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spk04: Thank you for standing by. Welcome to Tayshia Gene Therapy's third quarter 2022 financial results and corporate update conference call. At this time, all participants are in listen-only mode. Following management's prepared marks, 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.
spk00: Good morning and welcome to Tayshia's Third Quarter 2022 Financial Results and Corporate Update Conference Call. Joining me on today's call are Ari Session II, Tayshia's President, Founder, and CEO, Dr. Suresh Prasad, Chief Medical Officer and Head of R&D, and Cameron Alon, Chief Financial Officer. After our formal remarks, we will conduct a question and answer session and instructions will follow at that time. Earlier today, Tayshia 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 Estellas. 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 TASHA 120 and the regulatory status and market opportunity for TASHA 120, TASHA 102, and TASHA'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 TASHA'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 patients' actual results to differ materially from those stated or implied in such forward-looking statements. These risks include surgeries 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 8, 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 applicable securities law. I would now like to turn the call over to our President, Founder, and CEO, R.A. Session II. R.A.?
spk15: 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 TASHA 120 for gynexonal neuropathy, or GAN, and TASHA 102 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, Estellas will make a $50 million investment in Tayshia in exchange for 15% of Tayshia's outstanding shares pre-follow-on financing, as well as an exclusive option to license the worldwide development, manufacturing, and commercial rights to Tayshia 120 in GAN For a period of time after receipt of the formal Type B into Phase II meeting minutes from the FDA, a cellist will also receive an exclusive option to license the Worldwide Development, Manufacturing, and Commercial Rights to TASHA-102 in Rett Syndrome for a period of time after we provide a cellist access to certain clinical data from the planned Rett female pediatric studies. Estellas will also receive a right of first offer related to a change in control of Tayshia for a period of time after receipt of the REC clinical data package. To further strategically align the two companies, Estellas will also receive one board observer seat on the Tayshia Board of Directors, enabling us to leverage Estellas' 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 Estella's clinical development and commercialization experience, combined with Tayshia'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 TASHA 120 in GAN in January, following our Type B into Phase II meeting with the FDA. In addition, we intend to disclose preliminary clinical data for TASHA 102 from the first cohort of adult patients with Rett syndrome and initiate a Phase 1-2 clinical study for TASHA-102 in female pediatric patients with Rett syndrome in the first half of 2023. I will now turn the call over to Suyesh to discuss our clinical programs. Suyesh?
spk18: Thank you, R.A., and 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 TASIO 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 MFM32 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 LOGMA, stabilized after treatment with TASHA 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 TASHA 120 treatment. Electrophysiologic nerve conduction studies support recoverability, stabilization, and in some cases, improvement in sensory response in patients treated with TASHA 120. Nerve biopsies confirm that treatment with TASHA 120 result in active regeneration of nerve fibers. And 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 two meeting scheduled with the FDA via teleconference on December the 13th, 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 registration 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 data set per EMA guidance documents. In the US, the first scenario is immediate filing for approval based on the current data set 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 Zolgesma 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 data set available. Next slide, please. Let's move on now to TASHA-102, the first and only gene therapy in clinical development for Rett syndrome. TASHA-102 utilizes the novel and 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 TASIA-102 represents the most robust data package supporting the clinical advancement of a gene therapy in Rett syndrome. This includes preclinical data in neonatal RET 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 RET knockout mice. Toxicology data supported a favorable safety profile of TASHA-102 in wild-type rats up to doses fourfold 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. And 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 MI-RARE platform worked well with low levels of RNA and minimal expression of MEKP2 in wild-type cells, which have normal pre-existing levels of MEKP2. These four preclinical studies together represent a comprehensive and robust package supporting the clinical advancement of TASHA-102 for Rett syndrome. Our first in-human phase 1-2 trial of TASIA-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 in the entire first cohort that includes up to six 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, Tayshia 102 has received orphan drug and rare paediatric 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 TASIA 120 in GAN and preclinical package for TASIA 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?
