the first response we have is, "This is incredibly exciting. This is good news for patients, for providers, and for caregivers as well," so we're excited to be here.
It's awesome. I just also think about, I mean, you had asked the question, I think, too, about how we think about the different paradigms of where treatment is. And I think where DMD has spent a lot of time on the therapeutic space is focusing on ambulatory boys kind of in that mid-cycle stage of disease. And where I think we're seeing an opportunity, and obviously, this is where one begins, is really in the other bookends of life, meaning the earlier setting and how do you get into the earlier treatment setting. I think the work that we've done that sees stem cell distribution, getting into those regenerative cells early, producing dystrophin, and actually driving that restoration lets us think differently about how do you get in early and actually preserve muscle function over time as opposed to trying to come in and rescue and treat.
I think the other opportunity we see is in the later setting, in the non-ambulatory setting, where our data preclinically, both in NHPs as well as in the double knockout show, we're actually getting higher levels of exon skipping and protein production and heart and diaphragm and skeletal muscle. So our skeletal muscle data is probably underrepresenting the exposures that we're getting elsewhere. And in those tissues, that's where actually those boys you want to preserve respiratory function, cardiac function. So I do think about how we all kind of think about this development landscape that obviously right now the focus is in that ambulatory setting. But I do think both early and late is a tremendous opportunity.
Yeah, and I'd like to piggyback off that. I think that's a very important message there. And the non-ambulatory boys, they're the ones that actually have less time. And we really need to be urgent in driving drugs to them and to these kids and these young men. And that's why we do the same thing that Paul's talking about. So we spend a lot of time looking at diaphragm as well as heart and how can we transduce and express in the diaphragm and the heart to help these children that have already lost mobility. They might not even be able to move their upper limbs, but they still need the heart and the diaphragm to function.
And so the capsids that we work on are specifically for heart transduction or diaphragm transduction to address the population that Paul is talking about because I think that's, unfortunately, because of the way that regulatory, maybe not for you, Paul, but for us, thinking about endpoints on stride velocity or six-minute walk tests, even though we don't do that, but six-minute walk tests, 10-minute run walk, they're all for ambulatory children. And the kids that actually need it the most are the ones that are not going to have those endpoints. And so it's a valid point. We need to focus on how do we get to the heart and diaphragm for these young men?
That's a really good segue then. I mean, can we talk a little bit about the regulatory environment for DMD specifically, but more broadly for just across neuromuscular disorders? What are you seeing and how do you think about those endpoints where it's maybe a little bit more difficult for some of the populations for those children?
Yeah, I mean, we can all have discussions of the evolving regulatory landscape, but I'm an optimist. I think you have to be in our space, and so I think actually for drug development, everything that we're seeing, we're hearing, and I can speak to that after we're coming off of our interactions in Huntington's. I think continues to support that it's an agency that's interested in working with patients and families to make sure there's medicine, so I think that's encouraging as we think about drug development. I think what's incumbent upon sponsors and drug developers is to have those interactions and to think through what those endpoints are and how do you demonstrate that.
I think case in point. I'll kind of give a Huntington's example, but I think there the agency has been working for a while recognizing, and we have seen a big shift from an agency that I think viewed Huntington's for a long time as a disease that was probably more akin to Alzheimer's. Here's a neurodegenerative disease over time and realizing that this is a severe, devastating neurologic disease that's killing patients and really making that paradigm shift and acknowledging that and even recently having closed-door meetings with the patient community. I do think the agency is sensitive and trying to think through how do you have surrogate endpoints. I think the age-old challenge of, well, give some grace.
I think the challenge that they always have is what are those endpoints that are going to give confidence on both sides that medicines are delivering? And I think in the case of Huntington's, the data around, in this case, caudate atrophy has become pretty astounding with the investment that CHDI has made in Track-HD and Enroll-HD, two longitudinal outcome studies that show that rates of caudate decline is steady, whether you're in stage one of the disease or stage four, and that becomes a steady biomarker of erosion. And that's correlated with clinical surrogate endpoints like Total Motor Score, TFC, cUHDRS. You can now put those pieces together. And so therefore, being able to use that as a clinical surrogate endpoint to demonstrate.
And so I think these are examples of the agency really working with sponsors and working with families and patients to realize that on one hand, they want medicines and two, they need to draw that connection. I think DMD is a great example with dystrophin. I mean, if you think about the field before Sarepta and Exondys and the work that you guys did, there was a big gap of how do you develop that with clinical endpoints that could take a while to develop in patients who are waiting. And so I think the key is, and what's incumbent upon sponsors always is how do you close that gap in thinking about confirmatory studies and how do you demonstrate in the end that that is translating to clinical benefit?
