Taysha Gene Therapies, Inc. (TSHA) Earnings Call Transcript & Summary

Good morning, and welcome to Taysha Gene Therapies 2023 R&D Day. [Operator Instructions] As a remainder, this webcast is being recorded today, June 28, 2023. I will now turn the call over to Hayleigh Collins, Director, Head of Corporate Communications. Please go ahead, Hayleigh.

Thank you. Good morning, and welcome to Taysha's 2023 R&D Day. Joining me on today's call are Sean Nolan, Taysha's CEO; Dr. Sukumar Nagendran, President and Head of R&D; Dr. Salman Bhai, Assistant Professor of Neurology at UT Southwestern and Director of the Neuromuscular Center at Institute for Exercise and Environmental Medicine; and Dr. Azhar Rana Taysha's Head of Medical Affairs. We will hold a question-and-answer session following our prepared remarks. Please note that on today's call, we will be making forward-looking statements, including statements relating to the therapeutic and commercial potential of TSHA-120 and TSHA-102. These statements may include the expected timing and results of clinical trials for our product candidates, our clinical and regulatory plans and the market opportunity for those programs. This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway and future operating results, discovery and development of product candidates, strategic alliances and intellectual property as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials of and regulatory interactions for our product candidates, our dependence upon strategic alliances and other third-party relationships; our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities. For a list and description of these risks and uncertainties that we face, please see the reports that we have filed with the Securities and Exchange Commission, including our annual report on Form 10-K for the year ended December 31, 2022. This investor event contains time-sensitive information that is accurate only as of the date of this live broadcast, June 28, 2023. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws. I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh, and welcome, everyone, to our 2023 R&D Day. It is a pivotal and exciting time at Taysha, and we've made significant progress across two new clinical programs in giant axonal neuropathy, or GAN, and Rett syndrome. Today, we're excited to present our comprehensive data analysis from the ongoing natural history and interventional trial evaluating TSHA-120 in GAN and provide a preliminary clinical update based on early available data on our investigational TSHA-102 program in Rett syndrome. For TSHA-120 in GAN, an ultra-rare disease with no currently approved treatments, we have generated promising and robust new long-term clinical data supporting a therapeutic benefit and safety profile. In response to the constructive feedback we received from the FDA regarding our follow-up questions to the Type B, end of Phase II meeting, we have undertaken an extensive analysis of the totality of the data from the natural history and interventional trial to more fully assess the data sets and determine potential avenues that offer a feasible regulatory path forward. The new data and analyses are highly encouraging and we intend to share these findings with the FDA to further discuss the potential regulatory path forward. We've submitted a formal FDA meeting requests, which we expect to take place in the third quarter of this year. Today, we will present to you our compelling new findings that we plan to discuss with the FDA. For TSHA-102 in Rett syndrome, we are excited about the potential of our innovative miRARE technology to address the challenges that have historically limited the ability to use traditional gene replacement approaches in Rett syndrome and allow for MECP2 expression to be mediated on a cell-by-cell basis, which we believe may enhance the potential safety and effectiveness of the therapy. Just a few weeks ago, the first adult patient was dosed in our Phase I/II REVEAL trial in Canada. We are pleased to share the initial clinical observations from that patient and our anticipated clinical milestones for the second half of 2023. Today, I am pleased to have our Taysha team, together with our collaborator from UT Southwestern, provide updates on the advancement in our clinical programs. We will begin with GAN. Dr. Sukumar Nagendran, President and Head of R&D of Taysha, will provide an overview of our TSHA-120 program in GAN and walk through the recent program history, including feedback from our FDA regulatory interactions. Our collaborator, Dr. Salman Bhai, Assistant Professor of Neurology at UT Southwestern and Director of the Neuromuscular Center at the Institute for Exercise and Environmental medicine, will be -- will then review key aspects of the disease course and biology of GAN before sharing new data from the recent comprehensive analyses. Next, Sukumar will present a regulatory strategy toward potential FDA approval for TSHA-120 before we shift the focus to our Rett program. Dr. Azhar Rana Head of Medical Affairs at Taysha will provide an update on TSHA-102, including new preclinical data further supporting TSHA-102 , the miRARE technology in Rett syndrome. Key program milestones and initial safety observations from the first adult patient dose in the Phase I/II REVEAL trial. I will provide closing remarks before we begin our Q&A session. I will now turn the call over to Suku to provide a more in-depth overview of our GAN program. Suku?

Thank you, Sean, and good morning, everyone. We are pleased to share exciting progress in our GAN program. GAN is an ultra-rare autosomal recessive progressive neurodegenerative disease with no approved treatments. The clinical phenotype of GAN is driven by biallelic variance in gigaxonin gene, which causes deficiency or complete loss of function of gigaxonin and the accumulation of intermediate filaments resulting in the progressive bursting of motor function, vision, neurological and respiratory function. GAN at times is misdiagnosed at CMT2 after the physicians realized their error and do genetic analysis to discover that the patient actually has GAN. Patients typically do not live beyond the second to third decades of life. There is an urgent need for a treatment option to address the devastating impact of this disease, which is why we are encouraged by the opportunity to bring a potentially transformational gene therapy through this community. TSHA-120 is a self-complementary intrathecally delivered AAV9 gene therapy in clinical evaluation program that's designed to address the root cause of the disease. Constructed from an engineered transgene encoding the full length human gigaxonin protein, TSHA-120 is the first AAV9 gene therapy candidate to deliver a code on optimized functional copy of the GAN gene with optimal tropism and rapid ubiquitous expression under the control of a Jet promoter. TSHA-120 has received orphan drug and rare pediatric disease designation from the U.S. FDA and has been granted orphan drug designation from the European Commission. TSHA-120 is currently being evaluated in our ongoing clinical trial. The trial is separated into two categories: the natural history study and the interventional trial, which were both initiated by the National Institute of Health, or NIH. So let's start with the natural history study. In 2012, the alliance initiated a comprehensive prospective logitudinal natural history study of GAN. The study is ongoing and 53 patients aged 3 to 21 years have been enrolled today. This is the largest and most comprehensive GAN database in the world. The purpose of this natural history study was to identify reliable and feasible outcome measures for comparison to changes observed post-transfer treatment. The data of a prospectively collected for use in the TSHA-120 interventional trial. Natural history data of the first 45 GAN patients was published in the Journal Brain in 2021. It's important to understand that the cross-sectional baseline data from GAN patients with the natural history studies serve as the foundational baseline of comparative data for the Phase I/II clinical trial evaluating TSHA-120 for the treatment of GAN. Now let's discuss the interventional trial. The interventional trial is currently ongoing and being conducted by the NIH under the leadership of principal investigator, Dr.Carsten Bonnemann. The Phase I/II dose escalation trial is an open-label, non-randomized trial in which patients are intrathecally dosed with 1 of 4 doses of TSHA-120. The endpoints for this study are pre-specified with the primary endpoint, evaluating safety and the secondary endpoints measuring efficacy. The first patient was dosed in 2015 and 14 patients aged 6 to 14 years have been treated to date. We have over 7 years long-term clinical data supporting the safety and tolerability profile of TSHA-120, which we will discuss in greater detail later. Importantly, in our initial analysis present to the FDA in December 2022, an individual subjects own pre-study of leading natural history was used as comparison for all post-treatment assessments of the efficacy in the interventional study by comparing the change from baseline in the TSHA-120 treated patients during the pre-treatment and post-treatment periods. All data frommy initial submission to the FDA prior to the Type B end of Phase II meeting was based on this patient and their own control model. Interestingly, pre-clinical data on TSHA-120 showed transitional correlation between preclinical and clinical studies. With TSHA-120, GAN knockout [indiscernible], improved dorsal root ganglion pathology and motor function, both of which are translated to our human studies with improved sensory nerve integrity and of sensory nerve action potentials, as detected by nerve conduction studies and biopsy analysis and improvement or stabilization in strength. We saw similar clinical translational impact with spinal muscular atrophy and the Delta 7 mouse model, which we developed zolgensma at AveXis which showed improvement of stabilization in motor function and strength of the treatment with gene therapy that were conversely seen in human studies. Now let's discuss the history of the company's FDA interaction related to TSHA-120 in December 2022 at the Type B end of Phase II meeting with the FDA. Taysha presented a subset of the available data on the possible treatment effect of TSHA-120, significant emphasis was placed on MFM32, a validated 32-item scale for motor function measurements of neuromuscular disease as the primary efficacy endpoint in combination with supporting secondary measures as evidence of efficacy in GAN patients, using patients' historical running data and rate of deterioration as their own control. In written minutes sent to the company in January 2023, the FDA provided feedback regarding the need to address both the heterogeneity of the disease progression in GAN and effort the dependent nature of MFM32 as a primary endpoint, considering the unblinded study design, specifically the FDA acknowledged moderate efficacy, but stated that because MFM32 is effort dependent, it can be a relevant primary endpoint only in the setting of a randomized, double-blind, placebo-controlled trial. To address the FDA comments, Taysha obtained the full data set from the NIH and embarked upon the more comprehensive analysis of the entire GAN database, given the data presented at the Type B end of Phase II meeting was based on subset of the existing data. To be clear, this is the most comprehensive data available on GAN in the world. The purpose of the exercise was to determine if there was highly compelling new evidence that could bolster the case for BLA approval of TSHA-120 in GAN. In parallel, we submitted a written questions to the FDA to further clarify feedback we have received in the meeting minutes. In February 2023, the FDA responded and clarified that MFM32 can be a relevant primary endpoint point only in the setting of a randomized, double-blind placebo-controlled trial and acknowleged Taysha's challenge in designing such a study due to the rare nature of GAN. The FDA indicated it is open to regulatory flexibility in a controlled trial setting and willing to consider all narrative study designs, utilizing objective measurements to demonstrate a relatively large treatment effect that is self-evident and clinically meaningful. Since January 2023, we have been collecting and reviewing the full data set from the natural history and interventional trial that includes over 7 years of data. We have conducted a comprehensive analysis of the totality of the data, including functional electrophysiological and biological assessments and have identified several new findings from the existing data set that we believe may address the FDA concerns regarding the effort dependence of some clinical endpoints and the heterogeneity of GAN based on the subset of data that was submitted previously. Collectively, the new data analysis supports our previous findings and further demonstrates that TSHA-120 has a clinically meaningful treatment effect on patients suffering from GAN across multiple objective measures, including functional measures, such as Modified Friedreich's Ataxia Rating Scale or mFARS and the logarithm of the minimum angle of resolution, or logMAR, electrophysiological measures such as sensory nerve action potential, or SNAP, and compound muscle action potential, or CMAP, and biological/structural measures such as visual equity and nerve biopsies. The data analysis has enabled the development of our disease progression model, or DPM, that we've applied to cross-sectional and longitudinal data from all natural history from the database. It demonstrates a highly predictable and homogeneous disease progression, allowing us to utilize the natural history data as an external control. These findings will inform our upcoming discussion with the FDA regarding alternative study designs utilizing additional objective measures and ultimately, a regulatory path forward for TSHA-120. We expect a formal meeting to take place in the third quarter of this year. Additionally, recent comments made by the FDA Center for Biological Evaluation of Research Director, Dr. Peter Marks signals support for clinical trial flexibility, including expanding the use of accelerated approval for gene therapies in rare and severe indications with no approved treatments where the benefit outpace the risk. Given the ultra-rare nature of GAN and urgent need for treatment options that address the unmet medical need, we believe the FDA shift towards more flexibility in the clinical trial setting reinforces the potential for appropriate position, the companying and objective findings from our new comprehensive analysis to achieve FDA support for the sufficiency to submit the BLA based on existing data of TSHA-120 in GAN. Today, we are pleased to have -- share detail findings from the data analysis and clinical relevance to disease progression observed through natural history and why we believe the data satisfies the FDA requirements for the regulatory path forward in an ultra-rare disease with no approved treatments. I will now ask our collaborator from UT Southwestern, Dr. Salman Bhai, to provide a high level disease overview of GAN and discuss the new findings from our analysis of the totality of data. Dr. Bhai earned his medical degree from Harvard Medical School and specializes in neuromuscular disorders. He completed his residency in urology through Harvard Medical School at Brigham and Women's Hospital in Massachusetts General Hospital, where he also received advanced training through a fellowship in neuromuscular medicine and earned a medical education certificate. Dr. Bhai has been working with Taysha on the development of TSHA-120 program for over 1.5 years who has been heavily involved in a comprehensive analysis of the totality of data. Dr. Bhai, I will hand it over to you now.