spk12: Thank you, Suyash. This morning, I will discuss key aspects of our financial results for the third quarter ended September 30, 2022. More details can be found in our Form 10-Q, which will be followed 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 30, 2022, compared to $39.5 million for the three months ended September 30, 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 30th, 2022 was $26.3 million or 64 cents per share as compared to a net loss of $51.2 million or $1.35 per share for the three months ended September 30th, 2021. As of September 30th, 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 Estella's and the net proceeds received from the public offering, will enable funding of operating expenses and capital requirements into the first quarter of 2024. And with that, I will hand the call back to RA.
spk15: The next six to 12 months will be a busy time for Tayshia. On December 13th, we are scheduled to have a teleconference with the FDA to discuss the pathway to a BLA filing for TASHA 120 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 TASHA 102 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.
spk04: We will now open the call for questions. To join the question queue, you may press star, then 1 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 Bloom with Needham Company. Please go ahead.
spk03: Good morning, everyone, and thanks for taking our question. So 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 Udenta sector was. Thank you.
spk15: Hey, Gil. Good morning. Thanks for the question. Maybe I'll start now, and I'll turn it over to Fred, because he's had an extensive experience with the gene therapy manufacturing group over at Audente, and actually took a tour of the new manufacturing site in Sanford. So, the original Estellis programs in Pompe and in extubular myopathy, Those are AAV-8 programs, not AAV-9 programs. But what I will say is the manufacturing is nearly identical. They're using HEC-293 triple plasma transfection and suspension, just like we are. And as we were actually building our facility that we've now paused, the layout was almost identical. And so 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 want to give some insights.
spk11: Sure. Yeah, thanks, RA, and I certainly agree with you. I think while Astellas' main experience is in AVA, the platform manufacturing approach that Astellas is taking and we are developing at Tayshia 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. So, I think It's still, again, very well suited to a collaboration. So, thanks for the question.
spk04: The next question is from Yun Yang with Jefferies. Please go ahead. Hi.
spk07: This is Mac Chandler on for Yun Yang. Thank you for taking the question. Just want to know, with Estella's option for patient 120 available for a period of time following the receipt of those minutes, are there any specified outcomes from the end of that phase two meeting or that type two meeting with the FDA for Estella to opt in? Are you expecting anything there?
spk15: Good morning. It's a really good question. You know, so what we've shared with Estella is the the full data set from that study as presented to the FDA. And 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 three to five for, you know, somewhat of a period of time, hopefully around six months or less in order to kind of demonstrate clinical comparability. And 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 Estella and how they would make their decision, but this is the way that we framed the conversation with Estella, 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... with no treatment alternatives, the fact that the data set here is as robust as it possibly can get for gene therapy assets. 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 leads itself ultimately to a high probability of success of an eventual approval. So 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 Estella, but the way that I've laid it out to you today is the way that we framed it for them.
spk04: The next question is from Gula Likshith with Chardhan. Please go ahead.
spk08: Hi, good morning. Thanks for taking our questions. 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 one or two in Rett syndrome in terms of the control group, patient types, and endpoints. And 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 this space.
spk15: Hey, Gula. Good morning. Thanks for the question. I'll turn that question over to Suyesh to discuss how we're thinking about a pivotal design for Rett syndrome. Suyesh?
spk18: 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 and 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, and can we reduce the burden there. Another bucket is looking at specific RET-type behavioral assessments, such as the RET syndrome hands function sale, the RET 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-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. So 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 Bailey's developmental assessment. which looks at development progression across early childhood. So that's a scale we'll be including within the actual pediatric study that is not in the adult study. So 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 a 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 standpoints are generally the same.
spk05: I'll stop there. Thanks, Suresh. Thanks, Gula, for the question.
spk04: The next question is from June Lee with Truist Securities. Please go ahead.
spk13: Hi. Good morning. This is Mehdi on for June. Congrats on the quarter and the deal with Stellas. So, 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.
spk15: Thanks for the question. I'll ask Suyash to answer the question. And 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 MI Rare 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.
