Thank you for standing by. Welcome to Taysha Gene Therapies third quarter 2022 financial results and corporate update conference call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a brief question and answer session. As a reminder, this call is being recorded today, November 8, 2022. I will now turn the call over to Dr. Kimberly Lee, Chief Corporate Affairs Officer. Please go ahead.
Good morning and welcome to Taysha's third quarter 2022 financial results and corporate update conference call. Joining me on today's call are R.A. Session II, Taysha's President, Founder, and CEO, Dr. Suyash Prasad, Chief Medical Officer and Head of R&D, and Kamran Alam, Chief Financial Officer. After our formal remarks, we will conduct a question and answer session, and instructions will follow at that time. Earlier today, Taysha issued a press release announcing financial results for the third quarter ended September 30, 2022. A copy of this press release is available on the company's website and through our SEC filings. Please note that on today's call, we will be making forward-looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational product candidates, as well as the strategic investment by Astellas.
These statements may include the expected timing and results of clinical trials for our product candidates, our expectations regarding the data necessary to support regulatory approval of TSHA-120, and the regulatory status and market opportunity for TSHA-120, TSHA-102, and Taysha's other clinical programs, as well as the potential benefits of the strategic investment by Astellas, including the potential for Astellas to exercise any of the options we granted to them. This call may also contain forward-looking statements relating to Taysha's growth and future operating results, discovery and development of product candidates, strategic alliances and intellectual property, as well as matters that are not of 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 and preclinical studies of 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 the risks and uncertainties that we face, please see the reports that we have filed with the Securities and Exchange Commission. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, November eighth, 2022. 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 SEC, applicable securities law.
I would now like to turn the call over to our President, Founder, and CEO, R.A. Session II. R.A.?
Thank you, Kim. Good morning and welcome everyone to our 2022 third quarter financial results and corporate update conference call. I am very proud of what the company has accomplished in the past few months. The strategic investment from Astellas and the successfully completed public follow-on offering have strengthened our balance sheet and extended our cash runway into the first quarter of 2024. We are excited about the recent strategic investment from Astellas to support the development of Taysha one twenty for giant axonal neuropathy or GAN and Taysha one oh two for Rett syndrome. The partnership with Astellas underscores the therapeutic and market opportunity of these two programs, and importantly, further validates our scientific approach of combining established gene therapy technology with innovative targeted payload design.
Under the terms of the agreement, Astellas will make a $50 million investment in Taysha in exchange for 15% of Taysha's outstanding shares, pre-follow-on financing, as well as an exclusive option to license the worldwide development, manufacturing, and commercial rights to TSHA-120 in GAN for a period of time after receipt of the formal Type B end-of-phase 2 meeting minutes from the FDA. Astellas will also receive an exclusive option to license the worldwide development, manufacturing, and commercial rights to TSHA-102 in Rett syndrome for a period of time after we provide Astellas access to certain clinical data from the planned Rett female pediatric study. Astellas will also receive a right of first offer related to a change in control of Taysha for a period of time after receipt of the Rett clinical data package.
To further strategically align the two companies, Astellas will also receive one board observer seat on the Taysha board of directors, enabling us to leverage Astellas' clinical and commercial expertise. The economics associated with the potential licenses will be negotiated by both companies at a later date should Astellas decide to exercise any of its options. Next slide. We believe we have selected the best possible partner in Astellas, a premier biopharmaceutical company that has built global R&D, manufacturing, and commercialization capabilities. Astellas is a dedicated leader in the field of gene therapy with large-scale, fully integrated in-house GMP manufacturing. Building upon Astellas' acquisition of Audentes, this partnership fits strategically within their long-term vision of expanding its gene therapy capabilities and enhancing focus on genetic regulation to ultimately bring new transformative gene therapies for serious genetic diseases with limited treatment options.
We believe Astellas' clinical development and commercialization experience, combined with Taysha's capabilities and know-how in gene therapy will help us achieve our shared objectives. We look forward to this partnership and the potential to bring life-changing treatments to patients around the world. In 2023, we expect to provide an update on the regulatory pathway for TSHA-120 in GAN in January, following our Type B meeting in phase 2 with the FDA. In addition, we intend to disclose preliminary clinical data for TSHA-102 from the first cohort of adult patients with Rett syndrome and initiate a phase 1/2 clinical study for TSHA-102 in female pediatric patients with Rett syndrome in the first half of 2023. I will now turn the call over to Suyash to discuss our clinical programs. Suyash?
Thank you, R.A. Good morning, everyone. Our two lead clinical programs have generated a significant amount of compelling evidence and have exciting upcoming milestones that could support their potential to make life-changing impacts for patients worldwide. I'll begin with a recent update on TSHA-120 for GAN. Our GAN program includes a comprehensive and robust clinical package that is supported by evidence generated across multiple clinical, functional, neurophysiological, and pathological endpoints. These include the MFM-32 Motor Function Assessment, demonstrating clinically meaningful slowing of disease progression across all therapeutic dose cohorts compared to natural history decline, with a durability of effect observed up to five years post-dosing. The progressive loss in visual acuity towards blindness, as assessed by logMAR, stabilized after treatment with TSHA-120.