Thanks, Suku, and thank you to the attendees for joining us. A special thank you to the NIH and the Taysha team, without which none of this would be possible. And of course, I have to acknowledge the patients and the families that support us. They are our inspiration, they are what guide us in what we do. And so without them, again, we wouldn't be here as a special thank you to them. Now I got to be honest, I'm excited, and I hope you are too. Because today, my goal is to give clarity to this complex disease to give you a context to apply to the data. GAN is a light shortening disease characterized by weakness and in coordination. There's more to us. That's where the complexity comes in, but stay grounded in the weakness and incoordination that brings morbidity, that brings early mortality. Now as a neuromuscular neurologist, I want to share my clinical experience with you. And the three principles of medicine that I've learned along the way that I think apply beautifully here, I'll share those with you. Number one, use it or lose it. Now I know you weren't expecting that. In the age of gene therapy, you probably were expecting something more complicated, but it's as true today as it was years and years ago. And in the context of GAN, these patients with weakness that get muscle damage because they have a neuropathy. That muscle gets bad. The muscle scars and becomes fibrotic. That limit how much recovery you can have. So because they can't use it, they continue to lose function. And that's an opportunity for us to intervene. It's also applicable in your life. So keep exercising. You got to use your muscles. Number two. Now as a neurologist, I may be biased here, with all my brain is one of the most important organs. And the further away you get from the brain, the longer the nerves are, the more susceptible they are to damage in a length dependent pattern. And the harder they are to recover. So nerves in the feet get damage first in a length-dependent disease like GAN, followed by the arms. So you can imagine that the legs would be more affected than the arms and then the legs, therefore, would be harder to recover than the arms. Lastly, the patient's experience is absolutely key for us to understand this disease. What they say is the most important thing is what matters, not mean as a doctor. The onus then is on us, the physicians, the nurses, the researchers, but also the investors, industry, regulators to help patients by finding clinical data that would support their claims, right? If a patient said they feel better, but we need to go into the data to understand what that means. Can we capture that with outcomes? So that's our goal today, and we're going to talk about that. So I'm going to try something different here. I'm going to ask you to stop taking us. I am going to ask you to just listen for a moment because what you see here, you can Google, but you can't Google clinical experience. And I want you to visually understand what patients like this go through. So let's go back to this morning. When you were laying in bed, just as a patient like this would be, you have to roll over bed and get to the edge of the bed. Patients like this struggle to do that because of weakness and incoordination. They struggle to roll over, okay, something that we take for granted. They struggle to stand up from a seated position, something we take for granted. Now their visual acuity starts to go. So say you got up in the middle of the night, go to the restroom, you may be too young for that, but that does happen as we age. And these patients, because of their poor visual acuity, it's like walking in dimmer light, so their balance is worse. Their nerves are damaged, so they don't know where their feet are in relation to the ground. So they walk slightly wider. Again, the balance is off. They're at risk of falling because of the balance, the incoordination, the weakness. Now they get to the restroom, they're about to brush their teeth. Well, because of the incoordination and weakness, you missed the toothbrush with the toothpaste. There's a little bit on that. And now as you start and try brush your teeth, well, you're getting toothpaste all over your cheeks. No one likes that. Now I want to tell you for my clinical experience that patients with neuromuscular diseases. What do they complain most about in terms of function that gets lost? Is it the legs? Is it the arms? Well, when the leg start to go, we have a lot of accommodations for that. We have ambulatory aids, we have wheelchairs, we have power wheelchairs. But what happens when the hands start to go? That's what the most. You can't test, you can't type, you can't write, you have trouble feeding yourself, When you go and try and feed yourself, food falls all over the place. Say you're so weak that you're in a wheelchair, you're using a power wheelchair, you have independence still. But what happens when your fingers get so weak that your incoordination is so bad that you cannot control the joystick? These are things we don't think about, but this is what happens to patients like GAN with neuromuscular That independent [Audio Gap] usually you lose interaction with the environment. You're unable to care for yourself. So that is what we're after. That is something that we want to impact -- And that's why I'm excited to show you the data today to talk about that. Now you see from the slide, right, you can read again, you can read the slide, you can start taking notes again. Take a look at this, right? We know that intermediate filaments start to accumulate nerves, the axons get damaged, there's a dieback, the neurons die too. We know that. What really happens here is that GAN in its simplest form is a disease of the central and peripheral nervous system. Centrally, this disease is like a leukodystrophy. There's significant white matter damage. That leads to all sorts of issues. The cerebellum particularly involved. And the cerebellar outflow tracks also involved. So that's what produces some of the cerebellar ataxia. From a neuromuscular standpoint, this looks like a Charcot-Marie-Tooth or CMT so you get a length dependent sensor motor neuropathy. What that leads to is poor sensation, which causes a sensory ataxia. So again, ataxia is a fancy word for incoordination. You get a motor neuropathy, which leads to weakness, right? That's when the nerve doesn't talk to the muscle. The muscle gets bad, you don't use it, you lose it, and there's muscle scarring, right? So the clock is ticking. The clock is always ticking, and there are windows of opportunity to treat patients. right? In any disease, there's windows of opportunity, and that's true in this disease, too. This disease shows up early, so classic GAN has significant CNS and PNS damage, central and peripheral nervous system damage. These patients have developed mental delays in terms of milestones. You can see that their balance and strength are altered early. They have an unsteady gait. They have ataxia that incoordination. They have weakness additionally and that weakness proximate the hip and shoulder girdles. That weakness escalate, they can't roll over in bed. And unfortunately, get passed away early in the late second to third decade of life due to respiratory failure. That trouble swallowing, so that puts them at risk with aspiration and respiratory issues. And of course, vision gets involved, too. I stress these things here, again, to simplify. It's a disease of the central nervous system that looks like the leukodystrophy. It's a disease of the peripheral nervous system that looks like Charcot-Marie-Tooth. And the combination of the two explain the symptoms, weakness and ataxia. It's that simple. Keep that in mind as we talk about the data. Keep in mind that if we don't use it, we lose it. Keep in mind that the harder the nerves are, the harder is to get recovery. The legs are less likely to respond than the arms given the time of dosing these patients. And again, what matters most [Audio Gap] this ultra-rare disease. It's only palliative. And that's another key point here. So how do we capture all this. With a complicated disease like this, as neurologists, we love neuroanatomy. So let's get a crash course in neuroanatomy. And let's figure out which endpoints correlate to different parts of neuroanatomy. And that will give you a context to understand why we measured what we did. And you'll also notice that there are several outcome measures because this is an ultra-rare disease, right? We need to be broad in how we capture this disease. It's difficult from the hypothesized outcome X, easy, just measure that, that's our answer. That will tell us about what the disease does. It's not like that. And the goal here really is to understand how these clinical functional measures, these performance outcome measures like MFM, mFARS. How they are supported by objective clinical data, objective biological data. So let's start with MFM, right? I told you this disease involves the peripheral nervous system. So you can see that in the bottom in the green box, that's a performance of functional outcome measure. We ask patients to do things. That test your peripheral nervous system very nicely. We use it commonly in neuromuscular diseases and we use it here. It tests strength, it tests function. And while that can be effort dependent as the FDA has said. So What I would say is that the biology can support that. And what I mean by that is we can look at objective data. We can look at CMAPs, compound muscle action potentials. We can look at SNAPs, sensory nerve action potentials. And why are they important? But because the CMAPs are nerve to the muscle. And if they're there, I can tell you that there is a connection there, and we can activate the muscle. So that might explain why there's still some strength there. The SNAPs are important. If you don't know where your muscles are, you cannot use them properly. So let's try something. So I want you to close your eyes, I want you to put your hands down in front of you, put your palms to the sky, take your left pointer finger and touch your nose. I do the same thing with the right one. Take your right pointer finger and touch your nose. You'll notice it wasn't shaky, you'll notice that you were able to touch your nose accurately. By the way, if you missed, send me a chat message, I'll get you into my clinic, no big deal. But patients with sensory issues where their SNAPs to go away, where there's a sensory they missed their nose. Their hands are shaky with the cerebellar ataxia. They might touch their ears, they might test their eyes. So you need your SNAPs to coordinate your muscles in the movement. So if the SNAPs are getting better, well, that would make sense to me that it might support muscle function and help with MFM. And then we also had myometry, right, objective strength measurements. Normally, in neurology, we push and pull on muscles. It's a little silly in this day of advanced medicine, but that's what we do. We push and pull and we say, "Well, you look strong or you don't look strong." Well, myometry has numbers to that as a pressure gauge. So we can calculate it, we can see it, we can track it. So adding the electrophysiology of the SNAPs and CMAPs with the myometry is a great combination to say, well, there's a biologic relevance here. There's a clinical data piece here that fits together to explain a functional measure. So that's about strength. But of course, GAN is more complicated than that. And what you see here in this neuroanatomy picture, so start with the brain, this kind of neuroanatomy picture causes a lot of nausea for non-neurologists. So we'll keep it simple. When you want to move your hand, say to grab your pen, the motor cortex then activate its nerves, but it doesn't go straight to your muscle. It instantaneously checks it for coordination. You'll get signaling through the cerebellum, which coordinates your coordination. Keep your fingers from shaking. It's a kind of metric to make sure you reach your target and you're accurate. Then it goes to the basal ganglia, which helps that muscle tone so that you're muscle contracts and lose and they're not stuck in a position. When it goes down, your spinal cord to the corticospinal tract and then eventually gets to the muscle. Now there's feedback from the muscle through the dorsal columns into the somatosensory cortex, initiated by the sensory nerve and that's measured by the SNAP that's sensory nerve. Now you can see the circuitry is quite complicated. And there's issues with the circuitry in GAN. Now the weigh bring it up because the movement is so closely tied with coordination. You wouldn't want to spill water all over you at dinner when you're trying to drink, and that's because cerebellum checks that movement. And the reason why that's important is because that's what mFARS captures. That's what FARS captures, right. mFARS is just a pair down version of FARS that psychometrically valid. Now mFARS deals so much with cerebellum and the sensory ataxia component that it's important to look at the SNAPs, the sensory nerves. And let me show you what that looks like, a lot of neurologists don't even know what this exactly means. So you see that picture on the bottom right. You hook up electrodes to where the sensation is. And we know from anatomy where those nerves go. So we hook up those electrodes to G1, G2. And then you put an electrical stimulation where you see that happen. And then it's measured by those electrodes. So we're basically measuring what the nerve is doing when we zap it. That's all the SNAP is, but you can see how that's an objective measure, right? The patient doesn't tell me anything. I simply do the test and I interpret the test without knowing anything about the patient. And I do this routinely. I've got some coming up later this week. It's a great test to do to have objective data here. Now mFARS is a great test, a great tool because it combines central and peripheral nervous system, whereas MFM is really geared towards the peripheral nervous Additionally, we have ophthalmologic data so you see logMAR during MRI. So other pieces of data to help tie in the rest of the symptoms of this disease. Why is that important, right? Remember, I told you it's what the patient says matters. In an ultra-rare disease, we need to capture these different compounds. So keep think this as a pyramid, right, if you want to get to the top of the pyramid, those are the [ ADLs]. What the patient tells me, what's their function. That's what matters. So let's go down step. How do we get to that? Well, we have our clinical functional endpoints, the clinician-reported outcomes, the performance outcomes, right? So the performance outcome is MFM32. The clinician reported outcome is mFARS. That is a neurologic exam. I and the other neurologists are highly trained to do that exam. I'm highly trained to see how shaky your movements are. I'm highly trained to see how coordinated you are, and that's what mFARS captures. That is an objective test. Again, I'm neurologist and the big thing that we do is not rely on tube of truth, which is MRI, but we rely on the physical exam. So that's mFARS. So I would argue that that's an objective test. And then we have logMAR,right? It's basically a visual acuity. It's a transformation from the numbers you're used to 2,020, 2,200 into a way that we can compare numbers. But you might say, well, that introduces bias. There may be a lack of objectivity. Well, taking a step further. Remember the electrophysiology I just showed you. Those nerve connection studies, SNAPs and CMAPs. It's not subject to effort dependency, but it fits clinically with what the patients have. Taking a step further, look at the biology, look at the nerve biopsies and see what that means. Now we use a Bayesian disease progression model. The reason we did it -- if you look at the data, if you look at ultra rare diseases, there's limited data here. So simply using patients as their own control with limited run-in data, not using the natural history data can be problems. It's good in some ways, but that has its downsides, too. And that's where the disease progression model comes in. And it was really preempted when the FDA asked is this a heterogeneous disease? I mean that's a good question. right? How can you compare it if you're not sure that this is a homogeneous disease? So when you look at classic GAN, it shows a homogeneous monotonic decline, meaning it's a progressive disease, it will not get better, as you would expect for neurodegenerative disease. And it accounts for limited pre-treatment data. It uses all of the natural history data from the classic GAN patients. It creates a model and tells you this is what disease progression looks like. And that is key. That adds power to our analysis in an ultra-rare disease with a limited number of patients, right? We've treated over 25% of the patients in the natural history cohort. And that goes along with the regulatory guidance about using a -- we have patients from the natural history cohort, where we use statistical analysis that does not show selection mines. We have those same patients in the trial from a single site, and we've treated approximately 25%. Now that's a great thing because that allows us to then say, we can compare it to this external arm in a rare disease, right? That gives us power. And then what it really allows us to do is take a look at the treatment effect. It's the treatment effect that we look towards in a disease like this, can we slow down the disease progression? Can we buy more time for a patient to use their hands to interact with the social environment. to be able to keep some independence to reduce caregiver burden, right? Those are the things that matter. And so the disease progression model allows us to do that. Now surely, we want patients to walk again. We want to gain their function rather than slowing the decline. But that's not always possible. Remember the principles, use it or lose it. The further away you are from the brain, the longer the nerves are, the harder it is to recover. Central nervous system damage is typically irreversible, right? So that speaks to the windows of opportunity that we need to think about. So let me orient you before we get into the data, right? We think about effect size here. And when the effect size is between 0 and 1, we have slowing of disease progression to varying treatment effects, right? The closer it is to 1, the higher the treatment effect. The closer it is to 0, the less the treatment effect. If you get to 1 to 2, you're actually improving the disease. You're not just slowing it down. If you're less than 0, you're continuing to decline. Now as an example of an ADL, social contact and engagement score that was pulled from mFARS -- from excuse me. Now you can see here that there's a treatment effect that's between 0 and 1, and we put gradation there, so you can see it's between 0.5 and 0.75. And you see the confidence interval around it. So this, you can say, with approximately 100% probability, there is a positive treatment effect here. There's a slowing of disease progression. We like that, right? And so we'll talk about how we support what the patients tell us. And remember, the onus is on us. So let's take a look at that. So let's start with the patient -- let's start with the ADL and then we can deconstruct to understand the clinical measures, the biology and how that go together. Now I told you the length are further away. So would you, if you were to hypothesize, expect any improvement in the legs, like walking I would not, and that's what the data show. It's clear that outcome measures related to the legs do not perform well. We do not have an impact there, but that's okay. We impact the arm, we impact measures related to arm function. And I think look near the bottom of this core spot. Patients, when they fill out the questionnaire related to FARS and then when data is extracted in a validated way from MFM to look at ADLs, you see that patients report that we are slowing progression of cutting food and handling utensils, right? That independence, that self-feeding that you can see there, personal hygiene. And most importantly, at least to me, when I think about what patients tell me, is social contact and engagement, we are social creatures. It's just that simple. We need others in our life. We need to interact with the world around us. And patients report here that there's slow progression that they're able to do that longer, and that's important. Another point that I'd like to make here is about trends, right? You might say, well, the some of them cross 0, that's not significant. And while that may be true from a statistic standpoint, you also have to keep in mind that this is a very small population, a very small number of patients we've treated. And we like to think about it in terms of trends. Trends are important and the biology and clinical data that fit with it are important because this could happen by chance or you might get one that crosses over. and says we have a very positive treatment effect. We're very happy, we're done. That's not what we're doing here. We see a shift across the board. So to have it by chance, it's extremely unlikely, sure, one, two, that can happen. But several endpoints with a trend for positive treatment effect is great. And what that tells us is that it's unlikely to be due to chance. These trends matter, especially in ultra-rare diseases, where we have a very small number of patients. So take a look at these ADLs, and this is what the patients report. Again, it's related to hand function the way I see it that patients report that the ADLs are slowing down, right? Riding in technology is a way of interacting with the world, social engagement, feeding yourself, taking care of yourself. Those are measures that we see slowing of disease progression. Now I told you this is the data here, and let me orient you to it. As I told you in the beginning that the legs are less likely to respond than the arms at the age with which we've treated these patients. And that's what we see. -- The core spot on the top left, you see several measures that are to the left of 0 and trends to the of 0. I'm not surprised. We did not impact leg function. But that's okay. Remember what I told you, when I see patients similar to this in neuromuscular clinic, what do they say bothers them most, they can get by with decreased life function and mobility. It's their hands that really bother patients. When they start to go, when they tingle, when they get weak, when they're incoordinated, that's what bothers patients. So don't worry about those exact measures. We're going to go into those in just a moment, but I want you to look at the trend. Look at the trend moving towards the right. Look at the trend that says we are slowing disease progression. And in fact, there are some measures that were even improving disease. You see the ulnar SNAP down there, the median SNAP, the time. And that's in relation to the ADLs, right? Some of those are related to leg function, right? As walking might seem so simple, but it's a very complicated neurologic test and really relies on your strength, your coordination, your balance. I wouldn't expect to improve that, unfortunately, at the time that which we've given this dose to patients. Now of course, MFM32, that is our primary measurement. What the prespecified outcome measurements. And to me, and the goal with a disease like this is to look at the totality of data and to really understand and ask how are we looking at the right measures. So MFM32 has a slight treatment effect. But take a look at the dimensions. Dimension 1 really looks at ambulation, looks at strength, axially, looks like your proximal muscle strength with transfers. There's no treatment effect there. We are not slowing disease progression, and that continues to progress. I would have predicted that, and I hope you would have too. Dimension 2 and 3, though, that's what's important here. Proximal muscle strength, especially in the arms, not the legs, shows a trend towards improvement. And with the Dimension 3, it's distal hand and distal foot function, but there's a lot of distal hand function pieces in Dimension 3. So that's just your hand, not the whole arm. What we see there is an approximately 100% probability of treatment effect. We are slowing disease down. We are improving the time with which patients had hand function, right? We're buying time. And let's see how that fits together, right? Was this by chance or does it make sense from clinical data? Does it make sense from biology? So I broke that core spot out, same data, but I want to talk you through it. So what we're seeing here, right, if we start from the top, there's Dimension 3 MFM32, right? There's a positive treatment effect, there was slowing down disease progression. What I would say that goes with this Dimension 3 or the ADLs riding and technology use, self-feeding score, engagement, cutting food and handling utensils, right? ADLs are complicated. They don't simply go with one outcome measure. But I'm drawing a line to say that hand function is important, at least in part to these ADLs. Again, basing this off in my clinical experience. So if we take the hand that's important and say, okay, patients are reporting it. We have a clinical performance measure. MFM32 Dimension 3 that says, it looks like you're slowing down the disease. But is it effort dependent is there a chance? Well, let me take you to the clinical data. Let me take you to the objective electrophysiology. So if we look at the median and ulnar sensory nerve action potentials, right? So the median and ulnar nerve, just a quick neuroanatomy, are the nerves that feed sensation to the front of the hands here. They also feed all the muscles, so the compound muscle action potentials, the motor nerve, feed all the muscles in the hand required for grip. It also feeds the muscles in the front of the forearm that help with grip. Those are the two nerves that are very important for the functions that you do with your hand. There's more to it, but we really care about grip and moving things towards our face. That's what median and ulnar nerve are there for. So the median and ulnar nerve SNAPs are improving. They're not just slowing disease progression, they are improving, and we'll talk about that more in just a second. But that helps with coordination. Remember, if you can feel where your muscles are, if you can feel where your hands are, that may translate into better function. That degree of change doesn't happen by chance. Now the compound muscle action potentials are a little more complicated. The sensory nerves I showed you, you just zapped the nerve and you get a response. The compound muscle action potentials rely not only on your nerve, they rely on the communication through the neuromuscular junction to the muscle. So if the muscle was damaged enough, you may not get that strong of a response in your CMAP. And that's what I hypothesized happened here. There is a treatment effect, not as strong into SNAPs, but there is a treatment effect where we have a trend towards improvement -- excuse me, a trend for slowing the disease. That should help us strength. So can we back that up with clinical data, objective data? And that's where mayo grip, mayo pinch, moving plate come in, right? Those are the tools that are used to measure strength in a quantitative way. So Mayo grip, you are going to grab something and grip it like that. Mayo pinch, you pinch like that, you may not be able to see my picture, but you're just pinching, you're gripping. And those show a treatment effect in terms of slowing disease progression. Again, which makes sense biologically, right? The CMAPs have gotten better. The SNAPs -- the CMAPs have slowed progression, SNAPs have gotten better, that should feed into the strength that we're measuring. Moving plate looks at the fatigue of the muscles of the wrists, the flexors and extensors. That shows a trend towards improvement with an approximately 100% probability of doing so, right? So we've got the nerve conduction study, which is our objective. We've got strength measurements that are objective that show a trend towards improvement. We have myometry, same thing, quantitative measure strength, looking at your biceps and triceps muscles, not related to median and ulnar function, but do contribute to arm movement, right? You need your biceps, you need your triceps. Those also show a trend towards improvement in terms of slowing disease progression. Now put that together, and you might saying, well, it makes sense now that Dimension 3 has slowed the disease progression. It makes sense that the ADLs related to hand and arm function are showing positive effects. Now that's MFM. Let me take you to mFARS, right? We talked so much about coordination. mFARS again, helps measure central, so cerebellar ataxia as well as sensory ataxia, which combines the peripheral nervous system. There, we also see a strong treatment effect with a high probability of a positive effect. Again, can we back that up, right? I say it's an objective test as a neurologist doing it. It's part of the physical exam. But can I back that up with clinical data, objective clinical data? And that's where the SNAPs come in again. Those contribute to sensory function. If I can make SNAPs better, it might help your sensory ataxia. And that's what we see there. Now we're still working on finalizing the MRI data, that's quite a rich data set. But if you were to say, mFARS capture central and peripheral nervous system function, right? If I'm using my exams to determine function of the central and peripheral nervous system. And we're seeing a trend towards slowing progression, then you may hypothesize that there could be a central nervous system effect, not just peripherally that the SNAPs are supporting. And I think that's an important component because it is a validated measure for looking at cerebellar ataxia. And part of FARS is to look at 9-hole [indiscernible], where you use your hand, you use you use coordination, you use strength to put items into a you go back and forth, you pick up an item, you put it on a pegboard and you time that. And you see that these patients have had improved function there in the realm of where the SNAPs improved, right? A functional test that goes with coordination, that goes with strength, that goes with sensation. So I hope you can see the story here where we have our functional, the performance measures, the clinician-reported outcomes of MFM, Dimension 3, mFARS, right? We care about weakness, we care about coordination, we care about hand function, right? We want to have patients have independence. And you can see from the ADLs. That's what they score it. And then we back that up with clinical data -- objective clinical data with electrophysiology. We back that up with myometry and mayo tools to measure strength. And that creates a line, that creates a story that tells you what you might be seeing in MFM, mFARS is not necessarily by chance it makes sense clinically. And in an ultra-rare disease, it's important to take this totality of data, combine it, understand the story to help you understand what you're seeing from a functional measure and what patients are reporting. Remember, what patients say is most important. We have to then to deconstruct the outcome measures to understand how that could be. I'm a neuromuscular neurologist. I have performed these electrophysiology studies all the time. And to me, seeing these SNAPs come back, so what we had was five patients had a gain or stability in nerve conduction amplitude, post-treatment. In my clinical experience, if I had a patient with Charcot-Marie-Tooth, which I do, several, these SNAPs do not come back. Once they're gone, they're gone. In the neurodegenerative disease, biology typically does not come back. This is a progressive monotonically declining disease. So if i took CMT for example, and the nerves were lost, they're not coming back. The fact that these nerves come back in some patients, their responses were 0 and they came back. To me, that's a wonderful thing. That's not something I see or have ever seen clinically. And I don't have as many gray hairs than other people. But I've done a lot of these nerve conduction studies. I have a lot of these neurodegenerative patients in terms of CMT or other neuromuscular neurodegenerative conditions. SNAPs do not come back once they're gone in diseases like this. Can we show that biologically? Well, of those five patients that have stability or regeneration, right, nerve regeneration. The four out of five those patients have regenerative clusters on nerve biopsy. Histologic evidence in terms of [Audio Gap] we have nerve regeneration of the sensory nerve or the neuron. And to me, that is a great thing, right? That is objective, wonderful data that we can put together in the entire clinical picture. But efficacy is only one part, right? We have to understand what the safety is. If this is not safe, we shouldn't use it, no matter what the treatment effect is. But thankfully, it is safe. We have approximately 7 years of clinical data that support the safety and tolerability of patient. There have not been significant safety issues. Now keep in mind that these patients have been dosed at different times. So the longest safety period that we had is 7 years. There's been no dose-limited toxicity. It's been well tolerated at multiple doses. All steroids have adverse events were deemed unrelated or unlikely to be related to TSHA-120 other than a fever that happened around the time of administration that can resolve within a few days. What's the takeaway? We'll take a look at the bar graph. You can see that from the early time point around infusion, so 0 to 3 months, that's when most of the adverse events happen and they quickly taper off. And you can see, as we get further away from treatment, there's less adverse events reported. To me, that is promising. To me, that describes tolerable that long-term safety data, and that's an important piece of what we have today. So let me summarize for what we talked about, right? I hope my timing didn't came out here. I hope my understanding and my clinical knowledge that experience made clear this complex disease into a simplified framework. What we have is GAN is a disease of the central and peripheral nervous system. It's a leukodystrophy. It's a CMT combined. Classic GAN is that. So what we have to do is understand how weakness in ataxia can be measured, and that's where MFM32 and mFARS come in. But of course, at the time when we dose these patients, there's been damage already, right? The principles that I told you about, use it or lose it, the further away you are, the longer the nerves they are, the harder they are to recover, the most susceptible they are to injury. So to me, it's a no-brainer. The lenghts, I would not have expected a treatment effect and that's -- we don't see that. But it's the arms, it's the hands that patients report means a lot to them when I see patients like this in clinic. And that's what we focus on here. And the disease progression model allows us to understand the homogeneity of this disease, right? Classic GAN is homogeneous. We can understand what the course will be. And we can compare it to understand if there's a treatment effect or not. It gives us strength to use natural history as an external control arm. And importantly, we're able to support these clinician reported, these functional, these performance outcome measures that could be subject advice. That may lack objectivity at time. And that's when we use our biologic data, that's when we use our clinical data. That's when we use how it appears that there's critical nerve regeneration, right? Something that, to me, is very exciting. Something that we're still looking into and making sure that this means something for these patients. And that's when we use the SNAPs. That's when we use regenerative clusters on biopsy that we see in a dose-dependent manner that supports those clinical measures. And when we combine all that, right, can we construct back up to those ADLs that the patients report that they can interact better, they can feed better, they can take care of themselves better, right? That's what we're able to show with this kind of data, and we truly believe in the transformative potential of TSHA-120. We're inspired by the patients and families, and hopefully, we can bring meaningful change to this devastating disease. I'll send it back to Suku.