And so I think that interaction and the agency's openness, and we're seeing this now across multiple programs, I think is a positive signal to the field, but we'll continue to take dialogue in various areas as people go into new areas and broach new endpoints.
Yeah, I think using real-world evidence too as well is critical in a rare condition. And so we're funding a study that looks at some of the benefits that we believe we can bring forward. So steroid use, typically patients who use steroids develop aggression. And so if you have a product that can reduce aggression and keep the patient on the right dose or growth, even though the young man may be in a wheelchair at some point in time, self-identity and their self-perspective matters and their height matters to them. They want to be like their peers. They want to be tall. So this becomes really important and the bone strength becomes really important. So we work with the FDA on identifying how we can have a real-world study because we don't want to have a study in which we have a control arm.
So working with the FDA to look at the side effects and then say, "This is a way to approach it." So I think the FDA, as Paul said, is really open to this. And I think we're looking at ways that we can deliver real value in the form of data to patients that can make a difference. And I think the agency is being as flexible as it can possibly be.
Yeah, and I'll just comment. I was happy to see Dr. Marks present, I guess, speak at the Broad Institute a couple of weeks ago in which he mentioned that accelerated approval for other gene therapies are still on the table. And so it's not one and done from an approval standpoint. He commented that all the other companies or all the programs are going to be looked at individually. And so accelerated approval is on the table for multiple companies. And I think that's great, not just for Solid, but for REGENXBIO and for others who want to develop next-gen therapies. To leave the door open shows that the FDA is thinking about the future, thinking about next-generation therapies and exon skipping as well as gene therapy and making sure that the door is not shut.
And doing what he did the other day and communicating that in an open setting is helpful for everybody in the field. And so grateful for the agency's flexibility. I think while the approval most recently might have been surprising to some, I think it's good for families. And it's good. It shows flexibility. It shows the community and the FDA care about the market and the future of Duchenne and eventually will hopefully cure this disease because of it.
So you've mentioned the capsid technology a few times. Do you want to expand on that a little bit and how you do the targeting with the peptides to the different tissues and what sort of tropism do you achieve?
Yeah, no, we spend a lot of time. So one of our pillars in our company is delivery. Gene therapy is very challenging, as we all know. And I fundamentally believe that the next gen is all around delivery. And delivery is three flavors for us. It's CMC purity, meaning how full or what percentage of full capsids do you have compared to partials and empties. It's promoters driving to specific tissues. And it's the capsids. So for the capsids, we do a lot of work there. We have directed evolution platform where we mutate millions and millions and millions of capsids down to liver de-targeting and specific for the target tissue, whether it's skeletal or cardiac muscle. We use three different animal species, so we don't rely on just one. And so we use pigs, non-human primates, and mice, and then take a holistic look at everything.
But for the other capsids, the one that we're actually using in Duchenne, it's hand-modified and it's integrated. It's a RGD peptide insertion plus some point mutations here and there specifically for integrin receptor. We never disclosed the integrin receptor. This receptor that we're using is specific for skeletal muscle because we already knew that the capsid was getting broadly to the heart. And we're actually targeting, and to Paul's point earlier, we're actually targeting some of the patients that we're looking at with underlying cardiomyopathy or the beginning of cardiomyopathy. And can we help reverse that in the long run? And so we're taking a hard look at that, whether we dose additional patients to be determined. But yeah, the capsid work we're doing, we believe, is beneficial for all the next-generation drugs.
We have to get away from the AAV9s, AAV8s, the AAVrh74s, and become very specific for targeted tissue, and so that's why we spend a lot of time on it now.
Can you give us a little bit of a flavor for how good the partitioning is to the different tissues?
Yeah, yeah, yeah, yeah. I mean, once again, going back to Paul's point, the capsid I'm working on is 10 times greater, 10-fold greater biodistribution in diaphragm than AAV9, and AAV9 was already doing pretty decent in diaphragm, but we're thinking about how do we help these kids in Duchenne that have nothing left but the heart and diaphragm and intercostal muscles, and so 10-15 times. Some of the capsids I'm working on for the cardiac side of the business, thousand-fold greater than AAVrh74, which was the parental capsid that we were using at the time, so those are not the ones for Duchenne right now, but that's for future cardiac programs and completely liver-free targeting. The future is going to be bright in gene therapy. It's just right now doesn't really reflect it.
Okay. Paul, I wanted to dive a little bit deeper into the DMD data that you presented earlier this year. One of the things you showed is that you were able to get into the stem cells. Maybe you could just elaborate a little bit about what you've seen, why it's important to be in the stem cells, and what is different about your product that's allowing you to achieve this?
Yeah, I mean, it starts fundamentally at the building block of, as we say, building the oligonucleotide. And it really comes down to the phosphoryl guanidine in the PN modifications. So proprietary chemistry we've been using really since about 2020 in the next generation of the pipeline. And one of the things we've seen with that is we presented at an R&D day recently demonstrating kind of how not to have it be this black box of it seems to be working and editing and silencing. And we have 30 times AGO2 loading over best-in-class siRNA. And that was in a paper a while ago. And we've got a lot of questions of, well, what is it about the chemistry that's driving that? And we see a couple of features that it's a neutral backbone modification. So let us take about four of the oxygens off the backbone.
In and of itself, actually, it was driving an increase in endosomal escape. We're getting better cell accessibility, but we were actually getting better intracellular delivery. It was also driving stabilization that we saw intrinsically, not just, and I know we talked a lot about delivery and the oligo world talked about delivery too. Not only is it about delivery, which is, we spend lots of time on drug in, but it actually retains drug. It focuses on reducing drug out. The ability to have with the catalytic enzyme and catalytic efficiencies, this is not the case in splicing, but at least when we're thinking about RNAi and AGO2 and RNase H and ADAR for editing, the drug's highly efficient.
If we think about the next generation of skippers that we move forward from our first generation to then N531, looking at the double knockout mouse, which we thought was just a much better way to do screens where you have a mouse that actually has a phenotype, dies at eight weeks, rescuing is all about dystrophin restoration. You can look at respiratory endpoints. You can really study the impact of the medicine in that model. We could see that translate. So we could see the chemistry translate. And then as we looked at the functional benefits, we saw restoration of respiratory tidal volumes back to wild type. We could then actually go back in section.
What we saw in the animal model, so this was before we even got to humans, was that we were getting not just skipping and muscle protection and survival, but we're actually getting exposure to the stem cells in the model system. So that was kind of the first insights that, okay, these distribution parameters look different. It was not just getting into the skeletal myoblasts themselves and the cardiomyoblasts. It's actually getting into restorative regenerative cells. When we ran the first exploratory study in patients, that was the three-patient study. They got six weeks, three doses. And we saw in that study that we had substantial skipping, 53% skips transcript. We had 42,000 nanograms per gram of drug in the muscle. So an extraordinary amount. Again, that was about 20 times the amount seen with the transferrin conjugates.
We also saw in those same boys distribution to the stem cells. So we saw great translation between the preclinical model systems and then ultimately in DMD boys and continue to see that out at six months. And so that's exciting as we think about the regenerative potential of muscle. So again, even in boys who are ambulatory, that need to restore muscle fibers and having those stem cells that can now produce dystrophin be part of that restorative muscle fiber are not just transfecting the cells that are going to be helpful in maintaining and sustaining potentially ambulation. It's also about those cells that are filling that in.
And I think that really opens up that prospect, as I say, to think about getting in earlier in the disease setting of what happens when you're not just rescuing cells or at the end of that fibrotic cell, but how are you getting into developing boys where actually the stem cells are going to play a much greater role in terms of population of muscle. So it was an exciting finding both preclinically because it hadn't been seen before, but ultimately great to see that translate into the human clinical trials.
Yeah, agreed. Rich, for you, you had an Agamree launch. It's been about two quarters and change now that we've seen.
Yeah.
Yeah. So I mean, quite strong launch. I guess, can you just talk about, I talked about it a little bit, but maybe elaborate on what are the drivers there? What are you seeing in terms of the market dynamics on who is moving to AGAMREE? And what can we look forward to as launch continues?
So the market drivers, I think, are the profile of the product. So we have data that shows that the patients have a better behavior profile once they're on it compared to traditional steroids. There is some clinical data that shows that there are patients who could have improved growth pattern, improved stature, and potentially bone health as well. But the behavior pattern is what is playing out in the marketplace, obviously, because it's almost immediate. So we're sourcing patients from, this is quite surprising, actually, the two major players in the marketplace before we got there were generic prednisone and Emflaza. And we're sourcing patients equally from both, about 45% from generic prednisone and 45% from Emflaza and then 10% from de novo patients. Prior to the launch, we saw this as a cannibalization opportunity almost from Emflaza.
And so when we see this and it's consistent from the launch all the way through the most recent data at the end of Q3. So it's quite surprising. And we're thrilled because the profile is bearing up and physicians are happy, the caregivers are happy, and the patients are happy as well. So it's quite astounding to see this. And as I said before, one of the reasons why we're doing this safety study is to then build on the data set and continue to build the story for the product. It's a very attractive product profile and a very attractive launch. So we're really thrilled at this point.
Do we know when we'll see the first data from Summit yet?
So we're enrolling patients. There's 250 patients in it. It's an open-label trial against standard of care that's out there. So we think we can pull data probably within about a year, but we're not sure. So obviously, it depends on the speed of enrollment. But we're going to do it as quickly as we can. And we're not really constrained so much by the enrollment per se because it is open-label. We can see what's going on. But if we get that behavior right away and we get those behavioral endpoints quickly, then I think we can take a look at the data. So we're hoping a little more than a year, I think.
Got it. Okay. And then your business model, you are pretty active on the BD front. Can you just maybe just talk about what type of opportunities are most exciting for you and maybe something, a flavor of what we could look forward to?
Sure. So we love the CNS area. We feel like we have great expertise in CNS and then also in muscle and movement disorders. And so we like this space a lot. And we feel like this is an area of opportunity for us. We would love to stay in Duchenne's. We have a real great affinity for the community, and we want to spend a lot of time here and a lot of effort. So we're looking at this. We want to be looking at opportunities that are immediately accretive or nearly immediately accretive. As you see with the Santhera opportunity with Agamree, we took on regulatory risk, which was a little bit new for us. And then we're working our way back in the pipeline. So we're looking to potentially partner with companies that have development capabilities and work with them as they develop their products.
And then we bring them to market and partner with them. It's classic rare orphan opportunity. Those are the kind of opportunities we want. But we're agnostic to therapeutic area because we believe our infrastructure supports just about any orphan space. But those are the kinds of opportunities we're looking for.
Exciting. And then, Paul, if I could squeeze one more in for you. We're going to have updated DMD data in the first quarter. And we should hear, as you were kind of alluding to, a little bit more about your next steps in Huntington's, I think, in the new year as well. Can you just give us a flavor of what we should expect from both of those? Then I'll turn it back to you, Yigal, after that.
Yeah, so next year, first quarter, we'll have both the regulatory feedback off of the six-month data in DMD and the 48-week data for biopsies, so again, beyond dystrophin, really looking to see a separation on clinical endpoints to drive a decision forward. Separate from that, to your point on HD, the next step for that is IND in the second half of the year, and that'll be the beginning of a potentially phase two, three registrational study, so that's focused on the primary endpoint of caudate atrophy, and then we'll have our multi-dose data for AATD and INHBE dosing and inhibiting for obesity first quarter.
Okay. Let's just squeeze a few more in for you, Bo. 003. So you had some safety data, I believe, recently over the summer. And then can you just kind of recap that for everyone? And then you have an update coming in the first half of next year. What are we looking forward to there? And then beyond that, can you just frame out the commercial opportunity for 003 in DMD?
Yeah. So we're very excited. We dosed our first three boys already. And no SAEs, knock on wood or plastic, whatever I have here. And we're going to continue to dose. And so we're starting to screen now. We're going to be dosing our next child soon. And very excited about that. Readout will be Q1. And what we're going to be looking for is muscle integrity. And I think that Paul slightly touched on it here. It's like at this stage, I'm going to be three months in. So we're taking a biopsy at 90 days. So you're not going to be looking for clinical benefit at 90 days. What you're looking for is muscle integrity shoring up and signs that you're producing dystrophin, looking at dystrophin-positive fibers and looking at biomarkers to see if there is activity within the child's muscle.
That should give you a lot of confidence that over time, you're going to start separating out clinical benefit from natural history or a placebo-controlled trial, depending on the trial. But it all starts with muscle integrity, making sure that you're producing dystrophin, getting up to a steady state of positive fibers, and you're seeing biomarkers that are all aiming in the right direction. That's what I'm going to be looking for. Because safety, we've already announced safety for these three boys. No SAEs. We only use steroids. We didn't use other third agents, that sort of steroids. So we feel really good there. Now it's about muscle integrity. That'll be Q1. We're going to go to the agency. We're going to be going after accelerated approval in the United States.
We're going to be looking to dose additional patients, go to the agency sometime next year. We'll update the Street when we do so. We'll hopefully get feedback next year, and then that'll start our process for working toward accelerated approval. We will be doing a double-blind placebo-controlled trial ex-US, because you need it for reimbursement. As a commercial guy, I know how hard it is in France and U.K. and other countries to get reimbursement with natural history or something like that. They really want to see a double-blind placebo-controlled trial. I can use that trial for confirmation for the United States accelerated approval. However, realistically, I'm using it so I can get reimbursement for the children ex-US that need a drug. Because we sit here and we talk about the United States, but there's 280,000 kids that need Paul's drug, my drug, Rich's drug.
So we got to work on that as well. And so there's a lot coming on in 2025. And I'll knock on plastic again that things are good right now.