This was supported by the findings in retinal nerve fiber layer thickness, or RNFL, as assessed by optical coherence tomography, which demonstrated stabilization and prevention of further retinal tissue loss following TSHA-120 treatment. Electrophysiologic nerve conduction studies support recoverability, stabilization, and in some cases, improvement in sensory response in patients treated with TSHA-120. Nerve biopsies confirm that treatment with TSHA-120 result in active regeneration of nerve fibers. Lastly, CMC comparability testing validated that our clinical and commercial-grade material are comparable via our release assays and next-generation sequencing. We have a Type B end-of-Phase 2 meeting scheduled with the FDA via teleconference on December 13, which will enable us to have discussions regarding a pathway to a BLA filing. We expect receipt of the formal meeting minutes by mid-January, at which time we will provide an update. Next slide, please.
We continue to work with regulatory agencies with the goal of achieving conditional approval in Europe and accelerated approval in the United States based on EMA and FDA industry guidance for gene therapies in neurodegenerative diseases. Based on key registrational requirements from regulatory agencies, including the FDA and EMA, we have outlined some possible scenarios for approval. In Europe, we believe there is potential to file for conditional approval based on current dataset per EMA guidance documents. In the U.S., the first scenario is immediate filing for approval based on the current dataset and comparability. The second scenario, which we view as our base case, sees us dosing a few more patients to demonstrate comparability of clinical effect between clinical and commercial-grade material, which was a similar approval pathway for Zolgensma in spinal muscular atrophy.
The last scenario is to initiate a new pivotal trial, which we think is unlikely given the recently published final guidance document on human gene therapies for neurodegenerative diseases and the extensive long-term safety and efficacy dataset available. Next slide, please. Let's move on now to TSHA-102, the first and only gene therapy in clinical development for Rett syndrome. TSHA-102 utilizes the novel microRNA, or miRNA, responsive autoregulatory element platform to regulate transgene expression genotypically on a cell-by-cell basis. The totality of preclinical data generated to date for TSHA-102 represents the most robust data package supporting the clinical advancement of a gene therapy in Rett syndrome. This includes preclinical data in neonatal Rett knockout mice demonstrating near normalization of survival, normalization of body weight, and normalization of behavior as assessed by the Bird Score.
Pharmacology data demonstrated significant improvement in survival, body weight, motor function, and respiratory health across treatment ages in Rett knockout mice. Toxicology data supported a favorable safety profile of TSHA-102 in wild-type rats up to doses four-fold over the clinical starting dose. Nerve conduction studies remained in the normal range, signifying no evidence of dorsal root ganglia inflammation or other neuropathic deterioration. Lastly, toxicology data in non-human primates demonstrated that all doses studied were well-tolerated while showing broad biodistribution to the brain and spinal cord. Importantly, NHP studies demonstrated that the down-regulatory miRARE platform worked well with low levels of RNA and minimal expression of MeCP2 in wild-type cells, which have normal pre-existing levels of MeCP2. These four preclinical studies together represent a comprehensive and robust package supporting the clinical advancement of TSHA-102 for Rett syndrome.
Our first-in-human Phase 1/2 trial of TSHA-102 for Rett syndrome, also known as the REVEAL study, is ongoing. Considering our partnership with Astellas and our intent to provide them with a more comprehensive data set, we now expect to report preliminary clinical safety and efficacy data from the entire first cohort that includes up to 6 adult patients with Rett syndrome in the first half of 2023. Also, in the first half of 2023, we intend to initiate a female pediatric study in Rett syndrome. As a reminder, TSHA-102 has received orphan drug and rare pediatric disease designations from the FDA and has been granted orphan drug designation from the European Commission. In summary, we believe we have a compelling and robust clinical package for TSHA-120 in GAN and preclinical package for TSHA-102 in Rett syndrome.
We are extremely excited about the strategic investment and support from Astellas and look forward to providing additional updates in the first half of 2023 for our two lead clinical programs. With that, I'll turn the call over to Cameron to review our financial results. Cameron?
Thank you, Suyash. This morning I will discuss key aspects of our financial results for the third quarter ended September thirtieth, 2022. More details can be found in our Form 10-Q, which will be filed with the SEC shortly. As indicated in our press release today, research and development expenses were $16.4 million for the three months ended September thirtieth, 2022, compared to $39.5 million for the three months ended September thirtieth, 2021. The $23.1 million decrease was due to a reduction of $11.7 million in research and development, GMP, manufacturing, and other raw material purchases. Additionally, we incurred $6.7 million less expense in third-party research and development consulting fees, primarily related to non-clinical GLP toxicology studies, and a decrease of $4.7 million in employee compensation expenses.
