Good morning, and welcome to Taysha Gene Therapies 2023 R&D Day. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a brief Q&A session. As a reminder, 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, 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 the 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 31st, 2022. This investor event contains time-sensitive information that is accurate only as of the date of this live broadcast, June 28th, 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 lead 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 and the 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, we intend to share these findings with the FDA to further discuss a potential regulatory path forward. We've submitted a formal FDA meeting request, 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. We'll then review key aspects of the disease course and biology of GAN before sharing new data from the recent comprehensive analyses. Suku will present our regulatory strategy toward potential FDA approval for TSHA- 120, before we shift the focus to our Rett program.
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. 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 bi-allelic variants in the gigaxonin gene, which causes deficiency or complete loss of function of the gigaxonin, and the accumulation of intermediate filaments, resulting in the progressive worsening of motor function, vision, neurological, and respiratory function. GAN, at times, is misdiagnosed as CMT2 until the physicians realize 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 to this community.
TSHA-120 is a self-complementary, intrathecally delivered AAV9 gene therapy in clinical evaluation for GAN 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 codon-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 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 Institutes of Health or NIH.
Let's start with the natural history study. In 2012, the NIH initiated a comprehensive prospective longitudinal natural history study of GAN. The study is ongoing, and 53 patients aged three-21 years have been enrolled to date. 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 gene transfer treatment. The data were 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 in 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. 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 Bönnemann. The phase I/II dose escalation trial is an open-label, non-randomized trial in which patients are intrathecally dosed with one of four doses of TSHA-120. The endpoints for the 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 six to 14 years have been treated to date.
We have over seven 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 presented to the FDA in December 2022, an individual subject's own pre-study or leaving 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 from our initial submission to the FDA prior to the Type B end of phase I meeting was based on this patient and their own control model. Interestingly, preclinical data on TSHA-120 showed translational correlation between preclinical and clinical studies.
With TSHA-120, GAN knockout mice showed improved dorsal root ganglion pathology and motor function, both of which have translated to our human studies with improved sensory nerve integrity and 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 or stabilization in motor function and strength after treatment with gene therapy that were congruously seen in human studies. 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 MFM-32, 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 the effort-dependent nature of MFM-32 as a primary endpoint, considering the unblinded study design. Specifically, the FDA acknowledged moderate efficacy, but stated that because MFM-32 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 a more comprehensive analysis of the entire GAN database, given the data presented at the Type B end of phase II meeting was based on a 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 written questions to the FDA to further clarify feedback we had received in the meeting minutes.
In February 2023, the FDA responded and clarified that MFM-32 can be a relevant primary endpoint only in the setting of a randomized, double-blind, placebo-controlled trial, and acknowledged Taysha's challenge in designing such a study due to the ultra-rare nature of GAN. The FDA indicated it is open to regulatory flexibility in a controlled trial setting and willing to consider alternative 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 seven 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 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 acuity and nerve biopsies.
The data analysis has enabled development of a disease progression model, or DPM, that we've applied to cross-sectional and longitudinal data from all natural history patients 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 Biologics Evaluation and 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 outweighs 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's shift towards more flexibility in the clinical trial setting reinforces the potential to appropriately position the compelling and objective findings from our new comprehensive analysis to achieve FDA support for the sufficiency to submit a BLA based on existing data for TSHA-120 in GAN. Today, we are pleased to have share the initial findings from the data analysis and clinical relevance disease progression observed through natural history, and why we believe the data satisfies the FDA requirements for a 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 at Harvard Medical School and specializes in neuromuscular disorders. He completed his residency in neurology through Harvard Medical School at Brigham and Women's Hospital and 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 a year and a half and has been heavily involved in the comprehensive analysis of the totality of data. Dr. Bhai, I will hand it over to you now.
Thanks, Suku. 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. 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. Without them, again, we wouldn't be here. Special thank you to them. Now, I got to be honest, I'm excited. 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 life-shortening disease characterized by weakness and incoordination. There's more to it. That's where the complexity comes in. 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. 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. 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 limits how much recovery you can have. 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.
As a neurologist, I may be biased here, but the almighty 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. Nerves in the feet get damaged first in a length-dependent disease like GAN, followed by the arms. 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. 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 me as a doctor.
The onus 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 says they feel better, well, we need to go into the data to understand what that means. Can we capture that with outcomes? That's our goal today. We're going to talk about that. I'm going to try something different here. I'm going to ask you to stop taking notes. I'm 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. I want you to viscerally understand what patients like this go through. 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. Their visual acuity starts to go. Say you got up in the middle of the night to go to the restroom. You may be too young for that, but that does happen as we age. These patients, because of their poor visual acuity, it's like walking in dimmer lights, 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, their balance is off.
They're at risk of falling because of the balance, the incoordination, the weakness. They get to the restroom. They're about to brush their teeth. Well, because of the incoordination and weakness, you miss the toothbrush with the toothpaste. There's a little bit on there. Now as you start to try and brush your teeth, well, you're getting toothpaste all over your cheeks. No one likes that. I want to tell you from 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 legs start to go, we have a lot of accommodations for that. We have ambulatory aids, we have wheelchairs, we have power wheelchairs. What happens when the hands start to go? That's what the most.
You can't text, 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. 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 diseases. You lose interaction with your environment. You're unable to care for yourself. 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.
You see from the slide, all 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 in nerves, the axons get damaged, there's a die back, 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 is particularly involved, and the cerebellar outflow tracts also involved, so that's what produces some of the cerebellar ataxia. From a neuromuscular standpoint, this looks like a Charcot-Marie-Tooth, a CMT, so you get a length-dependent sensory motor neuropathy. What that leads to is poor sensation, which causes a sensory ataxia.
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 sad, you don't use it, you lose it, and there's muscle scarring. 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, classic GAN has significant CNS and PNS damage, central and peripheral nervous system damage. These patients have developmental 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 distally, hands and feet. They have weakness proximally, their hip and shoulder girdles.