spk18: 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 six microRNA binding sites in the actual construct itself, plus an additional three 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. But because of this issue of maybe acyl getting two, three, or four copies, Steve Gray, our chief scientific advisor in partnership with Sarah Sinnott, built in 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 fourfold dose over the initial starting dose. The initial starting dose is a 5E14 total VG. And in both NHPs and in rats, over a three- and six-month period. We gave three doses in both toxicology studies, all the way up to 2E15 human equivalent. And so we know that at a four-fold over dosing of the initial clinical starting dose, you actually see minimal adverse... Well, no adverse toxicological findings. And we know that there's high numbers of... gene copies getting to cells with an intrathecal dose of that high. So we have absolute confidence that going into the 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 have you dose on a VG per kilo basis so for example a six-year-old boy will generally weigh 20 kilos so if you're giving I don't know 1E14 VG per kilo you multiply that by the 20 kilos that he weighs and obviously a A larger boy or a girl, a 12-year-old, may weigh 30, 35 kilos. An adult may weigh 60, 70 kilos. So you multiply that number and you 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. And 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. And 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. And so 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. And so 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. And 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 um and the brain volume and we've got a very thoughtful way of doing this and it's been discussed with the fda and other regulators and they're very much in agreement but 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, so it's likely to be the way the current pediatric protocol is designed, it's going to be the same 5E14 total VG starting dose. Sorry, there were two long answers, but hopefully I gave you comprehensive answers to your questions.
spk05: Thanks, Lewis.
spk04: The next question is from Salveen Richter with Goldman Sachs. Please go ahead.
spk10: 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 red, what's your view on the bar for success and what threshold you would view as clinically meaningful? Thank you.
spk15: Hey, Mason. Good morning. Thanks for the question. Maybe I'll just give a start and then we'll turn it over to Sush 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 going to be extremely important and more so important in the RET 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 MEKP2 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 And 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. And to also give you a little bit further detail in the disease is too much MeCP2 is toxic. And so 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. And so, 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 the NHPs is going to be extremely important. And I think as we look across the spectrum of disease from an efficacy perspective, In the initial study, it's really going to be the totality of data across the spectrum. And CS laid out some of those key endpoints that we'll be looking at. But 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 CS, maybe you have something to add.
spk18: I could add a little bit more colour. Everything you say is absolutely accurate. And 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 RA 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. And 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. And also from our animal studies where we did a very large pharmacology study looking at dosing many different ages of retinal 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. But 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 RET 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. And this causes incredible stress to the families. And so 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. But 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 the subtle change across several different outcome measures will be very, very impactful to the patients and the families.
spk04: The next question is from Mike Oles with Morgan Stanley. Please go ahead.
spk01: Good morning, everyone, and thanks for taking the question. Just given the importance of the pediatric RET 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 level of follow-up prior to deciding to start the pediatric study. Thanks.
spk15: Hey, Mike. Good morning, and thanks for the question. Maybe I'll just start, and 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 at and follow-up in the adult study. And for us, we don't think that that's a large number of patients, but we do want to make sure that that level of experience is going to be for, you know, multiple months of follow-up. And really, for us, it's a safety issue. We want to make sure that that down-regulatory microRNA, those binding sites and that construct are the MI Rare 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 going to be a global study. The goal is to do this study in multiple countries around the world. And for us, it's really going to be around laying out kind of the right sequence of filings of both CTAs and then the IND in the United States will also kind of play a role for the way that different sites come online. But 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 streets. 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, to include that into the data package for the pediatric study. And so 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. So really excited about it. And the fact that, you know, this is a population with significant medical need. There's a large number of patients out there, so recruitment should not be an issue. The RET Advocacy Group puts the prevalence of RET worldwide at somewhere of around 350,000 patients worldwide. We've calculated in the U.S. and Europe somewhere between around 25,000 to 35,000 patients just in those two geographies. So 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.
spk17: Hopefully that answers your question, but thanks for the question.
spk04: Next question is from David Huang with SMBC. Please go ahead.