General and administrative expenses were $8.7 million for the three months ended September 30, 2022, compared to $11.2 million for the three months ended September 30, 2021. The decrease of approximately $2.5 million was primarily due to a reduction of $1.3 million in professional fees related to pre-commercialization, recruiting, and patient advocacy activities. Additionally, compensation expense decreased by $1.2 million compared to the same period in 2021. Net loss for the three months ended September 30, 2022 was $26.3 million or $0.64 per share as compared to a net loss of $51.2 million or $1.35 per share for the three months ended September 30, 2021.
As of September 30, 2022, the company had cash and cash equivalents of $34.3 million, which does not include the recent $50 million strategic investment from Astellas or the net proceeds of $25.6 million generated from the follow-on offering closed in October 2022. We expect that the existing cash and cash equivalents, along with the investment from Astellas and the net proceeds received from the public offering, will enable funding of operating expenses and capital requirements into the first quarter of 2024. With that, I will hand the call back to Ra.
The next 6 to 12 months will be a busy time for Taysha. On December thirteenth, we are scheduled to have a teleconference with the FDA to discuss the pathway to a BLA filing for Taysha one twenty in GAN. We expect to provide a regulatory update on the program once we receive the final meeting minutes from the FDA, likely in mid-January of 2023. In the first half of 2023, we anticipate clinical data for Taysha one oh two from the entire first cohort of adult patients with Rett syndrome and intend to initiate a female pediatric study in Rett syndrome. We look forward to providing updates on our progress throughout the year.
We will now open the call for questions. To join the question queue, you may press star then one on your telephone keypad. You'll hear a tone acknowledging your request. If you're using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press star then two. You are asked to limit yourself to a single question with no supplemental. Our first question is from Gil Blum with Needham & Company. Please go ahead.
Good morning, everyone, and thanks for taking our question. Maybe one on Astellas here. Can you remind us if Astellas has experience in manufacturing of AAV9-based genetic medicine? I can't remember exactly what the Audentes vector was. Thank you.
Hey, Gil. Good morning. Thanks for the question. Maybe I'll start, and then I'll turn it over to Fred because he's had an extensive experience with the gene therapy manufacturing group over at Audentes and actually took a tour of the new manufacturing site in Sanford. The original Astellas programs in Pompe and in X-linked myotubular myopathy, those are AAV8 programs, not AAV9 programs. What I will say is the manufacturing is nearly identical. They're using HEK293 triple plasmid transfection and suspension just like we are. As we were actually building our facility that we've now paused, the layout was almost identical. We feel like there's a significant opportunity to be able to leverage that asset as the collaboration moves forward. I'll pause there.
Fred, maybe you wanna give some insight.
Sure. Yeah. Thanks, Ra. I certainly agree with you. I think, while
Astellas' main experience is in AAV8. The platform manufacturing approach that Astellas is taking, and we are developing at Taysha are really complementary. You know, it's our intention that as we move forward our programs, that it's really our know-how that will follow these programs through, in partnership with Astellas or independently. I think it's still, again, very well suited to a collaboration. Thanks for the question.
The next question is from Yun Yang with Jefferies. Please go ahead.
Hi. This is Max Chandler on for Yun Yang. Thank you for taking the question. Just wanted to know, with Astellas' option for TSHA-120 available for a period of time following the receipt of those minutes, are there any specified outcomes from the end of that phase 2 meeting or that Type B meeting with the FDA for Astellas to opt-in? Are you expecting any anything there?
Good morning. It's a really good question. You know, so what we've shared with Astellas is the full dataset from that study as presented to the FDA. We've also shared with them the range of possible outcomes that we've laid out for you guys and what we kind of consider the base case, that being, you know, to dose a few more patients, let's call it 3-5, for, you know, somewhat of a period of time, hopefully around 6 months or less in order to show in order to kind of demonstrate clinical comparability. That's something that we've been consistent with in our communication with them.
One thing I will say is I can't speak for Astellas and how they would make their decision, but this is the way that we framed the conversation with Astellas, and they're fully aware and understand, you know, how either one of those scenarios could play out. I think what's most important to them is the fact that this is a severe neurodegenerative disease with no treatment alternatives. The fact that the dataset here is as robust as it possibly can get for gene therapy asset. Also, the fact that we have not only long-term safety, but long-term durability, long-term efficacy, functional endpoints, pathological endpoints, and really one that I think lends itself ultimately to a high probability of success of an eventual approval.
I think that's the way that they're framing it versus, you know, one particular outcome or another. But again, I think that's probably a better question posed to Astellas. The way that I've laid it out to you today is the way that we framed it for them.
The next question is from Geulah Livshits with Chardan. Please go ahead.
Hi. Good morning. Thanks for taking our question. We're wondering if you could give some color on how a potential registrational trial design would be similar or different from the ongoing phase 1 or 2 in Rett syndrome in terms of the control group, patient types, and endpoints. If you have an understanding of, among the several functional outcome buckets, if there are any particular ones that carry more weight in the eyes of regulators or experts in the space.
Hey, Geulah, good morning. Thanks for the question. I'll turn that question over to Suyash to discuss how we're thinking about a pivotal design for Rett syndrome. Suyash?