They have weakness axially, they can't roll over in bed. Unfortunately, they pass away early in the late second to third decade of life due to respiratory failure. They have trouble swallowing, that puts them at risk of aspiration and respiratory issues. 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 a leukodystrophy. It's a disease of the peripheral nervous system that looks like Charcot-Marie-Tooth, 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 further the nerves are, the harder it is to get recovery.
The legs are less likely to respond than the arms, given the time of dosing these patients. Again, what matters most. for this ultra-rare disease, it's only palliative, and that's another key point here. How do we capture all this? With a complicated disease like this, us 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. That will give you a context to understand why we measured what we did. You'll also notice that there's 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 for me to hypothesize, you know, outcome X, easy, just measure that. That's our answer. That will tell us about what the disease does. It's not like that.
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. Let's start with MFM. I told you this disease involves the peripheral nervous system. You can see that in the bottom, in the green box. That's a performance, a functional outcome measure. We ask patients to do things. That tests 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, what I would say is that the biology can support that. 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. Why are they important? Well, because the CMAPs are a nerve to the muscle, and if they're there, I can tell you that there's a connection there, and we can activate the muscle. 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. Let's try something. I want you to close your eyes. I want you to put your hands out in front of you. Put your palms to the sky. Take your left pointer finger and touch your nose. Now 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. Patients with sensory issues where their SNAPs go away, where there's a sensory ataxia, they miss their nose. Their hands are shaky with the cerebellar ataxia. They might touch their ears, they might touch their eyes. You need your SNAPs to coordinate your muscles and the movement. If the SNAPs are getting better, well, that would make sense to me that it might support muscle function and help with MFM. We also have myometry, right? Objective strength measurements. You know, 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." Myometry adds numbers to that. Has a pressure gauge, we can calculate it, we can see it, we can track it. Adding the electrophysiology of the SNAP and CMAP 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." That's about strength. Of course, GAN is more complicated than that. What you see here in this neuroanatomy picture. Start with the brain. You know, this kind of neuroanatomy picture causes a lot of nausea for non-neurologists, we'll keep it simple. When you want to move your hand, say, to grab your pen, the motor cortex activates nerves, it doesn't go straight to your muscle.
It instantaneously checks it for coordination. You'll get signaling to the cerebellum, which coordinates your coordination, keeps your fingers from shaking. It's a kind of metric to make sure you reach your target and you're accurate. It goes to the basal ganglia, which helps with muscle tone, so that your muscles are nice and loose and they're not stuck in a position. It goes down your spinal cord to the corticospinal tract and then eventually gets to the muscle. 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 sensory nerve. You can see the circuitry is quite complicated, and there's issues with the circuitry in GAN. The reason I bring it up is because 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, that's because your cerebellum checks that movement. The reason why that's important is because that's what mFARS captures. That's what FARS captures, right? mFARS is just a pared-down version of FARS that's psychometrically valid. mFARS deals so much with cerebellum and the sensory ataxia component that it's important to look at the SNAPs, the sensory nerves. Let me show you what that looks like, right? A lot of neurologists don't even know what this exactly means. You see that picture on the bottom right? You hook up electrodes to where the sensation is, we know from anatomy where those nerves go.
We hook up those electrodes, you see G1, G2, and then you put an electrical stimulation where you see that cathode, and then it's measured by those electrodes. We're basically measuring what the nerve is doing when we zap it. That's all the SNAP is. 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. 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. 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 system. Additionally, we have ophthalmologic data, so you see logMAR up there in MRI.
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 outcomes. If you think of this as a pyramid, right? If we 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. Let's go down one step. How do we get to that? Well, we have our clinical functional endpoints, the clinician-reported outcomes, the performance outcomes, right? The performance outcome is MFM-32. The clinician-reported outcome is mFARS. That is a neurologic exam. I and 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 Kahesized. I'm a neurologist, and the big thing that we do is not rely on the tube of truth, which is MRI, right? We rely on the physical exam. That's mFARS. I would argue that that's an objective test. We have logMAR, right? It's basically a visual acuity. It's a transformation from the numbers you're used to, 20/20/200, into a way that we can compare numbers. You might say, "Well, that introduces bias." There may be lack of objectivity. Well, take it a step further. Remember that electrophysiology I just showed you, those nerve conduction studies, SNAPs and CMAPs. It's not subject to effort dependency, but it fits clinically with what the patients have. Take it a step further.
Look at the biology, look at the nerve biopsies, and see what that means. We used a Bayesian disease progression model. The reason we did this, you know, if you look at the data, if you look at ultra-rare diseases, there's limited data here. Simply using patient as their own control with limited run-in data, not using the natural history data, can be troublesome, right? It's good in some ways, but that has its downsides, too, and that's where the disease progression model comes in. It was really preempted when the FDA asked, "Is this a heterogeneous disease?" That's a good question, right? How can you compare if you're not sure that this is a homogeneous disease? When we 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 a neurodegenerative disease, and it accounts for limited pre-treatment data. It uses all of the natural history data from the classic GAN patients, creates a model, and tells you, "This is what disease progression looks like." 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. We have patients from the natural history cohort, where we do statistical analysis that does not show selection bias. We have those same patients in the trial from a single site, and we've treated approximately 25%.
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. 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 hand, to interact with their social environment, to be able to keep some independence, to reduce caregiver burden? Right. Those are the things that matter. The disease progression model allows us to do that. Surely, we want patients to walk again. We want gain of function rather than slowing of 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? That speaks to the windows of opportunity that we need to think about. Let me orient you before we get into the data. We think about effect size here, and when the effect size is between zero and one, we have slowing of disease progression to varying treatment effects, right? The closer it is to one, the higher the treatment effect. The closer it is to zero, the less the treatment effect. If you get to one to two, you're actually improving the disease. You're not just slowing it down. If you're less than zero, you're continuing to decline.