spk14: Hey, good morning, and thanks so much for taking the question. I just had one on, in the case of Rett syndrome, if you were to get MEKT2 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, and then, you know, how quickly and definitively would it manifest?
spk15: Thanks, David, for the question. Maybe I'll start and I'll turn it over to Siyesh. So we didn't see that in our animal studies. And again, I think Siyesh 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. But 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 fourfold over what the human equivalent starting dose would be at 2E 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 Suyesh answer the question theoretically, of what you would see. And this is really informed by the experience of MeCP2 duplication, most likely. So, yes, do you want to kind of comment there?
spk18: Yeah, I'll just reemphasize that, you know, we gave very high doses in the toxicologist, so there's no evidence of any toxicity due to overexpression. And, 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 TASHA-102 into all the tissues in the NHP, but very low levels of RNA and correspondingly low levels of MeCP2, meaning the down-regulatory system is working well. Having said that, it's a very good question to ask. Just in case you see some kind of neurological toxicity that's totally not predicted, what might that look like? And 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. So in the clinical situation, there is a condition known as MECP2 duplication syndrome, where children inherit two copies of the MECP2 gene. So they have double the amount of MECP2, and they have associated neurobehavioral and neurological issues related to that. And in fact, it doesn't look that different to Rett syndrome. These are children who, it's actually a little more severe than Rett, and the symptoms come on a little earlier, but 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. So 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, and 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.
spk05: Thanks, David, for the question.
spk04: The next question is from Jack Allen with Barrett. Please go ahead.
spk06: Hello, this is Benjamin Palooch calling in from Jack Allen. How quickly could you begin dosing patients with a commercial product of Tayshia-120, and will the commercial product require a new IND? Thanks for any comments.
spk15: 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. So, as we've disclosed, we plan to have a teleconference with the FDA on December 13th. This is a Type B into Phase 2 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 studies. endpoints, as well as really nice safety over the history of the study. And the study has been ongoing. Keep in mind, this is the first interfecally dosed gene therapy study in history. The study was initiated in 2015. So we're going on the seventh year of the study. And 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 And the interventional trial rolled over from so we really have nice levels of control and comparison from kind of a pretreatment experience and a post treatment experience. And so we're going to 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. And 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. So 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. And 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. um and it's really to kind of outline the path forward to approval uh that's really going to be the key question so i think anytime after that meeting we're ready to go to dose additional patients uh if that is the need but that may not necessarily be the need but we'll have to just wait um 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 cases, 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 is to file some sort of rolling submission as we're generating that data, because keep in mind, the CMC data is not changing anymore. The clinical data for the most part is not changing and certainly the preclinical data is not changing and there's a lot of data to put forward in a submission. So, you know, we'll inform you guys more post that meeting sometime in January when we have those official meeting minutes in hand. But, you know, our base case is kind of the providing some level of clinical comparability, most likely three to five patients, six months in that range.
spk05: Operator?
spk04: Yes. The next question is from Yananzu with Wells Fargo. Please go ahead.
spk16: Hi. Thanks for taking my questions. So the Rett syndrome, could you talk about from this panel of endpoints, which might be the earliest from which you expect to see signals? And also, is the adult study a 3 plus 3 design in that you have the opportunity to expand the treatment cohort should you see any safety events? And 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.
spk15: Thanks, Yana, for those questions. And 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. And I just want to keep in mind the design of the study for the first court is up to six patients. Somewhere between three to six patients would be included in that first cohort to just be clear. And that would be patients on treated 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. And so for that question, Suresh, I'll turn it over to you, but maybe it's helped inform by what we saw in the animal studies.