Sure. Thank you for the question. Yeah, I think it's an interesting one. You know, we actually know we're moving forward to the adult study. Currently this clinical trial is ongoing and the intent is to open up the pediatric study in the first half of next year. I think a registration-enabling study will really focus on the pediatric population more than anything. I think this is the key population that is of interest, but that also will be applicable to the wider population because we do feel the gene therapy will be applicable to all populations across the age spectrum in Rett syndrome. In terms of differences between a registration-enabling pediatric study and an adult study, the buckets are the same. The buckets of assessments are the same, i.e., one big bucket is looking at seizures.
How frequently are the seizures? How severe are they? How long are they? Can we reduce the burden there? Another bucket is looking at specific Rett-type behavioral assessments, such as the Rett Syndrome Hand Function Scale, the Rett Syndrome Behavior Questionnaire, and there's two or three others that we include in both the adult study and the pediatric study. Another big bucket is looking at autonomic features of disease, i.e., the respiratory outcomes, which we've demonstrated very clearly an improvement in the animal studies and which we know from a patient and family perspective is incredibly distressing to both adults with the disease and children with the disease. We're also looking at communication capability as a bucket and also a mix of different biomarkers, whether they're exploratory CSF or blood-based biomarkers or EEG neurophysiological biomarkers.
The buckets are the same from the adults to the children. Some of the specific assessments are a little bit different, i.e., there are some specific assessments that are more relevant for children than for adults. One example would be the Bayley Scales of Infant and Toddler Development, which looks at development progression across early childhood. That's a scale we'll be including within the actual pediatric study that is not in the adult study. I think there's a lot we can learn from the adult study that moves into the pediatric study. I do think that the likelihood is that registration enabling study, and we're looking a long way out now here. A registration enabling study will most likely be in the pediatric population, but the bucket span points are generally the same. I'll stop there.
Thanks, Suyash. Thanks, Geulah, for the question.
The next question is from Joon Lee with Truist Securities. Please go ahead.
Hi. Good morning. This is Maybe on for Joon. Congrats on-
Good morning.
About the quarter and the deal with Astellas. About the buffering capacity of the miRARE system, what is the range of tolerated viral copy numbers per cell? And, basically, what is the expected translatability of the outcomes from adult patients to pediatrics? Would the same dosing be used in this group? Thank you.
Thanks for the question. I'll ask Suyash to answer the question. Suyash, just to clarify, I think the question was, you know, is there a limit in cell copy number or kind of genomes per cell in the miRARE platform and how that actually responds would be the first question. The second question would just be the translatability from a dose perspective from the adult population into the pediatric study.
Sure. Got it. Yeah. Two very, very good questions, I have to say. You know, the first question is a really interesting one. The way the construct was designed, it was over-engineered. So there are 6 microRNA binding sites in the actual construct itself, plus an additional 3 in the untranslated region of the construct. These are binding sites to down-regulatory microRNA. Now, you only need one, to be frank, to be able to keep the level of MECP2 within the appropriate physiological range.
Because of this issue of maybe a cell getting two, three or four copies, Steven Gray, our chief scientific advisor, in partnership with Sarah Sinnett, built in a kind of an overabundance of these down-regulatory microRNA binding sites in order to make sure we really are truly going to make sure that we do not overexpress any MECP2. Now, the exact number of genome copies, we don't know that. What we do know from the toxicology studies is that we've given a four-fold dose over the initial starting dose. Initial starting dose is 5 × 10^14 total VG. In both NHPs and in rats over a 3- and 6-month period, we gave three doses in both toxicology studies all the way up to 2 × 10^15 human equivalent.
We know that a 4-fold overdosing of the initial clinical starting dose, you actually see no adverse toxicological findings. We know that there's high numbers of gene copies getting into the cells with an intrathecal dose of that high. We have absolute confidence that going in at a 5e14 level in the humans, which is far below the highest dose given the toxicology studies, is not going to result in overexpression. I hope that answers your first question. The second question about dose translatability from children to adults or from adults down to children, in this case, it's very interesting. You know, most of the time when you give a drug systemically, i.e., into the vein, you dose on a VG per kilo basis.
For example, a 6-year-old boy will generally weigh 20 kilos. If you're giving, I don't know, 1e14 VG per kilo, you multiply that by the 20 kilos that he weighs. Obviously a larger boy or a girl, a 12-year-old may weigh 30-35 kilos. An adult may weigh 60-70 kilos. You multiply that number and do the dose translatability on the weight. It's different for a CNS-delivered drug, an intrathecally delivered drug, because you're giving the gene therapy into a very limited space. The other thing that's different is that as children develop from babies through toddlerhood into teenage years, their organs all grow at different rates. The organ that grows the fastest, the organ that's the biggest in proportion to the rest of the body at birth is the brain.
Dose translatability is only really an issue between the ages of about zero and four. Once a child hits four years of age, the CSF volume and brain volume are pretty similar to adults. We've done a lot of animal modeling, and we've done a lot of looking at the literature, and we've got an approach for kind of moderating the pediatric and the adult doses. After the age of about four years of age, we give every patient, whether they're a child or an adult, the same dose. Below the age of four, we ratio the dose down dependent on both the CSF volume and the brain volume. We've got a very thoughtful way of doing this, and it's been discussed with the FDA and other regulators, and they are very much in agreement.