Now, here's an example of an ADL, social contact and engagement score that was pulled from mFARS, from mFM, excuse me. Now, you can see here that there's a treatment effect that's between zero and one, and we put gradations there, so you can see it's between 0.5 and 0.75, and you see the confidence interval around it. This you can say with approximately 100% probability, there is a positive treatment effect here. There's slowing of disease progression. We like that, right? We'll talk about how do we support what the patients tell us? Remember, the onus is on us. Let's take a look at that. Let's start with the patient, right? Let's start with the ADL, and then we can deconstruct to understand the clinical measures, the biology, and how that go together.
I told you the legs are further away. Would you, if you were to hypothesize, expect any improvement in the legs, like walking? I would not. 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. Take a look near the bottom of this forest plot. Patients, when they fill out the questionnaires related to FARS, and then when data is extracted in a validated way from MFM-32 to look at ADLs, you see that patients report that we are slowing progression of cutting food and handling utensils.
Like 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. Patients report here that there's slowing of progression, that they're able to do that longer. That's important. Another point that I'd like to make here is about trends, right? You might say, "Well, the effect size, some of them cross zero. That's not significant." 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, where 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 is extremely unlikely. Sure, one, two, that could happen, but several endpoints with a trend towards positive treatment effect is great. 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 very small number of patients. 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 their ADLs are slowing down, right?
Writing and technology is a way of interacting with the world. Social engagement, feeding yourself, taking care of yourself, those are measures that we see slowing the disease progression. I told you, this is the data here, and let me orient you to it. 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. That's what we see. The force plot on the top left, you see several measures that are to the left of zero and trends to the left of zero. 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 leg 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. 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. In fact, there's some measures that we're even improving disease. You see the ulnar SNAP down there, the median SNAP, the nine-hole pegboard time. That's in relation to the ADLs, right? Some of those are related to leg function. Now, walking might seem so simple, but it's a very complicated neurologic task 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. Of course, MFM-32, that is our primary outcome measure. Right? That's what the pre-specified outcome measure was. The goal with a disease like this is to look at the totality of data and to really understand and ask: Are we looking at the right measures? MFM-32 has a slight treatment effect. Take a look at the dimensions. Dimension one really looks at ambulation, looks at strength. Axially, looks at 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 two and three, though, that's what's important here.
Proximal muscle strength, especially in the arms, not the legs, shows a trend towards improvement. With the dimension three, it's distal hand and distal foot function, but there's a lot of distal hand function pieces in dimension three. 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 have hand function, right? We're buying time. 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? I broke that force plot out, same data, but I want to talk you through it. What we're seeing here, right, if we start from the top, there's dimension three, MFM-32. There's a positive treatment effect there.
We're slowing down disease progression. What I would say that goes with this dimension three are the ADLs that I've listed there. Writing 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 of my clinical experience. If we take the hand as important and say, "Okay, patients are reporting it, we have a clinical performance measure, MFM-32, dimension three, that says it looks like you're slowing down the disease." Is it effort dependent? Is it chance? Well, let me take you to the clinical data. Let me take you to the objective electrophysiology.
If we look at the median and ulnar sensory nerve action potentials, right? The median and ulnar nerve, just a quick neuroanatomy, are the nerves that feed sensation to the front of the hand here. They also feed all the muscles to 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. 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.
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 just zap 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. If the muscle is damaged enough, you may not get that strong of a response in your CMAP. That's what I hypothesized happened here. There is a treatment effect, not as strong as the SNAPs, but there is a treatment effect where we have a trend towards improvement. Excuse me, a trend towards slowing the disease. That should help with strength.
Can we back that up with clinical data, objective data? That's where MyoGrip, MyoPinch, MoviPlate come in, right? Those are the myo tools that are used to measure strength in a quantitative way. MyoGrip, you're gonna grab something and grip it like that. MyoPinch, you pinch like that. You may not be able to see my picture, but you're just pinching, you're gripping. Those show a treatment effect in terms of slowing disease progression. Again, which makes sense biologically, right? The CMAPs have gotten better. The SNAPs have, the CMAPs have slowed progression. The SNAPs have gotten better. That should feed in to the strength that we're measuring. MoviPlate looks at fatigue of the muscles of the wrist, the flexors and the extensors. That shows a trend towards improvement with an approximately 100% probability of doing so.
Right, we've got the nerve conduction studies, which are objective. We've got strength measurements that are objective, that show a trend towards improvement. We have myometry, same thing, quantitative measure of strength, looking at your biceps and triceps muscles, not related to median and ulnar nerve 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. Put that together and you might say, "Well, it makes sense now that Dimension three has slowed the disease progression." It makes sense that the ADLs related to hand and arm function are showing positive effects. 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 high probability of a positive effect. 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? 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. We're still working on finalizing the MRI data. That's quite a rich data set. If you were to say, mFARS captures 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. I think that's an important component because it is a validated measure for looking at cerebellar ataxia. Part of FARS is to look at nine-hole pegboard time, where you use your hand, you use dexterity, you use coordination, you use strength to put items into a pegboard. You go back and forth, you pick up an item, you put it on a pegboard, and you time that. 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.
I hope you can see the story here, where we have our functional, the performance measures, the clinician-reported outcomes of MFM, Dimension three, mFARS, right? We care about weakness, we care about coordination, we care about hand function, right? We wanna have patients have independence. You can see from the ADLs, that's what they score it. Then we back that up with clinical data, objective clinical data with electrophysiology. We back that up with myometry and myo tools to measure strength. 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. 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 deconstruct the outcome measures to understand how that could be. You know, I'm a neuromuscular neurologist. I have performed these electrophysiology studies all the time, and to me, seeing these SNAPs come back. 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 a neurodegenerative disease, biology typically does not come back. This is a progressive, monotonically declining disease. 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, the responses were zero, and they came back. To me, that's a wonderful thing.