spk18: Yeah, and just to clarify, Yanan, the way the protocol is designed, RA is quite correct that we're having up to six 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 I-II clinical trials. So 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 are the breathing dysfunction that I've already mentioned previously. There is the alternating patterns of rapid and shallow breathing. And in our animal studies, we saw that improve relatively quickly. So that's one possibility. Although, frankly, we'll wait and see what happens. But 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 in the, if you look at the Acadia Trophenitide study, where they use an analog of IGF-1 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 they in the RSBQ, which is a caregiver-rated Rett syndrome general development questionnaire. And both of those showed improvements relatively quickly. Within about four to five weeks, you can see the separation from placebo. So I would say 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 Trophenicide data is that, don't forget, with the gene therapy, you've got to wait about two or three weeks to get maximal transgene expression. So it may not be quite as rapid as an IGF-1 analog being dosed. but I still think it's going to be, we're going to see potential signs within a matter of weeks.
spk05: I'll stop there. Thanks, Elias. Thanks, Janet, for the question.
spk04: The next question is from Sammy Corwin with William Blair. Please go ahead.
spk09: Hi, this is Tiffany. I'm for Sammy. Thanks so much for taking our question. For the GAM 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? And also, like, what sort of range of follow-up could you imagine you might reasonably need to demonstrate comparability? And just as a quick second, do you still have any plans for filing MMA with the EU? Thanks.
spk15: Tiffany, thank you. Thank you for the question. You know, so I could probably answer this relatively quickly. So, 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 all rolled over from the natural history study. And so 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. So what's really nice is you actually have, you know, call it one to two, even three years of pre-treatment experience or kind of natural history decline. And 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 MFM32. We're talking about visual acuity. We're talking about retinal neurofiber 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 1 year, and we see the clearly see in a statistically significant manner, the regeneration of nerve clusters and kind of this active regeneration and which is really exciting. So. 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. So, again, I think all things considered, we feel pretty good going into that meeting and about proposing what an accelerated pathway could look like. Uh, to approval patients have been identified because keep in mind, we've only dose we've only dose 14 patients over the history of the study and there's around 50 plus patients in the natural history data set right now. And so. 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, hopefully that answers your question in the U.S. 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 want to also have that agreement with the regulators in Europe, so you're only doing it once. in order to support that MAA. But we see the pathways on almost a parallel kind of parallel path. But we would certainly want to 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.
spk05: Hopefully that answers your question.
spk04: The next question is from Whitney Ijem with Canaccord Genuity. Please go ahead. Hey, guys.
spk02: Follow-up on the RET 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 – delayed treatment controls or just kind of help us understand what you think or what you say when you say complete, excuse me, what you mean when you say complete cohort. Thanks.
spk15: Sure. Thanks, Whitney, for the question. So what I'll just reiterate is the fact that that first cohort is up to six patients, most likely somewhere between three to six patients. And 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 kind of how we see complete. And that's somewhat of a subjective answer, but, you know, the way that we're looking at this is three to four patients, including a delayed treatment patient that could act as kind of a 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. And the patient advocacy groups who led the way here have done a fantastic job. So you also have that data set to compare to. But really for us, it's getting to three to six patients, including a delayed treatment patient, enough data, enough follow-up in order to inform the initiation of the pediatric study. And 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.
spk04: That's all the time we have for questions. I'll turn the call back over to Mr. Session for closing remarks.
spk15: Thank you, operator. And again, I just thank everybody for joining the call this morning. It's been a quite interesting quarter for Tayshia 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 into this cycle for over a year now, almost two years. And I just couldn't be prouder of the resilience of the employees of Tayshia, the resilience of the patient community, the fact that they supported us, been with us, encouraged us, and we really want to thank them. And so I think we're starting to now see the tide turn. We're starting to see that Tayshia spirit rise, and we're really excited about the next few months. and what that has to offer for Tayshia. Starting with the Type B into 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. And, you know, what we're also excited is to now be able to share this with a wonderful partner in Estella. It's one that has a real commitment to patients, but a commitment to gene therapy, the modality, and also innovative medicines. And so we're really excited to be embarking on this new journey with our partners, Estella, and look forward to a very fruitful partnership with them. With that, I wish you guys a wonderful day. Go vote, go vote, go vote. and we'll talk to you guys soon. Thanks.
spk04: Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation.
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