Thanks, Dr. Bhai. That was very well explained from a clinical standpoint and neurologist expertise. So patients with GAN and their caregivers are in urgent need of treatment options, and we believe our new compelling findings demonstrate a positive treatment effect across multiple objective measures and show that the benefit of treatment with TSHA-120 outpaces the risk in this ultra-rare disease with no approved treatments. To recap Dr. Bhai's remarks, our comprehensive analysis has enabled a deeper understanding of GAN and demonstrated the monotonicity and the homogeneity of its progression. We believe the robust GAN natural history data sets, which includes a significant percentage of known GAN patients is representative of the overall GAN population and therefore, an appropriate control to map the progression of central nervous system and peripheral nervous system outcomes in GAN with the disease progression model. The disease progression model is both useful and accepted by regulatory agencies and interventional studies of rare disease and small nation populations, and it is consistent with the FDA published guidance from February 2023 on externally controlled trials, considerations for assessing comparability of data across trial arms. Findings from the data analysis demonstrate that ataxia is a major source of disability in GAN and show multiple objective and clinically meaningful endpoints that can help demonstrate efficacy with treatment, including functional endpoints such as mFARS, MFM32, and logMAR; electrophysiological measures, including SNAP and CMAP; and biological measures, including visual acuity and nerve biopsies. Importantly, when we model the rate of progress and of these endpoints through the disease progression model, it showed disease slowing across multiple objective measures. The positive treatment response observed across multiple functional objective biological endpoints cannot make by chance. We believe this model addresses the FDA's concerned regarding the possible subjectivity of some clinical measures in the setting of an open-label, non-randomized interventional study. Notably, of the 53 patients enrolled in the natural history study, 14 were treated with TSHA-120 and assessed by the same study personnel in both the natural history and interventional studies. To further increase the risk of subjective examiner interpretation variability, interventional study examined by two independent physiotherapies are well published and recognized experts in neuromuscular outcome measures and quality control or assessments, which we believe further validate our findings. Interestingly, there are elements of GAN that are similar to spinal muscular atrophy given there is a treatment of optimal clinical impact, while SMA is a more actively progressive disease, the tenant that the early disease, the better the clinical outcome is remains true for GAN. In addition to this compelling efficacy data, there are approximately 7 years of long-term clinical data supporting the safety and tolerability profile of TSHA-120. These findings support our view that TSHA-120 should be approved for the treatment of GAN with the existing data set. FDA's willingness to consider alternative study designs, utilizing objective measurements as well as support for the expanded use of accelerated approval for gene therapies in rare and severe indications with lower growth treatments are consistent with seeking BLA approval based on the existing data. We plan to use this new data to inform our discussion with the FDA regarding alternative study designs, additional objective measures and ultimately a regulatory path forward. We anticipate a follow-up meeting to occur in the third quarter of 2023. Bottom line, we believe that the available data across multiple functional electrophysiological and biological structural endpoints in the patients treated with TSHA-120 compared to the natural history cohort in the disease progression model demonstrates a relatively large treatment effect in objective and clinically meaningful endpoints that support the approval of therapy. We continue to believe in the transformational potential of TSHA-120 and look forward to having a collaborative dialogue with the FDA regarding the potential registrational path to TSHA-120 to patients with GAN. Let's now transition to our TSHA-102 program in Rett syndrome. I will now turn the meeting over to Dr. Azhar Rana, Head of Medical Affairs at Taysha, who will provide TSHA-120 program and overview. Azhar?