As I say, I think the vast majority of patients who will be enrolling in the pediatric study will probably be over the age of three or four, and it's likely we're not going to change that dose therefore, because the size of a three- or four-year-old, by the time a child reaches three or four years of age, they've reached the brain size of an adult. It's likely to be the way the current pediatric protocol is designed, it's going to be the same 5 E 14 total VG starting dose. Sorry, that was 2 long answers, but hopefully I gave you comprehensive answers to your questions.
Thanks, Suyash.
The next question is from Salveen Richter with Goldman Sachs. Please go ahead.
Hi, good morning, and thanks for the question. This is Mason on for Salveen. Along the endpoints that are given for the first clinical data in Rett, what's your view on the bar for success, and what threshold you would view as clinically meaningful? Thank you.
Hey, Mason. Good morning. Thanks for the question. Maybe I'll just give a start, and then we'll turn it over to Suyash to give kind of a more detailed answer. I think the way that we've looked at these initial clinical studies is certainly safety is gonna be extremely important and more so important in the Rett population. The way that the construct is designed, and Suyash went into this in great detail, is to really make sure that patients get the level of MECP2 that they need and actually to see not only a significant improvement across, you know, kind of the spectrum of disease, but also make sure that we are able to do that safely in the presence of wild-type MECP2.
Keep in mind, these patients with Rett syndrome are mosaics, meaning 50% of their cells are normal and 50% of their cells are kind of null or not producing MECP2. To also give you a little bit further detail in the disease is too much MECP2 is toxic. The way that the construct was designed is to express the level of MECP2 that's needed in a genotypic manner on a cell-by-cell basis. Most importantly, confirmation that the construct is doing that the way that it's been proven in the animal models, both the knockout mouse, the rats, as well as in NHP, is gonna be extremely important.
I think as we look across the spectrum of disease from a efficacy perspective, in the initial study, it's really gonna be the totality of data across the spectrum. Suyash laid out some of those key endpoints that we'll be looking at. For us, it's kind of holistically the study. Safety, making sure that the down-regulatory microRNA construct is working well, and then the totality of efficacy. I'll pause there, but Suyash, maybe you have something to add.
I could add a little bit more color. Everything you say is absolutely accurate. Thanks for the question. It's exactly the right question to be asking. First and foremost, we've got to clear the bar of safety, as R.A. says. Secondly, we are expecting to and hoping to see preliminary efficacy. What I will say to set expectation is that when you look at adult versus children, we expect the children to do better than the adults from an efficacy perspective. We say that for two reasons. First of all, in general, treating a developing brain seems to result in better clinical outcomes and also functional outcomes in animal studies than an adult brain.
From our animal studies where we did a very large pharmacology study looking at dosing many different ages of Rett knockout mice, and it was clear that the younger mice performed better than the older mice. That's one thing, one important point I'll make. I think from a clinical meaningfulness perspective, we spend a lot of time talking to patients and families, and it's clear that subtle improvements, some of which if they're translated from the animals to the humans, will be beneficial. For example, I've already mentioned the autonomic dysfunction, this breathing dysrhythmia that both children and adults with Rett have, and it's due to autonomic dysfunction in the brain.
When they have these alternating periods of very rapid breathing, which is correlated with high levels of anxiety, and then hypoxic episodes where they don't breathe at all for a while and start to go a little blue and cyanosed. This causes incredible stress to the families. Anything that can help moderate even that dysfunctional rhythm in a subtle way, and which we saw significant improvements in the animal models, I think will be clinically meaningful to the patients and the families. In addition, if we can reduce the seizure burden at all or even bring in some functionality, a modicum of functionality in hand function, for example, all these things will be clinically meaningful.
I think another way to look at it is we're looking at many, many different outcome measures because this is a global neurological developmental disease, and even a subtle change across several different outcome measures will be very, very impactful to the patients and the families.
The next question is from Mike Ohl with Morgan Stanley. Please go ahead.
Good morning, everyone, and thanks for taking the question. Just given the importance of the pediatric Rett data to the Astellas decision, can you maybe comment on what the trigger is to starting the pediatric study in the first half of 2023? You know, just curious if you're looking to the adult study in terms of a certain number of patients or certain n-level of follow-up prior to deciding to start the pediatric study. Thanks. Hey, Mike. Good morning, and thanks for the question. Maybe I'll just take that question in the interest of time. You know, I think ultimately the main trigger for starting that pediatric study is really getting some level of patient experience and follow-up in the adult study.
For us, we don't think that that's a large number of patients, but we do wanna make sure that that level of experience is gonna be for, you know, multiple months of follow-up. Really, for us, it's a safety issue. We wanna make sure that that down-regulatory microRNA, those binding sites and that construct, the miRARE platform is doing exactly the way that we designed it and the way that it's performed in the preclinical studies. That's essentially what we're looking for. What I'll also say for the pediatric study is the pediatric study is gonna be a global study. The goal is to do this study in multiple countries around the world.