That's not something I see or have ever seen clinically. I don't have as many gray hairs as 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 had stability or regeneration, right, nerve regeneration, the four out of five of those patients had regenerative clusters on nerve biopsy. Histologic evidence in terms of We have nerve regeneration of the sensory nerve or the neuron. To me, that is a great thing, right? That is objective, wonderful data that we can put together in the entire clinical picture. 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. Thankfully, it is safe. We have approximately seven years of clinical data that support the safety and tolerability of TSHA-120. There have not been significant safety issues. Keep in mind that these patients have been dosed at different times, so the longest safety period that we have is seven years. There's been no dose-limiting toxicity. It's been well tolerated at multiple doses. All serious 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 then resolved within a few days. What's the takeaway? Take a look at the bar graph.
You can see that from the early time point around infusion, so zero to three months, that's when most of the adverse events happen and they quickly taper off. 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. Let me summarize for you what we talked about, right? I hope my assignment came out to you. 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.
What we have to do is understand how weakness and ataxia can be measured, and that's where MFM-32 and mFARS come in. Of course, at the time where 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 more susceptible they are to injury. To me, it's a no-brainer. The legs, I would not have expected treatment effect. We didn't see that. 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. 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 to understand if there's a treatment effect or not. It gives us strength to use natural history as an external control arm. Importantly, we're able to support these clinician-reported, these functional, these performance outcome measures that could be subject to bias, that may lack objectivity at time. 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 peripheral 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. That's when we use the SNAP, that's when we use regenerative clusters on biopsy, that we see in a dose-dependent manner that support those clinical measures.
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 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 a neurologist expertise. 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 outweighs 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 set, 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 in interventional studies of rare disease and small patient populations. 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, MFM-32, and logMAR, electrophysiological measures including SNAP and CMAP, and biological measures including visual acuity and nerve biopsies. Importantly, when we model the rate of progression of these endpoints through the disease progression model, it showed disease slowing across multiple objective measures. The positive clinical response observed across multiple functional, objective, biological endpoints cannot occur by chance.
We believe this model addresses the FDA's concern 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 decrease the risk of subjective examiner interpretation variability, interventional study videos were examined by two independent physiotherapists who are well-published and recognized experts in neuromuscular outcome measures and quality control of 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 window for optimal clinical impact.
While SMA is a more rapidly progressive disease, the tenet that the earlier you treat the disease, the better the clinical outcome is, remains true for GAN. In addition to this compelling efficacy data, there are approximately seven 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 our pre-determined status support for the expanded use of accelerated approval for gene therapies in rare and severe indications with no approved treatments, are consistent with seeking rare approval based on the existing data.
We plan to use this new data to inform our discussions with the FDA regarding alternative study designs, additional objective measures, and ultimately a regulatory path forward. We anticipate a formal 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 this 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 bring TSHA-120 to patients with GAN.
Let's now transition to our Taysha 102 program in Rett syndrome. I will now turn the meeting over to Dr. Azar Rana, Head of Medical Affairs at Taysha, who will provide a Taysha 102 program update and overview. Azar?
Thank you very much, Suku. Hello, everybody. Welcome to the meeting. My name is Dr. Azar Rana. I'm the Head of Medical Affairs at Taysha. I bring nearly two 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 here at Taysha to be working closely on the development of the TSHA-102 program. Very excited to help advance the gene therapy field with this innovative approach, as well as bringing a potentially transformational treatment to the Rett syndrome community. Before we get into TSHA-102 and understand what makes TSHA-102 so innovative, if we could have the next slide, please. We first need to understand a little bit about the pathophysiology of Rett syndrome.
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 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 is one of the most common genetic causes of severe intellectual disability. Across the U.S., E.U., and U.K., we know that there's between 15,000-20,000 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. This unmet need highlights the urgency that is required to deliver disease-modifying treatments for Rett syndrome. You know, again, we're very encouraged by the opportunity to bring this potentially transformational gene therapy to patients and their families. Let's talk a little bit about the construct. I think it's first, it's a few concepts behind this disease and Rett syndrome. 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 chromosome inactivation and silencing of the MECP2 expression can occur randomly and in an autonomous manner. 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 MECP2 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 overexpression in CNS cells that are already expressing the MECP2. 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 microRNA or miRNA on target binding sites into the three prime untranslated region of viral genomes.
What that gives us is TSHA-102, which is this 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 MeP426, coupled with a miniature version of the MECP2 transgene, or a truncated version, if you will, of the MECP2 transgene, as well as an miRNA or microRNA responsive autoregulatory element, or miRare, which is our novel microRNA target panel packaged within this self-complementary AAV9 capsule. A little bit more about the miRare technology and how this works. To mitigate the risk of MECP2 overexpression and still restore MECP2 in cells where the protein is lacking, we utilize the miRare technology to mediate levels of MECP2 on a cell-by-cell basis.
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 is not needed, as you can see on the left-hand side of your slide. 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. Preclinical data, we have a very robust preclinical data package that supports the TSHA-102 and the miRARE technology. These are from studies across three different animal species.
We've conducted pharmacology studies in MECP2 knockout and wild type mice, and that was to ascertain the minimally effective dose that's required. We've also done mouse distribution and gene expression studies. We've done toxicology and biodistribution studies in rats as well as in non-human 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 male MECP2 knockout mice. This was presented at the ASGCT annual meeting in Los Angeles in May this year. What this data has demonstrated is the ability of TSHA-102 to regulate cellular MECP2 levels and significantly improve survival, growth, and overall neurobehavioral function in knockout mice, which are the three graphs that you see on the slide right now.
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, or 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. 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 overexpression, resulting from this mosaic pattern of MECP2 silencing that we see in females with Rett syndrome. 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. We believe that these findings translate or could translate into clinical benefits for treating patients with Rett syndrome. We're actively exploring this in the ongoing REVEAL phase I/II trial in adult females with Rett syndrome currently. The 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. The participants in this study will receive a single lumbar intrathecal injection of TSHA-102, and as per protocol, dose escalation will evaluate two separate dose levels sequentially.