Thank you very much, Suku. Hello, everybody. Welcome to the meeting. My name is Dr. I'm the Head of Medical Affairs at Taysha. I bring nearly 2 decades of pharmaceutical experience across clinical development, medical affairs, regulatory affairs and commercial strategy with extensive experience across chronic and rare diseases. I'm really honored at Taysha to be working closely on the development of the TSHA-120 program. Very excited to help advance in gene therapy field with this innovative approach as well as bringing a potentially transformational treatment to the Rett syndrome community. So before we get into TSHA-102, I want to understand what makes TSHA-102 innovative, if we could have the next slide, please. We first need to understand a little bit about the pathophysiology of bread syndrome. So Rett syndrome is a very rare devastating neurodevelopmental disorder, which is caused by a pathogenic mutation in the X-linked MECP2 gene. Now this gene is essential for neuronal and synaptic function in the brain. So it's understandable that Rett syndrome itself is characterized by intellectual disabilities, loss of communication, seizures, slowing in and/or regression of developments, motor and respiratory impairment as well as ultimately a shortened life expectancy. Rett syndrome, we know is primarily occurring in females, and it's one of the most common genetic causes of severe intellectual disability. So across the U.S., EU and U.K., we know that there's between 15,000 to 20,000 patients who are affected by Rett syndrome by this pathogenic or likely pathogenic MECP2 mutation. We also know that currently, there are no approved disease-modifying therapies that treat the genetic root cause of the disease, and there remains significant unmet medical need within this community. Now this unmet need highlights the urgency that is required to deliver disease-modifying treatments for Rett syndrome. And again, we're very encouraged by the opportunity to bring this potential transformational gene therapy to patients and their families. So let's talk a little bit about the concepts. So I think it's -- first, it's a few concepts behind this disease and Rett syndrome. So we know that while too little MECP2 causes Rett syndrome, we also know that elevated levels can result in MECP2 duplication syndrome, which is a clinical phenotype, which is very similar to Rett syndrome in terms of symptoms and severity. We also know that X-chromosomal inactivation and silencing of the MECP2 expression can occur randomly and in an autonomous manner. So what that means is that patients with Rett syndrome can have a mixture of cells that are either deficient in MECP2 or they express MECP2 normally. Now this heterogeneity in MAP2 protein expression makes Rett syndrome a very challenging case for gene therapy. Given the need that we need to enable functional levels of MECP2 in deficient CNS cells, while also preventing an overexpression in CNS cells that are already expressing the MECP2. So in collaboration with UT Southwestern, we have developed TSHA-102, which is a very novel treatment approach designed to prevent gene overexpression-related toxicity by inserting human micro RNA or mRNA on target binding sites into the 3 prime untranslated region of viral genomes. So what that gives us is TSHA-102, which is the self-complementary intrathecally delivered investigational AAV9 gene transfer therapy, which is currently being evaluated for Rett syndrome. TSHA-102 is constructed from a neuronal specific promoter, which is the MECP2426, coupled with a miniature version of the MECP2 transgene or a truncated version, if you will, of the MECP2 transgene as well as an mRNA or microRNA responsive auto-regulatory element or miRARE, which is our novel microRNA target panel packaged within this self-complementary AAV9 capsid. So a little bit more about the miRARE technology and how this works. So to mitigate the risk of MECP2 overexpression and still restore MECP2 in cells where the protein is lacking, we utilized the miRARE technology to mediate levels of MECP2 on a cell-by-cell basis. So specifically, what this does is the miRARE uses a negative feedback loop to turn off gene expression in cells that are already expressing the MECP2 protein where it's not needed, as you can see on the left-hand side of your slide, but it also allows for expression in MECP2 protein-deficient cells where it is needed, as you can see on the graphic on the right-hand side. Now this targeted regulation of gene expression is critical to safely modulating the cellular expression of MECP2 in an appropriate and clinically relevant manner. Given the mosaic pattern of MECP2 silencing characteristic of female patients with Rett syndrome that we just discussed. So preclinical data, we have a very robust preclinical data package that supports the TSHA-102 and the miRARE technology. And these are 2 studies across 3 different animal species. So we've conducted pharmacology studies in MECP2 knockout and wild-type mice. And that was to ascertain the minimum effective dose that's required. We've also done mouse distribution in gene expression studies. We've done toxicology and [indiscernible] distribution studies in rats as well as in nonhuman primates. Recently, we further augmented this data set with a preclinical study evaluating the safety and efficacy of the TSHA-102 construct in neonatal wild type and [indiscernible] MECP2 knockout mice. And this was presented at the ASGCT Annual Meeting in Los Angeles in May of this year. Now what this data has demonstrated is the ability of TSHA-102 to regulate cellular MECP2 levels and significantly improved survival growth and overall neurobehavioral function in knockout mice, which are the 3 graphs that you see on the slide right now. But importantly, within these graphs, you can also see that in wild-type mice, TSHA-102 had no detectable impact on survival, as you can see on the graph on the left. The [indiscernible] on overall health assessed by increases in weight, as you can see in the middle, or neurobehavioral functions, as you can see on the right-hand side. Now this data putting into context what this highlights is the potential of the miRARE technology to enable safe cellular expression of MECP2 protein, which may address the risks associated with both under and over expression, resulting from this mosaic pattern of MECP2 silencing that we see in females with Rett syndrome. And we strongly believe that the totality of preclinical data generated represents a very robust package that supports the clinical advancement of TSHA-102 into Rett syndrome. I think importantly as well, the preclinical data generated suggests that TSHA-102 is well tolerated in the species tested with a very large therapeutic window of safety coverage for our first-in-human trial. And we believe that these findings translate or could translate into clinical benefits for treating patients with Rett syndrome. And we're actively exploring this in the ongoing REVEAL Phase I/II trial in adults females with Rett syndrome currently. Now the Phase II -- Phase I/II REVEAL study is the first in-human open-label, randomized dose escalation and dose expansion study, which is going to evaluate the safety and preliminary efficacy of TSHA-102 in adult females with Rett syndrome due to the MECP2 loss of function mutation. So the participants in this study will receive a single lumber intrathecal injection of TSHA-102. And as per protocol, dose escalation will evaluate 2 separate dose levels sequentially. The first cohort will receive a protocol-specified dose level of 5x, 10 to 14 total vector genomes. The second cohort will receive a protocol-specified dose level of 1x, 10 to 15 total vector genomes. And the maximum tolerated dose or maximum administered dose established will then be administered as we go forward into the dose expansion phase of these things. So very excited that on June 5, we announced the first adult patient dosed with TSHA-102, which took place at the CHU Sainte-Justine at the University of the Montreal, Mother and Child University Hospital Center in Montreal, Canada under the direction of our principal investigator, Dr. Elsa Rossignol. The day of dosing was successful, largely uneventful, and we are encouraged by the initial clinical observations of that first adult patients. We're very pleased to share that patient's doing well, has been discharged from hospital with follow-up visits planned as per protocol and ongoing. We look forward to providing further clinical updates on safety and efficacy for this first patient early in the third quarter of this year after the required adjudication of the initial clinical data by the IDMC or Independent Data Monitoring Committee. And then subsequent REVEAL trial updates will be provided accordingly after -- accordingly thereafter. We have identified a second potential patient for the study as well and the patients undergoing screening. And if all protocol-defined criteria are met, then we will have a second patient. Per this protocol, the IDMC will review all of the available clinical data from the first patient approximately 6 weeks post dosing. And that will determine if we can proceed with the dosing of the second patient. So TSHA-102 has received an Orphan Drug and Rare Pediatric Disease designation from the U.S. FDA, as Suku mentioned. And we've also been granted an Orphan Drug designation from the European Commission for the treatment of Rett syndrome. And so while Rett syndrome is considered a rare disease, as we've discussed, there is a very high unmet need reflected by the approximately 20,000 patients across the U.S., EU and U.K., the high burden of care associated and the lack of disease-modifying therapies. The previous feedback that we have received from Health Canada suggests that they would support the clinical trial expansion to pediatric patients following initial efficacy and safety data from our adult patients. We believe that younger patients are most likely to benefit from treatment with TSHA-102 due to that earlier intervention and the potential for slowing of disease progression. We remain on track to submit the CTA to the U.K. MHRA for TSHA-102 in pediatric patients mid-2023. We're also expecting to submit our IND application to the U.S. FDA in the second half of the year. So really looking forward to advancing TSHA-102 for the treatment of Rett syndrome, very happy to be a part of this team. And I'll hand back to Sean at least for some closing remarks.

Thank you, Roger. As you can see, we have achieved exciting milestones in our lead investigational clinical programs including obtaining new data from the world's largest database in GAN that further bolsters support for the therapeutic potential of TSHA-120 and providing an initial clinical observation from the first patient dose with TSHA-102 that supports the potential for a disease-modifying treatment for patients with Rett syndrome. These date support our growing body of evidence reinforcing the ability of our innovative onetime treatments to overcome challenges that have limited other treatment approaches in these devastating disorders with high unmet need. The next 6 months are critical for Taysha, and we remain focused on executing across our near-term milestones. Our financial runway continues to support our upcoming catalysts for this year across both our programs. In mid-2023, we expect to submit a CTA to the U.K. MHRA for TSHA-102 in pediatric Rett syndrome patients. We expect to provide further details on the safety and efficacy of the first patient dose in the REVEAL Phase I/II trial and receive approval to potentially dose the second patient early in the third quarter this year, following the required initial review of available safety and efficacy data by the IDMC. For TSHA-120 and GAN, we anticipate a formal meeting in the third quarter. In the second half of 2023, we plan to submit an IND application to the FDA for TSHA-102 in Rett syndrome and continue dosing patients in the ongoing REVEAL trial in Canada. Thank you, everyone, for joining us today. We look forward to providing updates on our progress throughout the year. With that, I will now turn the call over to the operator to begin our Q&A session.

[Operator Instructions] So the first question is going to come from Rick Miller at Cantor Fitzgerald.

Rick Miller from Cantor on for Kristen. We just have one for you today. So the rationale for looking at MFM results backed up by electrophysiology certainly makes sense. Given the positive affects you saw in social contact and engagement and the importance we understand here for quality of life, what's your sense of how regulators could look at these social benefits? And how are you thinking about objective measures to potentially support these kind of effects?

Rick, that's a great question. I'll ask Salman to expand upon that. But again, I think you'll see the strategy that we're employing and the way that the data was outlined by Salman is that there's extensive data across multiple clinical functional electrophysiological and biological endpoints. And what we're trying to do is map those objective findings back to patient ADLs that are compelling. And leverage that with the FDA to show how transformational this -- the program is. And in concert with that, we will be working with patient advocacy groups and families to also share their experiences about disease burden and what they've seen as a result of being treated as well, but I'll ask Salman to build on that.

Thanks, Rick. That's a great question. And ADLs are quite complicated, right? I was creating a story with the objective clinical data, as you mentioned and as Sean mentioned, to bring to light how they contribute to the ADLs. But there's more to it, right, the social engagement piece, which I find to be very important, and I imagine that regulators will also care about what patients are saying. But you know if I'm sleepy, I'm not so socially engaging, right? Those are other factors that can affect ADLs. And it's difficult to encapsulate all of that clinical data, all the factors of life and environment that might impact the ADLs. But if we're able to understand the biology, the clinical data, the functional measures and how they could potentially contribute to ADLs, right? Again, the onus is on us to show that there's evidence that we've captured to show that the ADLs mean something to the patients, and that's what the patients tell us. So we appreciate the question. I hope that regulators also see it in that way, and it's what the patient says that matters.

The next question will come from Yanan Zhu at Wells Fargo.

So I was wondering what would -- what might be the endpoint for approval or proposed endpoint for approval? Today, you walked us through this disease progression model calibrated results from the patients and some of the components look very encouraging. But if this kind of comparison admittable as endpoints for approval, or does it have to be the more conventional endpoints like either mFARS or MFM32 change from baseline in comparison to natural history?

I'll give a perspective on that and ask Suku to further opine on it. But again, I think what we have to do and what Salman did in his presentation was highlighted at MFM32 was the prespecified primary endpoint. So we'll certainly continue to demonstrate what's been exhibited by the therapy. Keep in mind, the FDA acknowledged in the initial feedback that we got back at the end of last year that the efficacy demonstrated was moderately effective. The concern was just trying to judge that given in their view, it was effort-based and there wasn't a placebo controlled. So I think now if we look at MFM32, we've got additional cuts looking at different domains, we could provide further clarity that there is a treatment effect. I mean the data does show that there's a treatment effect on that particular endpoint. But to your point, we wanted to augment that with all the data. Salman said it earlier, we didn't want to just pick one thing and hang our head on it, we wanted to show that when you look across the spectrum and you understand the biology of the disease that it's essentially irrefutable that there isn't a drug effect. So my last comment would simply be when we take a look at mFARS as the example, when you think about the ataxia associated with this disease, that is an endpoint that is validated that has been used recently for approval of the Reata product. And it's clinically objective. Again, it's measured by the clinician. And then we feel that we've got additional endpoints that are 100% objective when you start to look at the snaps and the CMA and some of the other things that all tie back to that to further support the case. But Salman, please expand on anything I might have said.

I think that's a great question. And I think we have to take a step back clinically. We're constantly learning about in discovering new diseases in this age of molecular medicine. How can we rely simply on conventional outcome measures without being more creative, without understanding the totality of the data and not limiting ourselves potentially to the detriment of patients by simply relying on conventional measures, when we don't fully know the disease, right? This study started by understanding the natural history with the intervention soon to follow. It's difficult to penalize patients, physicians, families when we fully don't understand the disease. But now we do, and that's where the totality of the data comes in to create this web of evidence that fits together rationally in a clinical and biologic manner.

[indiscernible] something h.

And what I would also add is the following. And I'll keep this very concrete. So keep in mind, these patients are all greater than 60 years of age and had an ultra-rare neurodegenerative order. And as Salman pointed out, in his talk, these patients have already progressed significantly. The second point that I want to make, as Salman again highlighted is we now have a very good understanding of the ultra-rare disease that never previously existed. We have access to the largest database in GAN. The third is the current FDA [indiscernible] position to Dr. Peter Marks and others that within an ultra-rare disease, where there is no other therapeutic option and the benefit outweighs the risks, one should see this to consider making the product accessible to patients. And then finally, beyond everything else that Sean and Salman have mentioned, I have never in my career in gene therapy seen in a neurodegenerative disorder, sensory nerve action potentials being restored in 5 patients in the ulna and median snap measurements, but beyond that, actually seeing the nerve [indiscernible] being regenerated. And as Salman pointed that out, to us, that is a very strong translational signal. But if we treated these patients with GAN much earlier, at a much younger age, 2 to 3 years of age, our clinical effect would have been far more greater, potentially transformational. And we would have also slightly impacted the lower extremities, long before the low extremities nerves completely degenerated. Do you agree, Salman?

Absolutely. Maybe I'll give a convoluted metaphor here. So stick with me for a second. If we consider the legs and the arms, right, the legs are further away, the arms are closer to the brain. So as we've mentioned, as Sean mentioned, we would expect that the arms would get better than the legs. Now for a moment, think about the legs as older patients and the arms as younger patients, right? You can think about that distance and that time dependency of where the damage happens. And you might expect that if you treat and you might hypothesize if you treat patients earlier before the muscle fibrosis, before the nerve is completely damaged, before the neuron is lost. You have a chance of having an impact not only in the arms, but also the legs also affecting walking, for example.

Great. If I may just ask a very quick follow-up on the point of the snap. Is there a possibility for it to become a surrogate endpoint for accelerated approval?

Actually, that's a very interesting and important question. I think, yes, there's a very strong potential to use it a surrogate end point with the collective broad clinical impact that we've already shown through multiple other objective measures when we have our discussions and interactions with the FDA.

The next question will come from Jack Allen at Baird. Although, he's traveling. So I will go ahead and read that out for him. I'd love to hear about the team's efforts engaging directly with the GAN patient community. Has Taysha been in contact with key patient advocacy groups? And are there well-established groups for the patient of GAN? Any thoughts on what role the voice of the patients may play as you look to approach the FDA to discuss these new analyses?

That's a very good question. And I would say that Taysha's very engaged with patient communities across all the therapeutic areas that we interface with. But specific to GAN, there are several that we've been working closely with, right? There's [indiscernible] Foundation. There's All In For Ethan. There's a Hereditary neuropathy foundation and the CMTA, which is the Charcot-Marie tooth association. so we definitely engage with them. Over the course of time, we've done focus groups with patients and caregivers to learn more about disease burden and also learn more about functionally what matters to them. That's really helped us understand as we analyze the data. We spend a lot of time on the ADLs because we also wanted to highlight what is meaningful to the patients. And so these groups have been very helpful in that. And we've also embarked upon an exercise to work with families that have gain -- that have been treated and those that have not been treated to again understand what it's like living with the disease, call it not having been given the opportunity for gene therapy. And then subsequent to gene therapy, to further inform how we approach and position the data with the FDA as well as the unmet need. And we will certainly work with these groups as we engage with the FDA to make sure that the voice of the patient and the families and the caregivers are well represented.

Can I add one thing? Just thank you to Jack. I mean you clearly get it. And I appreciate you bringing the voice of the patient and the family up. And that's crucial to what we do here at Taysha. And we have a wonderful team here doing exactly what Sean said.

Okay. [indiscernible], you may go ahead and unmute your lines.

And thank you for outlining in such great detail all the endpoints and extra measures that you have. Just coming back to MFM32, I really enjoyed the slide ratio, the efficacy on the different dimensions. And so obviously, dimension 1 with their legs, the outcome was poor, but 2 and 3 are actually very good. And so obviously, that impacts the efficacy. And so -- and if you just look at the dimension 2 and 3 efficacy size is much larger. So has the FDA looked at that in their previous MFM32 analysis or not? And then I have a follow-up question on SNAP and CMAP.

The answer to your question is no. What the FDA saw previously was total MFM measured in a different manner as well. And we certainly would plan to share with them what you saw as well as some of the -- I would call it, traditional analysis that were done initially. I don't know, Salman, if you would add to that.

And our goal is to have full transparency to have a discussion, right? So our original analysis was based on frequentis, patient has own control. And we show that, and that's something that we will show the FDA in its full form. However, given the rarity of this disease, the limited data -- the limited running data that we have, this is where a disease progression model guided by basin analysis gives us that power. So we'll show that too. And we'll talk about why that is a better method in terms of giving us a full picture with limited data. And so it's a great point. It's something that we'll put together in the totality idea and give the narrative, right?

And then on the slide where you discuss SNAP and CMAP. I have a question. Why is the SNAP measuring showing great improvements in median and ulnar, I guess, measures? But the CMAP did not show so much. What's the exact difference here?

Thank you. This is music to my ears. I mean, I love talking about this stuff. And the fact that you're asking that question shows me that you're thinking critically about this. Typically, you might expect that the motor nerves come back more robustly than the sensory nerves. However, the sensory nerve has no synapsis. It's simply the nerve and where you measure it on the skin. So it's just one order, right? It's just one thing that we're doing. The motor nerve -- and I didn't put a picture up and that probably would have helped, but the motor nerve, when I zap the motor nerve, it travels through the motor nerve. It jumps across the neuromuscular junction and then fires on to the muscle, which then activates and creates net electrical activity. In the sensory nerve, we're measuring that electrical activity directly. So you can see how the motor nerves has 3 things that are being measured, and the sensory nerve has one thing being measured. Now if we go back to that principle, if low muscles get sad when you don't use them, when the muscle and the nerve is not connected to them, they become fibrotic. So no matter how much nerve connection I do to that muscle, it will not get back to normal. It will stay diminished and it will plateau at some point. And that is what I believe is happening, limiting the response for the motor nerve. But again, to Suku's point, to Sean's point, there are windows of opportunity to treat these patients to prevent that fibrosis to give back more function and allow patients to use it and gain more function.

Yes. And if I may add, this is the reason we have to identify these patients and treat them early.

Absolutely.

And also when you restore the sensory nerve action potential, this closes that feedback loop for the [indiscernible] cell and the motor, right, at some to actually simulate and continue that circuit to the neuromuscular junction. So it continues to be functional. So this is a collective circuit that has to be fixed early rather than later. Do you agree Salman?

Absolutely.

The next question will come from Joon Lee at Truist.

This is Mahdi on for Joon. So we have 2 questions, 1 for GAN and 1 for Rett. On GAN, you tried to show homogeneity of disease for classic patients. So would it limit eventual approval now that you have like good objective measures to classic patients or it will be for the full cohort of GAN patients? And then I will ask the Rett question.

Yes. Suku is going to answer your question, but I think at a very high level, the answer is no, it's not going to limit. And you'll hear why when you get the genetic answer as to why all patients with GAN would be treated.

Yes. Thanks, Sean. By the way, that's a very important question, which we've obviously discussed internally, and we've also discussed with experts, including Dr. [indiscernible] here. So we think GAN as a whole, whether it's classic or non-classic or early or late GAN, the root cause of the disease is the same. The genetic basis of the disease is the same, where there is the effect in the [indiscernible] some in gene. And therefore, accumulation of this intermediate elements have resulted in the formation of this giant axonal in the peripheral or in the central nervous system resulting in the same electrophysiological outcome. And we feel that overall, our therapeutic intervention using intrathecal [ Phase II ] gene therapy should be able to address both classic and nonclassical GAN in the sense that it's all GAN. And what we've also discovered when we evaluated the different diagnostic processes for GAN in the CMTJ2 category based on the literature of some of the experts at times there is misdiagnosis of patients who fall into that category of GAN or the misdiagnosis CMTJ2. And when additional genetic testing is done to identify as GAN. So we feel that in part of our discussions with FDA, what we hope to do is hopefully to get a broader label, such that all of GAN can be addressed with our therapy or intrathecal. Do you want to add, Salman?

I'd like to add that there's a misnomer sometimes in the literature that might say nonclassic GAN is mild. Now if you see any of these CMT patients that may you tell them their disease is mild, you're looking for some trouble. These patients have high morbidity. And when it shows up early in life like it does for these nonclassic patients, right? You might say, well, CMT shows up later, they have trouble walking that strength, the person is older. It has less emotional valance. But these younger patients, right, it's absolutely crucial to understand that even non-classic GAN has significant morbidity for these patients. And it's not just the peripheral nervous system. They too have a degree of central nervous system involvement. So it is a disease that needs to be addressed and has the same pathophysiologic underpinning.

The only thing I would add to that, by the way, is that Suku mentioned, there are several publications out there that talk about a range of misdiagnosis that occurs. And it's not unexpected in many rare disease, you see underdiagnosis because there's no treatment. And we would fully expect that with approval of the drug availability of TSHA-120, you would see genetic testing occurring at a much earlier time point, and we would capture a lot more patients, absolutely. Because, again, just to reinforce the genotype, the root cause of the disease is the same. It may express itself temporarily a little bit different, but they're both devastating. So to us, GAN is GAN.

That's very helpful. So to the Rett syndrome, today, Anavex put out some results for their Sigma-1 receptor agonist, which is basically preventing mitochondrial dysfunction and oxidative stress in the disease. So how this would affect your positioning, thinking about this treatment for Rett patients -- gene therapy for Rett patients? And any color in that domain would be also helpful.

I think you're talking about the Anavex program, and I would say a couple of things and turn it over to the Docs. But essentially, it's a small molecule. What's been demonstrated clinically at this point in time is certainly encouraging. And there seems to be an effect, the studies seem to be shorter, 7 weeks studies, they may be a little bit longer in some of the non-U.S. countries. I would go back to -- it's similar to debut in that there appears to be an incremental effect. What we're striving for with any gene therapy that we're developing here is we want to see transformational effect on the disease state. So we think that by addressing the root cause and delivering the gene in an appropriate manner, we're going to get a result that is much more dramatic than anything that's been exemplified today by the Anavex program or debut. Again, I do want to say, though, any incremental step is good for patients. And so if you're thinking about a clinical trial, we would certainly contemplate that because of the half-life, you could certainly do a washout. You can consider allowing that to be part of the treatment. I mean there's different ways we can think about this. But overall, we see it as a good thing for the Rett community. But what we truly believe is that what we're developing here is going to be highly, highly impactful on the disease.

I think you nailed all of the points that we're -- it's important that there are options for patients in Rett community. But again, coming to Sean's point, we need to get to the root cause of the disease rather than looking just at downstream effects of treatment. So we're encouraged by the fact that there are options available that there is research being done in the Rett community space, but I think there are different molecules and different approaches to the [ fleet ].

The next question comes from Geulah Livshits from Chardan.

A couple of quick ones for me. So you presented that comprehensive data from the model. But on an individual patient basis, what kind of correlation do you see between mFARS and metrics like SNAP changes as we think about biomarkers and certain end points that might get functional benefit? Trying to understand what that correlation might look like for individual patients? And then I have a follow-up after.

Salman, would you take that please?

Yes, absolutely. Great question. That's something that we think deeply about. And I think the difficulty here, however, is given the limited number of patients and the trends that we're seeing. It's difficult to go further to stratify the data to do a responder analysis. And the issue is that the limited data in the treatment effect sizes can lead to compounding results. Additionally, mFARS is a combination of central and peripheral nervous system programming. mFARS also has several outcome measures, several tools within them that are primarily heavily weighted towards the legs. So there could be a dampening of that responder analysis. However, again, with the low number of patients that we had, we did not feel that, that would be statistically feasible and appropriate method to then slice the data.

Got it. And so kind of following up on that same kind of thinking, you mentioned that there were some differences in the different components of mFARS like those could result in the [indiscernible] components or maybe likely less benefit in the ones that weigh more heavily towards the legs. So how do you think the FDA will view those type of analyses. You think you'll make the mFARS more holistically or looking at the individual components typically just how you plan to starts that with them?

I'll ask Suku to comment on that, but I would just say at a macro level, if you take a look at the commentary from the agency and some of the mechanisms they've been using to evaluate data and sometimes seek approval. There might be a clinical study plan that's got an endpoint of X, but then ultimately, what's used to approve the product is an ad-hoc analysis and a very few number of patients. So I think given this is an ultra-orphan disease, the approach that we're taking is we're basically showing that essentially no matter what you're looking at, that should be relevant biologically based on [Audio Gap] There is a treatment effect. And so we're going to certainly make sure that we emphasize appropriately what we did methodologically with MFM in the past what we're doing now with the new basin model, but also then getting deeper into the subscales and showing across the board how all these things are lining up in concert together, again, from the functional, clinical, electrophysiological, biological perspective. I don't know, Suku or Salman, if you could add to that.

So let me make a regulatory comment and then hand it over to Salman from a clinical standpoint. So as Sean pointed out, what we have observed recently is that the FDA has shown a lot more flexibility in the rare and ultrarare disease [Audio Gap] understanding the disease for itself and the disease process because once you understand the disease process, then you can put end points and efficacy measures into context. So for the sake of GAN, you have to keep in mind, right, that we repeated this stage for 60 years and older, which means the neurodegenerative process has already continued for many years, which means the effect of our therapy on the low extremities may not be as great as on the upper extremities. So when you deconstruct that and then fix into measures like with mFARS, MFM [Audio Gap] context. So even though the prespecified endpoints may have a certain set of measures that they're looking at. The FDA has also repeatedly now shown that they're open to disease progression models where appropriate. They are open to postop analysis in very specific subpopulations to show that therapeutic can have significant impact. And actually, when you talk to experts, for example, who [indiscernible] other neuromuscular disorders, DMD included, products have in the past have been approved on a biomarker because there is belief that this product is going to make a difference. It actually had clinical impact on many patients who [Audio Gap] that they have a similar discourse with the FDA to put things in perspective and in the appropriate clinical context, such that this product that we think has brought clinical impact in the GAN population and remain available to patients. Salman?

Yes. You'll see in our press release, the exact effect size, and I'll share that with you here that there is an approximately 99% probability of slowing mFARS by 31%. Now I want that 31% to hang in the air a little bit because that, to me, is quite a significant [Audio Gap] I want to be fully transparent with you, with the FDA and everybody, right? [Audio Gap] you might find what you want to find. But MFM is typically broken out into these dimensions. mFARS, I wouldn't want to keep slicing and dicing the data, right? We have 31% slowing for mFARS. That's quite great. And that's something that I think we rely on patients to tell us what matters to them and slowing to that degree, I think, is clinically meaningful.

The next question comes from Gil Blum at Needham.

First one for Dr. Salman. So a bit about SNAP scores. Would you expect to see activity in the legs as well as the arms given this is a measure of nerve activity and not muscle function directly?

Awesome question. [Audio Gap] with nerve conduction studies are the big fibers, large fibers. And when we zap them, we are literally -- the wire is just a cable, right, with instillation that then goes and intervates the area. If it's -- if you are zapping and there's no electrical wire underneath it, you're not going to get a response, a true response. You can get artifacts, you can get fake responses that might confuse you. But to the experts that do this test, you would not get a response in the leg, and that's what we see in these patients. The sural nerve sensory action potentials are not there. They don't come back. And again, that speaks for the importance of we need to get to this before it causes irreversible damage, right? You hit it on the head right there.

Okay. In a hypothetical sense, is there any sort of newly generated data that is from new patients that could improve your case with the agency here?

[indiscernible] you go ahead.

Yes. So Gil, we have the 14 patients that in the interventional trial, and we don't have any additional patients. But remember, again, this is an ultrarare disease, right? So the natural history database is the largest we'll ever have, which is 52 or 53 patients that have multiple end points measured. And if you think of the treated population of 14 patients, that is a pretty large percentage of this ultra-rare disease community, which we think is more than ample data to have a very intelligent, hopefully, progressive discourse with the FDA and other regulatory agencies as is necessary. So I hope that answers your question.

I can add a clinical part to this too. When your nerves degenerate, so you hit your funny bone and damage your ulnar nerve, right? You get the tingling and say you damage it so much at the nerve, you lose sensation in the hand. That nerve will grow about a centimeter a day, an inch a month. So you can imagine that from these patients, what we see is it's not an immediate change. It takes time, typically over a year before we start to see responses come back, right? So there's a time component to this, but also a very physiologic practical component that given how many patients we dose, the data that we have, it's quite promising.

So are you saying 5 years from now, the low extremity SNAP could come back.

Excellent question. From pathology study, some human pathology studies done decades ago, we know that there's dorsal root ganglion involvement. Now that's the neuron in the peripheral nervous system that then feeds out the exon to the rest of the body. Clinically, in neuromuscular world, when patients have a dorsal root ganglionopathy, boy, those are tough patients to treat. So when this damaged done, that is not coming back and those patients are devastated. So in the legs, what we see and what we know is that these dorsal root ganglion, they have degeneration, right? The axon is so damaged, the nerve gets damage, the neuron gets damage. Once that happens, they're not coming to back.

And the last one for the company, and this is a bit of an open-ended question. Are there any examples of regulatory agencies being okay with this sort of single arm not based on necessarily the primary endpoint. The only -- I can think of the Sarepta, but that's supported by a randomized study.

You want to take that one, Suku?

Yes. So that's a good question, Gil. So let me kind of deconstruct your question a little bit. So remember Peter Marks and CBER have been recently discussed, right, Operation Warp Speed looking at ultrarare diseases in a broader context being a lot more flexible. So it kind of opens the door, I think, for very creative-based analyzed data, especially when there is significant unmet medical need and the therapeutic intervention is actually significant clinical difference in the patient population being studied. Now if you go back, yes, there are a single-arm studies. I mean for example, even with Zolgensma, with spinal muscular atrophy the first-in-human was a single arm, and then they went on to Phase II, those are single-arm studies to get a natural history and then product obviously got approve, Sean and I are very intimately involved with that program. There are multiple other programs which have used disease progression models as a natural history comparator in many rare not so rare diseases as equally Alzheimer's disease. And if you want, there's quite a comprehensive list that we can share with you some time that will give you a broader perspective of where the FDA in general has been flexible. So I absolutely think there is significant opportunity here for us to work closely with the FDA and other regulators, share data set for disease progression model, which I think is more than appropriate for a comparator. And hopefully, [indiscernible] the therapeutic can be made available to patients.

Can I add that underlying your question and the FDA is concerned, right, is how do we address bias and effort dependency without having another arm. And to that, that's what the story was about. If we can add objective data, data that is not subject to bias, right, can we understand how they trend in the right direction and make it extremely, extremely unlikely that this would happen simply by chance that it would happen simply by effort? Sure. Patient might try it harder, but they can't try harder to make their SNAPs come back. They can't try harder to make the regenerative clusters come back. So when that put together with the clinical data with quantitative muscle testing, that feed into the clinical functional data, that feed into the activities of daily living. But to me, that's a compelling story that says sure, effort dependency, bias, sure there's more to it, right? And that's what we hope to get across.

Yes. Just one more comment on that, and it may be further clarification, Salman, but be part of the robustness of the model is that we took all of the data that was prespecified, all the endpoints that were prespecified and they went into the model. So from an integrity perspective of the data, there was no selectiveness of it. And the agency would've seen everything in a month.

Absolutely.

Yes, there is no selection.

We did statistical testing to see if there's any difference between the treatment group and natural history. We did not find statistical significant results to suggest such a thing. And then the disease progression model, as you're aware, statistics, you can make them say a lot of different things. But we purposely fed in everything that we had into the model to not create a complex model that fits the things we care about. It's a relatively simple model that is best fit for all the data, not just MFM, not just mFARS, right? And that can lead the penalties, right? You saw how dimension 1 was not as strong as I think [indiscernible]. But that's just what the data shows. And so it's in full transparency. It's in with the context of the picture that we show, what we show and we get what we do.

The next question comes from [indiscernible] at Goldman Sachs.

This is [indiscernible] on for Salveen. In the off chance that the FDA is not convinced by the analysis that you presented today or they continue to recommend another blinded study, what is the path forward for TSHA-120 in your view? Is there any color you could provide us on that in the off chance that happens?

I think we've said since the -- back in January that we're open to what we would consider the feasible approaches to conduct a study in which we could satisfy FDA's requirements. We think what we're putting forward does that. We're looking forward to a dialogue with the agency on this particular matter. They've got -- we referenced it in our script, there's guidance out there that we're following in terms of where the definition of well controlled is. So we think we're certainly meeting the standard in terms of what's acceptable to the FDA. If there's some alternative that comes out of the discussion that we think is feasible and practical, we would consider that. And what I've said from the beginning is if it comes back to, well, it has to be a placebo-controlled trial, we would have to really just evaluate all strategic considerations with the program because we think that would be an insurmountable ask given the size of the patient population. And it's part of the reason that the model is so helpful is because when you try to look at key values, with numbers to slow, they're meaningless.

Can I bring it back to the patient, right? When you think about what these patients endure in this rare disease to travel to the NIH to spend several days there, right? It's the parents taking time off work. It's the parents with multiple kids. It's the children who have this disease who have to sit in that tight plan with musculoskeletal issues, overnight, long flights. In a way, it's quite difficult to demand more from these patients. And this is a long study. And so if you again think about it from the patient, it's quite a difficult ask to say, well, let's keep dosing patients in lieu of what the data we have, right? So I think we have to be patient centric in everything that we do.

Yes. If I add to that, Salman, you strike a chord here because the question, this has become an academic pursuit of process or this is a very pragmatic evaluation of the data where if one is convinced that the product is really making a difference in the patient, let's make it available to the patient. That is where I see a finished [indiscernible] based on the data that I've seen; I think this is a product that needs to be made available to patients as soon as possible.

And I think that has no other treatment.

Exactly.

I would just close that out was simply saying, what you're hearing from the team is a strong conviction that the data that's currently available is the data that should be sufficient to get this drug approved for patients that are in high need. And then we're going to take a what we think is a very professional, respectful but we think data-driven supported a sort of approach with the agency to get this out there for all the reasons that we went through.

And I think we have time for one last question from Eun Yang at Jefferies.

I have a few questions on the GAN program. Can you remind us if there have been or there has been a therapy that was approved by the FDA based on a single center interventional trial? And the second question is you're expecting 4 more FDA meeting in third quarter. So when do we expect it to get an update from you on the meeting outcome? Lastly, if the FDA says the current data is sufficient for filing, what are the steps that you would need to be ready for filing?

Yes, I think I can give the first answer, which is where has there been an approval of a single center interventional trial. I can say personally, I was involved with the approval of vigabatrin for infantile spasms, which was data generated by Dr. Shields to UCLA. And that was approved, I want to say, back in 2009. Eun we can look -- I don't know if others in the room have something off the top of their head, but we can look to see if there are others as well. I mean the basis of the approval of Zolgensma was on a single center trial as well. I don't know any other examples.

In one sense, a single-center interventional trial adds strength as well because it's not that patients were simply selected from the region, they were selected overly.

That's right.

And it reduces inter-rater variability, right? The same machines were used, the same raters, which is quite helpful for data validity.

Right. And I was also going to add this was the NIH. This was an NIH driven study [indiscernible] government who's highly respected, and many of these stations came from some from outside the country and others from multiple geographies in the U.S. So by default, you could say even though it's single site, the patients came from different areas, and therefore, you could separate that out and say in the traditional trial, you could have 3 centers, the patients are going to 3 different centers. So -- and I think in an ultrarare disease, my anticipation there will be a lot of flexibility on evaluating this program, we'll comes to there as it's coming from the NIH.

And there's also 2 independent in review adjudicating the data [indiscernible] What was question number 2 and 3? [indiscernible] one at a time.

No problem. The second question is when you -- now you're expecting to meet with the FDA in third quarter, so when should we expect an update from you on the outcome of the meeting? And the last question is, if FDA says current data is sufficient for filing, what are the steps that you would need to do be ready for filing?

So when we'll update and what we need to do.

So let me -- so the second question, and I'll respond based on is obviously, once we get and once you have the meeting in Q3, the minutes usually come 30 days after the meeting. Then obviously, after we review the minutes and decide what you have to do, then Sean and the company will make appropriate disclosures based on SEC rules. And I lost the third question.

The third quarter question is when we -- if the FDA asked us to file then what do you need to be prepared for filing?

Yes. So obviously, the team -- the whole process once we have the meeting with the FDA and they give us a lawyer to do the BLA filing, we obviously have to make sure the databases as [indiscernible] as possible. That takes obviously a few months in working with the NIH to make it BLA filing ready. And we also have a CMC component, right? So that was module 3 that was also submitted to the FDA a few months ago. And we have to make sure that, that is acceptable from a technical comparability standpoint such that our clinical lots can be used as GMP products so that I think they were about 50 clinical lots available, so that could create a number of patients in this ultrarare disease, et cetera. So from the time we get the go ahead, assuming that so this all works out with the FDA, it could take us 6 months or more to get everything together to submit a BLA. But that's kind of an aggressive time line at the present time, okay?

Thank you for the question. This concludes the Q&A session. I'll just quickly turn it back to Sean for some concluding remarks before we wrap up.

Thanks, everybody, for taking the time. Hopefully, you appreciated the level of data and the rigor that the team has gone through to assess the GAN opportunity fully. We think we're putting the absolute best data-driven put forward with the agency and look forward to sharing feedback with you once we have that. That will really determine the next steps and the time line. So I don't want to project out 6 to 12 months. I think we have to be informed before we come back with official guidance on that. And additionally, on the Rett side, once we have the formal meeting of the IDMC on patient number one, we will then have more specifics around safety as well as available efficacy measures that we can share with you when we plan to do so. We anticipate that to be early in the third quarter. And at that same meeting, if the IDMC does feel that the safety data is sufficient, they would also inform us that we could proceed with dosing on the second patient. So we have a better understanding around timing of that as well. So we look forward to sharing updates with you. Thanks again for your time, and hope you all have a good day. Take care.