For us, it's really gonna be around laying out kind of the right sequence of filings of both CTAs and then the IND in the United States will also kinda play a role for the way that different sites come online. For us, really, the main kind of gateway to us is just getting some level of follow-up, and we've kind of detailed this internally, and we haven't disclosed this to the street, but some level of follow-up for multiple months from a few patients in the adult study would give us the confidence to include that into the data package for the pediatric study.
We're well on our way to doing that, and we feel good about the guidance that we've laid out with initiating that study in the first half of next year. We're really excited about it and the fact that, you know, this is a population with significant unmet medical need. There's a large number of patients out there, so recruitment should not be an issue. The Rett Advocacy Group puts the prevalence of Rett worldwide at somewhere around 350,000 patients worldwide. You know, we've calculated in the US and Europe somewhere between around 25,000-35,000 patients, just in those two geographies. The issue around enrollment is a non-issue.
It's really for us to make sure that we're getting meaningful data from both the adult study as a gateway into the pediatric population. Hopefully, that answers your question, but thanks for the question.
Next question is from David Hoang with SMBC. Please go ahead.
Hey, good morning, thanks so much for taking the question. I just had one on in the case of Rett syndrome, if you were to get MeCP2 overexpression to a toxic level with the construct, can you just give us an idea about what that toxicity might look like based on your animal studies? Then, you know, how quickly and definitively would it manifest?
Thanks, David, for the question. Maybe I'll start, and then I'll turn it over to Suyash. We didn't see that in our animal studies. Again, I think Suyash laid out, you know, kind of the extensive package that we put forward to both the regulators up in Canada that we'll be putting into the follow-on CTAs and INDs to expand the study geographically. For us, you know, I think what we saw was the fact that we were able to dose up to really high doses, and we've kind of stopped at four-fold over what the human equivalent starting dose would be at 2 E to the 15.
We just didn't go above that, because we would never be dosing, theoretically above that level, but we didn't see any type of toxic effects. I think what we can probably do and have Suyash answer the question theoretically of what you would see, and this is really informed by the experience of MeCP2 duplication, most likely. Suyash, do you wanna kinda comment there?
Yeah. I would just reemphasize that, you know, we gave very high doses in the toxicology study. There's still no evidence of any toxicity due to overexpression. In fact, measured in all the tissues in the animals, DNA, RNA, and protein, we've got high levels of DNA, meaning we're getting good distribution of TSHA-102 into all the tissues in the NHP, but very low levels of RNA and correspondingly levels of MeCP2, meaning the down-regulatory system is working well. Having said that, it's a very good question to ask, you know, just in case you see some kind of neurological toxicity that's totally not predicted, what might that look like? In theory, there's two ways of really drawing that parallel.
The first is by looking at what happens in the clinical situation, and the second is looking at the animal situation. In the clinical situation, there is a condition known as MECP2 duplication syndrome, where children inherit two copies of the MECP2 gene. They have double the amount of MeCP2, and they have associated neurobehavioral and neurological issues relating to that. In fact, it doesn't look that different to Rett syndrome. These are children. It's actually a little more severe than Rett, and the symptoms come on a little earlier. Basically, you see a whole host of evidence of developmental regression, a lack of milestones. You get seizures, problems with autonomic nervous system dysfunction as well.
From a clinical perspective, you see neurological and neurobehavioral outcomes that are global in nature, and that's also true for the animal situation where you encourage overexpression.
Of MeCP2 in a mouse model, for example, you will see significant neurobehavioral toxicity and also a drop in survival. Once again, I'll emphasize these are highly theoretical. We've not seen anything of that nature whatsoever in our rat or toxicology studies, even when we've been given very high doses.
Thanks, Suyash. Thanks, David, for the question.
The next question is from Jack Allen with Baird. Please go ahead.
Hello, this is Benjamin Paluch calling in from Jack Allen. How quickly could you begin dosing patients with the commercial product of TSHA-120, and will the commercial product require a new IND? Thanks for any color.
Thanks for the question. Maybe I'll start and we could turn it over to Suyash to kind of talk about, you know, the regulatory pathway. As we've disclosed, we plan to have a teleconference with the FDA on December thirteenth. This is a Type B end of phase two meeting, and the goal of this meeting is really to lay out in detail the regulatory pathway to approval. What we've also disclosed is significant clinical safety and efficacy data across a number of meaningful functional pathological endpoints as well as really nice safety over the history of the study, and the study's been ongoing. Keep in mind, this is the first intrathecally dosed gene therapy study in history.
The study was initiated in 2015, so we're going on the 7th year of the study. There was a run-in study, a natural history run-in study that initiated two years before that in 2013 that all patients that were dosed in the interventional trial rolled over from. We really have nice levels of control and comparison from kind of a pre-treatment experience and a post-treatment experience. We're gonna be going in and discussing the totality of the data set as well as the manufacturing overview of the clinical trial material and the commercial material with the FDA. We've presented data on the commercial grade material by all of our key quality attributes and release assays as well as the next-generation sequencing.