The first cohort will receive a protocol-specified dose level of 5 x 10^14 total vector genomes. The second cohort will receive a protocol-specified dose level of 1 x 10^15 total vector genomes. The maximum tolerated dose or maximum administered dose established will then be administered as we go forwards into the dose expansion phase of these studies. Very excited that on June 5th, we announced the first adult patient dose for TSHA-102, which took place at the CHU Sainte-Justine at the Université de Montréal, 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 patient.
We're very pleased to share that the patient is 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. Subsequent REVEAL trial updates will be provided quarterly after quarterly thereafter. We have identified a second potential patient for this study as well. And the patient's undergoing screening. 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'll determine if we can proceed with the dosing of the second patient. TSHA-102 has received an Orphan Drug and Rare Pediatric Disease Designation from the FDA, as Suku mentioned. We've also been granted an Orphan Drug Designation from the European Commission for the treatment of Rett syndrome. 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. 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 now, please, for some closing remarks.
Thank you, Azar. 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 data support our growing body of evidence, reinforcing the ability of our innovative one-time treatments to overcome challenges that have limited other treatment approaches in these devastating disorders with high unmet need. The next six 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 UK 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 in 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.
Thank you very much, Sean. At this time, we'll begin conducting our Q&A session. As a reminder to our analysts, please raise your hand to indicate you would like to join the queue. To the rest of the audience, you may submit questions through the Q&A function at the bottom of the webcast player. As a reminder, you might have to exit full screen mode in order to access that function. With that, we'll now move into our Q&A section. Okay, the first question is going to come from Rick Miller at Cantor Fitzgerald. Rick, you may now go ahead and ask your question.
Hi, everyone, Rick Miller, from Cantor, on for Kristen. Thank you for taking our question. We just have one for you today. The rationale for looking at MFM results backed up by electrophysiology certainly makes sense. Given the positive effects 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? How are you thinking about objective measures to potentially support these kind of effects? Thanks.
Rick, that's a great question. I'll ask Salman to expand upon that. 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. 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, you know, program is. In concert with that, we will be working with, you know, 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. Let ask Salman to build on that.
Thanks, Rick. That's a great question. You know, 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. 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. 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. If we're able to understand the biology, the clinical data, the functional measures, and how they could potentially contribute to ADLs, right?
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. We appreciate the question. I hope that regulators also see it in that way, that it's what the patient says that matters.
Great. Thank you for the questions, Rick. The next question will come from Yanan Zhu at Wells Fargo.
Hi, thanks for taking the questions. I was wondering, 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 looked very encouraging. Is this kind of comparison admissible as endpoints for approval? Does it have to be the more conventional endpoints, like either mFARS or MFM-32, change from baseline in comparison to natural history? Thanks.
I'll, you know, give perspective on that and ask Suku, you know, to further opine on it. Again, I think what we have to do and what Salman did in his presentation was highlight that MFM-32 was the pre-specified primary endpoint. We'll certainly, you know, continue to demonstrate what's been exhibited by the therapy. Keep in mind, you know, the FDA acknowledged in the initial feedback that we got back at the end of last year that the efficacy demonstrated was moderately effective. Their concern was just trying to judge that, given in their view, it was effort-based and there wasn't a placebo control. I think now, if we look at MFM-32, we've got additional cuts looking at different domains. We can 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. To your point, we wanted to augment that with all the data. You know, Salman said it earlier: We didn't want to just pick one thing and hang our hat 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. 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. 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 CMAPs and some of the other things that all tie back to that to further support the case. Salman, please expound on anything I might have said.
I think that, I think that's a great question. You know, I think we have to take a step back clinically. We're constantly learning about and 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.
Something here. What I would also add is the following, and I'll keep this very concrete. Keep in mind, these patients were all greater than six years of age and had an ultra-rare neurodegenerative disorder. As Salman pointed out in his talk, these patients had already progressed significantly. The second point that I want to make, as Salman again highlighted, is we now have a very good understanding of this ultra-rare disease that never previously existed. We have access to the largest database in GAN. The third is the current FDA CBER position through Dr. Peter Marks and others, that is in an ultra-rare disease where there is no other therapeutic option when the benefit outweighs the risk. One should seriously consider making that product accessible to patients.
Finally, beyond everything else that, you know, 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 five patients in the ulna and median SNAP measurements. Beyond that, actually seeing the nerve clusters being regenerated. As Salman pointed that out, to us, that is a very strong translational signal that if we treated these patients with GAN much earlier at a much younger age, two to three years of age, our clinical effect would have been far more greater, potentially transformational, and we would have also most likely impacted the lower extremities long before the lower extremity nerves completely degenerated. Do you agree, Salman?
Absolutely. Maybe I'll give a convoluted metaphor here, so stick with me for a second. You know, if we consider the legs and the arms, right? The legs are further away, the arms are closer to the brain. As Suku 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?
That's a very interesting and important question. I think, yes, there's a very strong potential to use this as a surrogate endpoint 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.
Great. Thanks for taking the question.
Thank you.
Thank you.
Great, thank you for the question. The next question will come from Jack Allen at Baird, although he's traveling, so I'll 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 patients with 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, you know, Taysha is very engaged with patient communities across all the therapeutic areas that we interface with. Specific to GAN, you know, there are several that we've been working closely with, right? There's Hannah's Hope Fund, there's All In for Ethan, there's a Hereditary Neuropathy Foundation and the CMTA, which is the Charcot-Marie-Tooth Association. We definitely engage with them. You know, 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. You know, that's really helped us understand, you know, as we analyze the data, you know, we spent a lot of time on the ADLs because we also wanted to highlight what is meaningful to the patients.
The these groups have been very helpful in that. We've also embarked upon an exercise to work with families that have GAN, that have been treated and those that have not been treated to, again, you know, understand what it's like living with the disease. You know, call it not having been, you know, given the opportunity for gene therapy and then subsequent to gene therapy, to further inform, you know, how we approach and position the data with the FDA, as well as the unmet need. 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 a 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. We have a wonderful team here doing exactly what Sean said.
Thank you. Okay, MP, you may go ahead and unmute your line.
Thank you very much for taking my question, and thank you for outlining in such great detail all the endpoints and extra measures that you have. Just coming back to MFM-32, I really enjoyed the slide where you show the efficacy on the different dimensions. Obviously dimension 1 with the legs, the outcome was poor, but two and three were actually very good. Obviously, that impacts the efficacy. You know, if you just look at dimension two and three, efficacy size is much larger. Has the FDA looked at that in their previous MFM-32 analysis or not? 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. You know, we certainly would plan to share with them what you saw, as well as some of the, you know, I would call it traditional analyses that were done initially. I don't know, Salman, if you would add to that.
You know, our goal is to have full transparency, have a discussion, right? Our original analysis was based on frequentist, patient-led 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 Bayesian analysis, gives us that power. 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. It's a great point. It's something that we'll put together in this totality idea and give the narrative, right?
Great. Thank you. 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 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 synapse. It's simply the nerve and where you measure it on the skin. It's just one order, right? It's just one thing that we're doing. The motor nerve, I didn't put a picture up, and that probably would have helped. The motor nerve, when I zap the motor nerve, it travels through the motor nerve, it jumps across the neuromuscular junction and then fires onto the muscle, which then activates and creates that electrical activity. In the sensory nerve, we're measuring that electrical activity directly.
You can see how the motor nerves has three things that are being measured, and the sensory nerve has one thing being measured. If we go back to that principle of, well, muscles get sad when you don't use them, when the nerve is not connected to them, they become fibrotic. 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. 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.
If I may add, this is the reason we have to identify these patients and treat them early.
Absolutely.
Also, when you restore the sensory nerve action potential, this closes that feedback loop for the anterior horn cell and the motor, right?
Mm-hmm.
The axon to actually be stimulated and complete that circuit to the neuromuscular junction, so it continues to be functional. This is a collective circuit that has to be fixed early rather than later, right? Do you agree, Salman?
Absolutely.
Yeah.
Great. Thanks for the question. The next question will come from Joon Lee at Truist.
Hi, this is Mahdi on for Joon Lee. We have two questions, one for GAN and one for Rett. On GAN, you try to show homogeneity of disease for classic patients. Would it limit some, you know, eventual approval now that you have, like, good objective measures to classic patients, or it will be for the full, you know, cohort of GAN patients? I will ask the Rett question.
Yeah. 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, you know, Dr. Bhai here. We think GAN as a whole, whether it's classic or non-classic GAN 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 a defect in the gigaxonin cell and gene, and therefore accumulation of these intermediate filaments can result in the formation of these giant axons and then in the periphery or in the central nervous system, resulting in the same pathophysiology outcome. We feel that overall, our therapeutic intervention using the intrathecal Taysha gene therapy should be able to address both classic and non-classic GAN, in the sense that it's all GAN.
What we've also discovered when we evaluated the different diagnostic processes for GAN in the CMT2 category, based on the literature, and talked to some of the experts, at times there is misdiagnosis of patients who fall into that category of GAN, but they're misdiagnosed as CMT2. When additional genetic testing is done, they're identified as GAN. We feel that in part of our discussions with the FDA, what we hope to do is hopefully get a broader label such that all of GAN can be addressed with gene therapy or intrathecal. Do you want to add something?
I'd love to add that.
Yes.
There's a misnomer sometimes in the literature that might say non-classic GAN is mild. If you see any of these CMT patients of mine, and you tell them their disease is mild, you're in for some trouble. You know, these patients have high morbidity, and when it shows up early in life, like it does for these non-classic patients, right? You might say, "Well, CMT shows up later. They have trouble walking, they have strength." When the person's older, it has less emotional valence. These younger patients, right, it's absolutely crucial to understand that even non-classic GAN has significant morbidity for these patients. It's not just the peripheral nervous system. They, too, have a degree of central nervous system involvement. It is a disease that needs to be addressed and has the same pathophysiologic underpinning.
The only thing I'd add to that, by the way, is that, you know, Suku mentioned there's several publications out there that talk about a range of misdiagnosis that occurs, and it's not unexpected. In many rare diseases, you see underdiagnosis because there's no treatment. 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. Again, just to reinforce the genotype, the root cause of the disease is the same. It may express itself temporally a little bit different, but they're both devastating. To us, GAN is GAN.
Thank you very much. That's very helpful. To the Rett syndrome, today, Anavex, put out some results for their sigma-1 receptor agonist, which is basically preventing mitochondrial dysfunction and, you know, oxidative stress in this disease. How this would affect your positioning, thinking about this treatment for Rett patients, gene therapy for Rett patients, and any comment in that domain would be also appreciated.
I think you're talking about the Anavex program. I would say a couple things and turn it over to the docs. essentially, you know, it's a small molecule. You know, 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, you know, seven-week studies. You know, they may be a little bit longer in some of the non-U.S. countries. I would go back to, you know, it's similar to DAYBUE in that, you know, 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.
We think, you know, that by addressing the root cause and delivering, you know, the gene in an appropriate manner, we're gonna get a result that is much more dramatic than anything that's been exemplified today by, you know, the Anavex program or DAYBUE. I do want to say, though, any incremental step is good for patients. If you're thinking about a clinical trial, you know, we would certainly contemplate that. Because of the half-life, you could, you could certainly do a washout. You could consider, you know, 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.
What we truly believe is that what we're, you know, developing here is going to be highly impactful on the disease. Aneeza.
Yeah. I think you nailed all the points. It's important that there are options and for patients in the Rett community. 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. We're encouraged by the fact that there are options available, that there is research being done in the Rett community space, I think there are different molecules and different approaches to the treatment.
Thank you. The next question comes from Geulah Livshits, from Chardan.
Thanks for taking the questions. A couple of quick ones from me. You presented that comprehensive data from the model. On an individual patient basis, what kind of correlation do you see between mFARS and metrics like SNAP changes? You know, as we think about biomarkers or sort of the endpoints that might give functional benefit, trying to understand what that correlation might look like for individual patients. Then I have a follow-up after.
Sean, want me to take that?
Yeah, absolutely. Great question. That's something that we think deeply about. 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. The issue is that the limited data and the treatment effect sizes can lead to confounding 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. There could be a dampening of that response, responder analysis. However, again, with the low number of patients that we had, we did not feel that would be a statistically feasible and appropriate method to then slice the data.
Got it. kind of following up on that same, kind of thinking, you mentioned that there were some differences in the different components of mFARS, that, you know, it seemed like there was a good result in the pegboard, time components, but maybe a slightly 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? Do you think they'll look at the mFARS more holistically or, you know, looking at the individual components separately? Just how you plan to discuss that with them.
You know, I'll let 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, you know, there might be a clinical study plan that's, you know, got an endpoint of X, but then, you know, ultimately, what's used to approve the product is an ad hoc analysis of a very few number of patients. 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. There is a treatment effect.
We're gonna certainly make sure that we emphasize appropriately what we did methodologically with MFM in the past, what we're doing now with the new Bayesian 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, and biological perspecti.e. I don't know, Suku or Salman, if you-
Let me make a regular further comment and then hand it over to Salman from a clinical standard and expert comment. As Sean pointed out, what we've observed recently is that the FDA has shown a lot more flexibility in the rare ultra-rare disease. In, A, understanding the disease for itself and the disease process, because once you understand the disease process, then you can put endpoints and efficacy measures into context. For the sake of GAN, you have to keep in mind, right, that we've repeated this at this stage for six years and older, which means the neurodegenerative process has already continued for many years, which means the effect of our therapy on the lower extremities may not be as great as on the upper extremities. When you deconstruct that and then proceed to measures like whether it's mFARS, MFM. Context.
You right. The pre-specified 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 posthoc analysis in very specific subpopulations to show that a therapeutic can have significant impact. Actually, when you talk to experts, for example, who treat other neuromuscular disorders, DMD included, products that in the past have been approved on a biomarker because there's belief that this product is going to make a difference, it actually has significant clinical impact on many patients who. We have a similar discourse with the FDA to put things in perspective and in appropriate clinical context, such that this product that we think has broad clinical impact in the GAN population can be made available to patients. Salman.
Yeah. You know, you'll see in our press release, the exact effect sizes, and I'll share that with you here, that there is a approximately 99% probability of slowing mFARS by 31%. Now, I want that 31% to hang in the air for a little bit, because that, to me, is quite a significant. I want to be fully transparent with you, the FDA, and everybody, right? Like. You might find what you want to find, but MFM is typically broken down 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, you know, we rely on patients to tell us what matters to them. And slowing to that degree, I think is clinically meaningful.
Okay, thanks for the question. The next question comes from Gil Blum at Needham.
Hi, everyone, thanks for squeezing me in. The first one for Dr. Salman . A bit about SNAP scores. Would you expect to see activity in the legs as well as the arms, given this is, you know, a measure of nerve activity and not muscle function directly?
Awesome question. With nerve conduction studies are the big fibers, large fibers. When we zap them, we are literally, the wire is just a cable, right? With insulation that then goes and innervates an area. 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. Again, that speaks to 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?
You.
Sorry, we don't have. Oh, you go ahead. Yeah. Gil, we have the 14 patients that were in the interventional trial, and we don't have any additional patients. Remember, again, this is an ultra-rare disease, right? The natural history database is the largest we'll ever have, which is 52 or 53 patients, that we have multiple endpoints measured. 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 necessary. I hope that helps address the question.
I can add a clinical part to this, too.
Yeah.
You know, when your nerves degenerate, say you hit your funny bone and damage your ulnar nerve, right? You get the tinglies, and say you damage it so much that the nerve, you lose sensation in the hand. That nerve will grow about a centimeter a day, an inch a month. 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. There, there's a time component to this, but also a very physiologic practical component that if, you know, given how many patients we've dosed, the data that we have, it's quite promising.
Are you saying five years from now, the lower extremity SNAP could come back?
Excellent question. From pathology studies, from 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 axon to the, to the rest of the body. Clinically, in neuromuscular world, when patients have a dorsal root ganglionopathy, boy, those are tough patient situations. When it's damaged and gone, that is not coming back, and those patients are devastated. 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 damaged, the neuron gets damaged. Once that happens, they're not coming back.
All right. Thank you. 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, you know, single arm, not based on necessarily the primary endpoint? The only I can think of is Sarepta, but that's supported by a randomized study.
You want to take that one, Suku?
Yeah. That's a good question, Gil. Let me kind of deconstruct your question a little bit. Remember what Peter Marks and CBER have been recently discussing, right? Operation Warp Speed, looking at ultra-rare diseases in a broader context, being a lot more flexible. It kind of opens the door, I think, for very creative ways to analyze data, especially when there is significant unmet medical need, and the therapeutic intervention is actually making significant clinical difference in the patient population being studied. If you go back, yes, there are single arm studies. I mean, for example, even with Zolgensma, spinal muscular atrophy, the first in human study was single arm, and then when they went on to phase III, those were single arm studies compared to natural history, and that product obviously got approved.
You know, Sean and I were very intimately involved with that program. There are multiple other programs which have used disease progression models as the natural history comparator in many rare, not so rare diseases, including Alzheimer's disease. If you want, there's quite a comprehensive list that we can share with you sometime that will give you a broader perspective of where the FDA in general has been flexible. I absolutely think there's significant opportunity here for us to work closely with the FDA and other regulators, share our data set, the disease progression model, which we think is more than appropriate for a comparator, and hopefully gain approval such that the therapeutic can be made available to patients.
Can I add that, you know, underlying your question and the FDA's concern, right, is how do we address bias and effort dependency without having another arm? To that's what the story was about. If we can add objective data that is not subject to bias, right? Can we understand how they trend in the right direction and make it extremely unlikely that this would happen simply by chance, that it would happen simply by effort? Sure, a patient might try 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. 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, right? To me, that's a compelling story that says, sure, effort, dependency, bias.
Sure, but there's more to it, right? That's what we hope to get across.
Yeah, absolutely. Yeah.
You know, just one more comment on that, and it may need, further clarification, Salman, but I mean, part of the robustness of the model is that we took all of the data that was pre-specified, all the endpoints that were pre-specified, and they went into the model. From an integrity perspective of the data, there was no selectiveness of it, and the agency would see everything. There is no selection.
We did statistical testing to see if there's any differences between the treatment group and the natural history. We did not find statistically significant results to suggest such a thing. The disease progression model, as you're aware, you know, statistics, you can make them say a lot of different things, but we purposefully 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? That can lead to penalties, right? You saw how dimension one was not as strong as ideally anybody would like, but that's just what the data shows. It's in full transparency.
It's in with the context of the picture that we show what we show, and we did what we did.
Thank you, all. The next question comes from Sunatra Nisha at Goldman Sachs.
Hi, this is Sunatra on for Salveen. Thank you for taking my question. 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 clarity you could provide us on that in the off chance that happens?
Yeah, I think we've said since the, you know, back in January, that we're open to what we would consider to be feasible approaches to conduct a study in which we could satisfy FDA's, you know, requirements. We think what we're putting forward does that. We're looking forward to a dialogue with the agency. You know, on this particular matter, you know, we referenced it, you know, in our, in our script. You know, there's guidance out there that we're following in terms of what the definition of well-controlled is. We think, you know, we're certainly meeting, you know, 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, you know, we would consider that.
You know, what I've said from the beginning is, if it comes back to, well, it has to be a placebo-controlled trial, you know, we would have to really just evaluate, you know, all strategic considerations with the program, because we think that would be, you know, an insurmountable ask, given the size of the patient population. You know, it's part of the reason that the model is so helpful is because when you try to look at p-values with numbers this low, 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 plane 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. 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? I think we have to be patient-centric in everything that we do.
Yes, if I can add to that, Salman, you know, you strike at the core here, because the question is, does this become an academic pursuit, a process, or is it 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?
Yes.
That is where I sit as a clinician, 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.
In a disease that has no other treatment.
Exactly.
I would just close that out with simply saying, you know, 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. We're going to take a, what we think is a very, you know, professional, respectful, but we think data-driven, supported, assertive approach with the agency to get this out there for all the reasons that we've went through.
Thank you. I think we have time for one last question, from Eun Yang at Jefferies.
Thank you very much. I have a few questions on the Gene 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? The second question is, you are expecting formal FDA meeting in third quarter, when do we expect to get an update from you on the meeting outcome? If the FDA says the current data is sufficient for filing, what are the steps that you would need to be ready for filing? Thank you.
Yeah, I think I can get the first answer, which is, you know, 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 at UCLA. you know, that was approved, I want to say, back in 2009. Eun Yang, we can look, and 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, you know, a single-center trial as well. I don't know any other examples.
You know, 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 globally.
That's right.
It reduces inter-rater variability, right? The same machines were used, the same raters, which is quite helpful for data validity.
Right. I was also going to add, this was the NIH.
Yeah.
This was an NIH-driven study, the PI being Dr. Carsten Bönnemann , who's highly respected. Many of these patients came from some from outside the country and others from multiple geographies in the U.S. By default, you could say, even though it's a single site, the patients came from different areas, and therefore you could separate that out and say, in the traditional trial, you could have three centers, the patients go to three different centers. I think in an ultra-rare disease, I, my anticipation is there'll be a lot more flexibility on evaluating this program when it comes to the data set coming from the NIH.
There's also two independent.
Mm-hmm.
Reviewers adjudicating the data.
Right.
Yeah. What was question number two and three?
You love your question.
Can you take it one more?
Yeah, no problem. Second question is, when you're expecting to meet with FDA in third quarter, When should we expect an update from you on the outcome of the meeting? The last question is: If FDA says current data is sufficient for filing, what are the steps that you would need to be ready for filing?
When will we update and what we need to do?
The second question, and I'll respond based on what I think I heard, is obviously once you get and once you have the meeting in Q3, the minutes usually come 30 days after the meeting. Obviously, after we review the minutes and decide what we have to do, then, you know, Sean, the company will make appropriate disclosures based on its EC rules. I lost the third question.
The question is, when we, if the FDA asks us to file, what do we need to be prepared to file?
Oh, yeah. Obviously the team, you know, the whole process, once we have the meeting with the FDA and they give us the go ahead to do the BLA filing, we obviously have to make sure the database is as clean as possible. That takes obviously a few months in working with the NIH to make it BLA filing ready. We also have a CMC component, right? 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. That's, I think, we have about 50 clinical lots available, so that could treat a number of patients in this artery disease, et cetera.
From the time we get the go-ahead, assuming that's how this all works out with the FDA, it could take us six months or more to get everything together to submit a BLA. But that's kind of an aggressive timeline at the present time. Okay?
Thank you.
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. You know, we think we're putting the absolute best data-driven foot forward with the agency and look forward to sharing feedback with you once we have that. That'll really determine the next steps and the timelines. You know, I don't want to project out six to 12 months. I think we have to be informed before we come back with official guidance on that. Additionally, on the Rett side, you know, once we have the formal meeting of the IMC on patient number one, we will then have, you know, more specifics around safety as well as available efficacy measures that we can share with you, we plan to do so.
We anticipate that to be early in the third quarter. 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 a second patient. We'd have better understanding around timing of that as well. We look forward to sharing updates with you. Thanks again for your time. Hope you all have a good day. Take care.