The product is biologically indistinguishable, and we're really excited about the work that Fred and his team performed on the commercial product. That product is available and ready to go. What we would do is we're taking the full analytical comparability data set, including the validated potency assay to the FDA for our meeting in December, along with all the clinical data that we've laid out before. We're putting that in front of the FDA to really ask the question that, are we ready for prime time? We think that we are based off of their recent guidance that was finalized about a week or two ago, which is the development of gene therapy for neurodegenerative diseases.
Our program across both the CMC section, across the clinical section, checks all the boxes. It's really to kind of outline the path forward to approval. That's really gonna be the key question. I think any time after that meeting, we're ready to go to dose additional patients, if that is the need. That may not necessarily be the need, but we'll have to just wait. We'll have to wait on that conversation with the FDA in order to inform you guys further. What we would go back to is our base case, you know, kind of scenario two, which means, you know, we would need some level of minimal clinical comparability, call it three patients for six months, in order to demonstrate clinical comparability.
The goal would be to file some sort of rolling submission as we're generating that data, because keep in mind, the CMC data is not changing, the clinical data for the most part is not changing, and certainly the preclinical data is not changing. There's a lot of data to put forward in a submission. You know, we'll inform you guys more, you know, post that meeting, sometime in January when we have those official meeting minutes in hand. You know, our base case is kind of providing some level of clinical comparability, most likely 3-5 patients, 6 months in that range. Operator?
Yes. The next question is from Yanan Zhu with Wells Fargo. Please go ahead.
Hi. Thanks for taking my questions. On the Rett syndrome, could you talk about from this panel of endpoints which might be the earliest from which you expect to see signals? Also, is the adult study a 3 + 3 design in that you have the opportunity to expand the treatment cohort should you see any safety events? Lastly, is there a pre-specified duration at which point the placebo or the delayed treatment patients are supposed to be crossed over to treatment? Thanks.
Thanks. Thanks, Yanan, for those questions. Unfortunately, we're only going to be able to take a couple of those questions too, probably. I'll do the first when we talk about the design of the study. I just want to keep in mind the design of the study for the first cohort is up to 6 patients. Somewhere between 3-6 patients will be included in that first cohort, to just be clear. That would be patients on untreated drug as well as the delayed treatment patients.
On your first question, I think it was more so around, you know, what do we hope to see first from an efficacy perspective, in these adult patients that would give us confidence that that would translate into the rest of the population. For that question, Suyash, I'll turn it over to you, but maybe it's helped inform by what we saw in the animal studies.
Yeah. Just to clarify, Yanan, the protocol, the way the protocol is designed, R.A.'s quite correct that we're having up to 6 patients in the cohort. However, there is a proviso to extend that further if indeed there is some kind of adverse event that's seen, which as you know, is a relatively common proviso in most of these phase 1, 2 clinical trials. That proviso is there as part of the adaptive study design. In terms of endpoints that might improve, I think that it's an interesting one. I think for the animal studies, what we expect to improve quickly is the breathing dysfunction that I've already mentioned previously. There are these alternating patterns of rapid and shallow breathing.
In our animal studies, we saw that improve relatively quickly. That's one possibility, although frankly, we'll wait and see what happens. We assume that's one of the changes that may happen relatively quickly. The other point I will make is that, you know, the other precedent is. If you look at the Acadia trofinetide study, where they use an analog of IGF-I to try and encourage the growth of synapses in the brain, which are missing in Rett syndrome, as you know. They saw changes in the Clinical Global Impression of Severity scale and in the RSBQ, which is a caregiver-rated Rett syndrome general development questionnaire. Both of those showed improvements relatively quickly. You know, within about four to five weeks, you could see the separation from placebo.
I would say, you know, what we'd be looking for are the physiological changes in breathing and some of the global Rett syndrome behaviors improving within a few weeks after dosing. What I will say is that in comparison to the Acadia trofinetide data is that don't forget, with the gene therapy, you've got to wait about 2 or 3 weeks to get maximal transgene expression. It may not be quite as rapid as an IGF-I analog being dosed, but I still think it's going to be, we're gonna see potential signs within a matter of weeks. I'll stop there.
Thanks, Suyash. Thanks, Yanan, for the question.
The next question is from Sami Corwin with William Blair. Please go ahead.
Hi, this is Tiffany. I'm for Sammy. Thanks so much for taking our question. For the GAN 120 program, in sort of your base case scenario outcome for the FDA meeting, where you have to dose more patients for comparability, could you provide any color on maybe how quickly you might be able to enroll these patients? You know, have they already been identified? Also, like what sort of range of follow-up could you imagine you might reasonably need to demonstrate comparability? Just as a quick second, do you still have any plans for filing MAA with the EU? Thanks.
Hi, Tiffany. Thank you. Thank you for the question. You know, I could probably answer this relatively quickly. You know, the way that we're thinking about this, the way that we're thinking about patient 120 in GAN and kind of what the next stage of development would actually look like, these patients have all essentially from the interventional study have rolled over from the natural history study. We've dosed 14 patients to date, 12 of those patients in the therapeutic doses, and all of those patients rolled over from the natural history study. What's really nice is you actually have, you know, call it 1 to 2, even 3 years of pretreatment experience or kind of natural history decline.
You're able to compare that with the post-treatment intervention and kind of this ongoing stabilization in disease, which was really clear across a number of the key endpoints, not only clinically meaningful, but statistically significant. We're talking about the MFM-32, we're talking about visual acuity, we're talking about retinal nerve fiber thickness. What's also really interesting is the fact that we have biopsies and this is really kudos to the NIH and the fact that they just designed a very robust study and the fact that they were able to take biopsies pre and post, so pre-dosing and then after dosing up to one year.
We clearly see in a statistically significant manner the regeneration of nerve clusters and kind of this active regeneration, which is really exciting. Again, functional endpoints, pathological endpoints, you know, we feel really good about the data set, and you couple that with the fact that we have commercial-scale material that's biologically indistinguishable from our clinical trial material. Again, I think all things considered, we feel pretty good going into that meeting and about proposing what an accelerated pathway could look like to approval. Patients have been identified because keep in mind, we've only dosed 14 patients over the history of the study. There's around 50-plus patients in the natural history data set right now.
Essentially, we could roll patients over from that natural history study into the clinical trial in order to meet whatever the requirement the FDA has laid out for us in order to generate the data needed for regulatory filing. We'll know more here relatively quickly. The meeting is in December. We'll get the meeting minutes in January and we'll provide that guidance. But I think if you look at the recent finalized guidance that the FDA has laid out around the development of gene therapy for neurodegenerative diseases, and you look over this program both from a safety and efficacy perspective as well as a natural history perspective, the program checks all the boxes. So that takes your. That hopefully answers your question in the US.
In Europe, it is absolutely our intention to eventually file an MAA in Europe. We do think that pathway will be further clarified based on our conversations with the FDA. Because whatever you would do in the U.S., you would wanna also have that agreement with the regulators in Europe, so you're only doing it once in order to support that MAA. We see the pathways on almost a parallel kind of parallel path. We would certainly wanna make sure whatever we would need to do that would support registration in the U.S., that would also be an agreement that we could get with Europe. Hopefully that answers your question.
The next question is from Whitney Ijem with Canaccord Genuity. Please go ahead.
Hey, guys. Follow-up on the Rett study update in the first half of next year. I guess can you talk about what you mean when you say complete cohort that we'll be getting? Is it or I guess, is there a specific amount of follow-up you're waiting for in all of the patients, or are we waiting for early data from the delayed treatment controls? Or just kind of help us understand what you think or what you say when you say complete cohort. Excuse me. What you mean when you say complete cohort. Thanks.
Sure. Thanks, Whitney, for the question. What I'll just reiterate is the fact that that first cohort is up to 6 patients, most likely somewhere between 3-6 patients. What we're trying to make sure is that we have enough patients and enough robust follow-up from those patients in order to inform the initiation of the pediatric study. That's really what we're trying to define here, and that's kinda how we see complete. That's somewhat of a subjective answer, but you know, the way that we're looking at this is 3-4 patients, including a delayed treatment patient that could act as kind of a real-time level of control.
Keep in mind, the natural history in Rett syndrome is probably some of the most well-characterized natural history data out of any disease. The patient advocacy groups who led the way here have done a fantastic job. You also have that data set to compare to. Really for us, it's getting to 3-6 patients, including a delayed treatment patient, enough data, enough follow-up in order to inform the initiation of the pediatric study. For us, we feel like we'll have enough comfort for that to file the INDs and CTAs for the pediatric study to initiate that study in the first half of next year.
That's all the time we have for questions. I'll turn the call back over to Mr. Session for closing remarks.
Thank you, operator. Again, I just thank everybody for joining the call this morning. It's been a quite interesting quarter for Taysha and the company. I couldn't be prouder of the way that the company has responded. It's a very tough market, and I think we could all agree, it's a quite interesting market, and we've been in this cycle for over a year now, almost two years. I just couldn't be prouder of the resilience of the employees at Taysha, the resilience of the patient community, the fact that they've supported us, been with us, encouraged us, and we really wanna thank them. I think we're starting to now see the tide turn.
We're starting to see that Taysha spirit rise, and we're really excited about the next few months, and what that has to offer for Taysha, starting with the Type B end-of-phase 2 meeting we'll have in December with the FDA. We're quite excited to go into that meeting, and to get those meeting minutes to be able to share early next year, as well as continued generation of data in our Rett syndrome program and the initiation of the pediatric study in the first half of next year. You know, what we're also excited is to now be able to share this with a wonderful partner in Astellas, one that has a real commitment to patients, but a commitment to gene therapy, the modality, and also innovative medicines.
We're really excited to be embarking on this new journey with our partners Astellas and look forward to a very fruitful partnership with them. With that, I wish you guys a wonderful day. Go vote. We'll talk to you guys soon. Thanks.
Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect.